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APPLICATION NUMBER:

761063Orig1s000

CLINICAL/STATISTICAL REVIEW(S) Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality () for prevention of

CLINICAL REVIEW Application Type BLA Application Number(s) 761063 Priority or Standard S Submit Date(s) 9/27/17 Received Date(s) 9/27/17 PDUFA Goal Date 9/16/18 Division/Office DNP/ODEI Reviewer Name(s) Maria Lourdes Villalba, M.D. Review Completion Date 9/20/18 Established/Proper Name Galcanezumab (LY2951742) (Proposed) Trade Name EMGALITY Applicant Eli Lilly and Company (Lilly) Dosage Form(s) Single-dose prefilled pen or syringe for subcutaneous injection. 120 mg/mL in each single-dose. Applicant Proposed Dosing Loading dose of 240 mg, followed by 120 mg once a month Regimen(s) Applicant Proposed Prevention of Indication(s)/Population(s) Recommendation on Approval Regulatory Action Recommended Adults with migraine Indication(s)/Population(s) (if applicable)

CDER Clinical Review Template 1 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for

Table of Contents 1. Executive Summary ...... 6 3. Therapeutic Context ...... 11 3. Regulatory Background ...... 11 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ...... 12 5. Sources of Clinical Data and Review Strategy ...... 13 Table of Clinical Studies ...... 13 Review Strategy ...... 15 6. Review of Relevant Individual Trials Used to Support Efficacy ...... 15 7. Integrated Review of Effectiveness ...... 15 8. Review of Safety ...... 15 Safety Review Approach ...... 15 Review of the Safety Database ...... 16 Overall Exposure ...... 18 Relevant characteristics of the safety population ...... 22 Adequacy of the safety database ...... 26 Adequacy of Applicant’s Clinical Safety Assessments ...... 27 Issues Regarding Data Integrity and Submission Quality ...... 27 Categorization of Adverse Events ...... 27 Routine Clinical Tests ...... 28 Safety Results...... 29 Deaths ...... 29 Serious Adverse Events ...... 29 Dropouts and/or Discontinuations Due to Adverse Effects ...... 52 Significant Adverse Events ...... 70 Treatment Emergent Adverse Events and Adverse Reactions ...... 75 Laboratory Findings ...... 80 Vital Signs ...... 83 Electrocardiograms (ECGs) ...... 85 QT………………...... 85

CDER Clinical Review Template 2 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Immunogenicity ...... 86 Analysis of Submission-Specific Safety Issues ...... 86 Safety Analyses by Demographic Subgroup ...... 94 Specific Safety Studies/Clinical Trials ...... 94 Additional Safety Explorations ...... 94 Human Carcinogenicity or Tumor Development ...... 94 Human Reproduction and Pregnancy ...... 94 Pediatrics and Assessment of Effects on Growth ...... 95 Overdose, Drug Abuse Potential, Withdrawal, and Rebound ...... 95 Safety in the Postmarket Setting ...... 96 Safety Concerns Identified Through Postmarket Experience ...... 96 Expectations on Safety in the Postmarket Setting ...... 96 Additional Safety Issues From Other Disciplines ...... 96 Integrated Assessment of Safety ...... 96 9. Advisory Committee Meeting and Other External Consultations ...... 98 10. Labeling Recommendations ...... 98 Prescription Drug Labeling ...... 98 11. Risk Evaluation and Mitigation Strategies (REMS) ...... 98 12. Postmarketing Requirements and Commitments ...... 98 13. Appendices ...... 99 References ...... 99 Additional information not included in body of the review ...... 100 Eligibility criteria for phase 3 studies ...... 100 Exposure in Sets A and E of BLA 761063...... 103 Additional Applicant’s evaluation of selected AE of interest ...... 104 Analyses of increased menstrual bleeding in Set A by Preferred Term ...... 108 Other GMB studies...... 108

CDER Clinical Review Template 3 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Table of Tables

Table 1. Listing of Clinical Trials Relevant to (b) (4) Galcanezumab...... 14 Table 2. BLA 761063. Safety Population, Size, and Denominators. Original submission ...... 18 (b) (4) Table 3. BLA Duration of Exposure to GMB in Set E (original submission) ...... 19 Table 4. BLA 761063. Patient Exposure in GMB trials. Set E, Safety Update Report...... 19 Table 5. BLA 761063. Patient Disposition in Set A+C. SUR by modal dose...... 20 Table 6. BLA 761063. Galcanezumab. Patient Disposition in Set E, by modal treatment, SUR. .. 21 Table 7. NDA 761063. Baseline demographics in placebo-controlled trials ...... 23 Table 8. Patients with CV risk factors at baseline in placebo-controlled trials ...... 24 Table 9. Patients with a history of myocardial infarction, , angina, TIA or peripheral arterial occlusive disease in placebo-controlled trials ...... 25 Table 10. BLA 761063. Baseline cardiovascular medications, placebo-controlled trials ...... 25 Table 11. BLA 761063. Serious AEs in complete placebo-controlled trials. Set A+C, SUR...... 30 Table 12.BLA 761063. Patients with Serious adverse events in Set E, by treatment period ...... 32 Table 13. BLA 761063. Patients with Serious adverse events in Set E by SOC and PT...... 33 Table 14. BLA 761063. AEs leading to drug discontinuation in complete placebo-controlled studies. Set A+C, SUR...... 52 Table 15. Patients with AE leading to drug discontinuation in Set E (all doses) ...... 55 Table 16. BLA 761063. Patients with AE leading to drug discontinuation in Set E by SOC (b) (4) ...... 55 Table 17. BLA 761063. Severe AEs by SOC in Set A+C that occurred in at least 1% of patients and ≥0.5% greater than Placebo ...... 70 Table 18. Patients with Non-cardiac Chest Pain* in Set A...... 72 Table 19. Selected patients with chest pain, non-cardiac chest pain, chest discomfort and chest tightness in the GMB database...... 72 Table 20. BLA 761063. Patients with seizures in GMB database...... 75 Table 21. BLA 761063. Treatment emergent AE by SOC, Set A+C (placebo-controlled trials) ..... 76 Table 22. BLA 761063. Treatment emergent AE by SOC, Set E, (b) (4) ...... 77 Table 23. AE by MedDRA HLT with incidence of at least 2% on GMB and ≥1% higher than placebo in Completed Placebo-controlled Studies (Set A+C) ...... 78 Table 24. BLA 761063. FDA exploratory analysis of common adverse events with incidence ≥1% than placebo, using a customized FDA MedDRA query...... 79 Table 25. BLA 761063. Risk of ALT >3x ULN in placebo-controlled trials ...... 81 Table 26. Patients with potentially significant laboratory values in Set A+C (SUR) ...... 82 Table 27. Patients with potentially clinically significant laboratory values in Set E ...... 82 Table 29. BLA 761063. Outlier analyses of Blood Pressure measurements as per FDA pre- defined categories in Set E. SUR...... 84 Table 30. BLA 761063. All AEs. Potential cases of hypersensitivity in placebo-controlled trials* 91 Table 31. BLA 761063. All AEs. Potential cases of hypersensitivity in Set E SUR.* ...... 91

CDER Clinical Review Template 4 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Table 32. BLA 761063. Incidence risk and rate of Upper respiratory tract infections HLT in Set A+C ...... 92 Table of Figures

Figure 1. BLA 761063. Phase 2 and 3 studies of Galcanezumab for the prevention of migraine 16 Figure 2. BLA 761063. Study design for CGAG in Episodic Migraine ...... 100 Figure 3. BLA 761063. Study design for CGAI in chronic migraine ...... 101

Glossary AE, SAE, TEAE adverse event, serious adverse event, treatment emergent adverse event BLA biologics license application BRF Benefit Risk Framework CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CDTL Cross-Discipline Team Leader CRF case report form CGRP Calcitonin gene-related peptide CRT clinical review template CSR clinical study report CSS Controlled Substance Staff DMC data monitoring committee ECG electrocardiogram eCTD electronic common technical document ETASU elements to assure safe use FDA Food and Drug Administration GRMP good review management practice ICH International Council for Harmonization IND Investigational New Drug Application ISS integrated summary of safety ITT intent to treat ICHD International Classification of Headache Disorders MedDRA Medical Dictionary for Regulatory Activities NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event OCS Office of Computational Science PD PI prescribing information or package insert PK PMC postmarketing commitment PMR postmarketing requirement PPI patient package insert PRO patient reported outcome REMS risk evaluation and mitigation strategy

CDER Clinical Review Template 5 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

1. Executive Summary

Galcanezumab (LY2951742) is a humanized monoclonal antibody (mAb) that selectively targets calcitonin gene-related peptide (CGRP), which is implicated in the pathophysiology of migraine.

Migraine is a neurological disorder characterized by attacks of severe headache associated with hypersensitivity to environmental stimuli and a variety of symptoms such as nausea, dizziness and cognitive impairment that may lead to transient and/or long-term interference with normal functioning.

The applicant dosing recommendation is 120 mg injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose, via prefilled syringe or autoinjector, for the preventive treatment of migraine in adult patients.

This review focuses on the evaluations of risks and risk management of the product. For details on the analyses of effectiveness, patient’s experience data and benefit risk integrated assessments, the reader is referred to the clinical reviews by Dr. Suhail Kasim (primary clinical reviewer) and Dr. Heather Fitter (CDTL).

CDER Clinical Review Template 6 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Benefit-Risk Integrated Assessment (Risks only) Lilly is seeking approval of galcanezumab (GMB) for the prevention of migraine. This document reviews the risk profile of GMB. Please refer to Dr. Kasim’s clinical review for evaluation of efficacy. I believe that there are no safety concerns that prevent approval of GMB from the clinical safety point of view. GMB is associated with injection site reactions and hypersensitivity. Cardiovascular adverse events due to blockade of vasodilation by CGRP are a theoretical risk that has potential for more serious outcomes in the postmarketing period in which patients will have more cardiovascular risk factors than the patients included in the clinical trials. I will provide an assessment of the risk, and recommendations for labeling and postmarketing activities in an effort to mitigate the risk if GMB is approved.

Risks: Injection site reactions occurred in 18 to 23%of patients who received GMB compared to 13% in patients who received placebo. Hypersensitivity reactions (hypersensitivity, pruritus, rash and urticaria [excluding site reactions]) in the placebo-controlled studies occurred in 3% of patients on GMB and 2% on placebo. Overall, 6% of patients treated with GMB 120 or 240 reported adverse events consistent with hypersensitivity. Very few of these hypersensitivity events were serious. Approximately 1% of GMB treated patients discontinued treatment because of hypersensitivity. Cardiovascular adverse events: There was no imbalance in cardiovascular adverse events including ischemic events and hypertension in placebo-controlled trials. However, there is a theoretical concern of inhibiting vasodilation mediated by CGRP, particularly in patients with risk factors for cardiac disease, that may result in ischemic events. The clinical trials database is not sufficient to rule out this concern. There is uncertainty regarding potential for more serious cardiovascular outcomes in the post marketing period in which patients are more likely to have cardiac risk factors than the patients who participated in the clinical trials. A detailed FDA review of the literature concluded that there is not compelling evidence that antagonism of CGRP poses a cardiovascular risk. Without a better understanding, it is unlikely that nonclinical studies of galcanezumab could be designed and conducted that would provide useful information; therefore, no post-marketing study to further assess the cardiovascular safety of galcanezumab is recommended.

Potential for fetal harm: There is limited information on the effect of galcanezumab during pregnancy.

Analysis and Recommendation with Respect to Safety: - Adequate labeling and pharmacovigilance may mitigate potentially serious outcomes with galcanezumab. - I recommend a Postmarketing Pregnancy and Outcome study

CDER Clinical Review Template 7 Version date: September 6, 2017

Reference ID: 4327093

Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

2. Therapeutic Context

There are currently five drugs approved in the U.S. for the prevention of migraine headaches (, timolol, , divalproex and onabotulinumtoxin A) each one with their own benefit and risk profiles. Many more are used off-label. However, because of insufficient response or tolerability issues, a substantial number of patients discontinue preventive treatment within 6 months. Additionally, several drugs are approved for the treatment of migraine headaches. For analyses of the condition and current treatment options, please see Dr. Kasim’s review.

Small-molecule CGRP receptor antagonists (“gepants”) are being developed for the prevention of migraines with promising results. Development for one of these drugs was discontinued because of evidence of liver toxicity in a phase 3 trial. Other small-molecule antagonists are in various stages of drug development. Monoclonal antibodies against CGRP or its receptor are also being developed for this indication. and , two monoclonal antibodies against CGRP or its receptor, have been recently approved in the U.S. for the prevention of migraines. Galcanezumab is a monoclonal antibody against CGRP itself.

3. Regulatory Background

Galcanezumab has never been marketed in the U.S. or outside the U.S. IND 111295 was submitted to FDA in March 2011. Meetings/communications that included the discussion of safety aspects of the application were held on 4/11/14 (Type C development plans, which included the DNP request for evaluation of suicidality in the galcanezumab program); 10/9/15 (EOP2 meeting when doses to be evaluated and duration of the pivotal studies were discussed among other items); 2/28/17 (Type C Integrated Analysis Plans letter, that included a list of DNP standard Clinical Safety requests) and 7/18/17 (Pre-BLA meeting).

Of note, GMB has a long half-life (27 days). Therefore, safety data should ideally be evaluated up to at least 5 half-lives (135 days) after the last dose. At the time of the pre-BLA meeting Lilly noted that the treatment phase of the pivotal studies would be completed but the post- treatment follow up period would be ongoing. DNP stated that the original application should include all the safety data needed to support a full review.

BLA 761603 was submitted on 9/27/17. The applicant considered that the application included all the safety data needed to support a full review. (See discussion in Section 8.2 Adequacy of the database). The BLA was filed with a Standard review designation on 11/24/17. For additional details on the regulatory background see Dr. Kasim’s review.

CDER Clinical Review Template 11 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety

Galcanezumab is a humanized IgG4 monoclonal antibody that binds CGRP with high affinity and specificity and prevents its biological activity without blocking the CGRP receptor. CGRP is a neuropeptide highly expressed in anatomical locations activated during migraine attacks. It is a potent vasodilator and facilitates the production and secretion of numerous proinflammatory mediators. No significant toxicity issues have been identified with ant-CGRP mABs but main theoretical concerns include cardiovascular effects and immunogenicity. Other potential effects are in the regulation of insulin release and wound healing. [13.1, 13.1.2 ]

As per Lilly’s summary of Clinical Pharmacology, after single subcutaneous dose, maximum concentration of GMB is attained after 5 days. The estimated half-life from the population PK analysis is 27 days. A once-monthly dose of 240 mg achieved steady state concentrations after 3 to 4 doses. Patient factors such as age, body weight, race, ethnicity, and sex did not have a clinically meaningful effect on GMB PK or the exposure-efficacy relationship. Immunogenicity was not a significant factor affecting PK. In terms of PD effects, a single dose of 75, 200 or 600 mg resulted in attenuated capsaicin-induced dermal blood flow (DBF) by day 3, lasting until the final day measured (Day 42) compared to placebo. In a multiple dose study, 150 mg every 2 weeks for 6 weeks (4 total doses) resulted in an inhibition of capsaicin–induced DBF for at least 134 days after the last dose was given (5 half-lives).

As per Lilly’s summary of Toxicology, there were no significant findings relevant to human safety in this application. Some publications in the literature suggest that CGRP antagonism might increase the risk of ventricular and mortality in a rat model of myocardial ischemia [13.1.3] and that αCGRP knockout mice develop hypertension and aortic hypertrophy. [13.1.4] However, a detailed FDA review of the literature concluded that there is not compelling evidence that antagonism of CGRP poses a cardiovascular risk. The toxicology findings regarding cardiovascular safety are presented below (excerpted from Dr. Lois Freed, FDA Supervisory Pharmacologist’ summary) memo dated 9/27/18.

“Cardiovascular risk: Because of the potent vasodilatory properties of CGRP, concerns were raised regarding long-term antagonism of the CGRP in humans, particularly in patients with cardiovascular risk factors. The sponsor was asked to provide a review of relevant published literature and data available to the sponsor. Since this request was made, the Agency has conducted an independent evaluation of available published literature, primarily on a well-established probe (CGRP(8-37)), to investigate the potential for antagonism of CGRP to induce vasoconstriction or adversely affect coronary vessel size, blood flow, or coronary infarct size under ischemic conditions. The results of this evaluation suggest that regulation of vascular tone in healthy patients and those with cardiovascular risk factors involves multiple endogenous factors, of which CGRP is only one, and that there is limited understanding of the role of CGRP in normal hemodynamic CDER Clinical Review Template 12 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

processes or response to ischemic events. It was, therefore, concluded that there is insufficient information to dismiss the original concerns but that additional basic research is needed to further understand the role of CGRP in these processes. Without a better understanding, it is unlikely that nonclinical studies of galcanezumab could be designed and conducted that would provide useful information; therefore, no post-marketing study to further assess the cardiovascular safety of galcanezumab is recommended.”

For additional information, the reader is referred to FDA’s individual discipline reviews.

5. Sources of Clinical Data and Review Strategy

Table of Clinical Studies

Phase 2 and 3 studies in this application are summarized in the following table.

CDER Clinical Review Template 13 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Table 1. Listing of Clinical Trials Relevant to (b) (4) , Galcanezumab. Trial NCT no. Trial Design Schedule/ Route/ Treatment Duration/ No. of patients Study Centers Identity Regimen (mg) (Follow Up Status1) In Safety Population Populat. (Countries)2 Phase 3 (Pivotal) studies for Migraine indication I5Q-MC- NCT GMB 120 213 90 (2) CGAG- 02614183 Multicenter Monthly, via SC injection 6 months DB/ GMB 240 212 (U.S. and Randomized 4-month washout PBO 433 Episodic Canada) Double blinded - GMB 120 (with 240 Total 858 migraine I5Q-MC- NCT Placebo-controlled loading dose) (washout ongoing) GMB 120 231 109 (11) CGAH 02614196 Parallel - GMB 240 GMB 240 223 M & F, 18- (including - PBO PBO 461 65 yrs U.S.) Total 915 I5Q-MC- NCT Same as above, Monthly, via SC injection 3 months DB followed by 9 DB phase Total 1021 CGAI 02614261 with Follow up OL Double-blind phase months OL/ GMB 120 278 phase -GMB 120 (+240 loading) 4-month washout GMB 240 277 Chronic - GMB 240 PBO 558 Migraine 12 - PBO OL phase (including Open Label phase (OL and washout ongoing) GMB 120/GMB 259 M&F U.S.) -GMB 120 or 240 per GMB 240/GMB 261 18-65 yrs clinical judgement PBO/GMB 501 Phase 3 uncontrolled, long term safety in patients with Migraine (ongoing) 5Q-MC- NCT Multicenter, R, -GMB 120 (+ 240 loading) 1 year/4 month fu GMB 120 129 E or C 5 CGAJ 02614287 open label -GMB 240 (washout ongoing) GMB 240 141 Migraine (including U.S.) Phase 2 in patients with Migraine I5Q-AR- NCT Multicenter, BI-Monthly (q. 2 weeks) GMB 150 107 ART1 01625988 randomized, SC injection - GMB 150 3 months/ PBO 110 35 (1) DB, - PBO 3-month washout Total 217 Migraine (US only) I5Q-MC- NCT PC Monthly SC injection GMB 5 – 300 273 M&F, CGAB 02163993 -GMB 5, 50, 120 or 300 (Completed) PBO 137 18-65 yrs 37 (1) -PBO Total 410 (US only) As per the original submission (cut-off for analyses: March-May 22, 2017). 1 Status at time of original submission. EM= Episodic migraine allowed concomitant use of acute . CM= Chronic migraine (one third of patients continued preventive medications [topiramate or propranolol]). 2 Countries other than US: United Kingdom, Netherlands, Spain, Germany, Argentina, Israel, Korea, Taiwan, Mexico, Italy, Czech Republic. Total number of GMB patients= 2586.

CDER Clinical Review Template 14 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Review Strategy

This clinical review focuses on the safety profile of galcanezumab (GMB) for prevention of migraine in adults, following the format of the CDER Clinical Review Template, September 6, 2017, version. Main data sources have been summarized in Table 1 of this review. The clinical protocols for the studies relevant to the evaluation of safety are briefly summarized in Section 8.2 of this review. For details on individual studies design and assessment of the efficacy and effectiveness of galcanezumab, the reader is referred to Dr. Suhail Kasim’s clinical review.

6. Review of Relevant Individual Trials Used to Support Efficacy

For results of the evaluation of the effectiveness of GMB, the reader is referred to Dr. Kasim’s clinical review.

7. Integrated Review of Effectiveness

For results of the evaluation of the effectiveness of GMB, the reader is referred to Dr. Kasim’s clinical review.

8. Review of Safety

Safety Review Approach

My general approach to the safety evaluation in this application is to conduct analyses using JMP to confirm the Applicant’s findings and further evaluate specific issues as needed. Adverse event tables in this review refer to treatment emergent AEs. Tables are either reproduced/ modified from the applicant’s submission or generated by myself. The Jump Start team of the Office of Computational Science has assisted the review of this application by evaluating its data fitness and providing standard safety analyses of individual studies (CGAG, CGAH, CGAI and CGAJ) (analyses not shown). My review presents integrated pooled analyses of safety using JMP in the SUR datasets unless noted otherwise. For the placebo-controlled pivotal studies (Set A+C), I used the pooled SDTM datasets. For Set E, I used the ADAM datasets. This review includes selected narratives.

Based on the published literature, the main concerns associated with CGRP inhibitors are potential CV effects and immunogenicity [13.1, 1 – 6]. Safety topics of interest included in Lilly’s Integrated Summary of Safety will be presented in section 8.5: cardiovascular safety, hepatic safety, AEs related to injection sites, potential hypersensitivity events, upper respiratory tract infections, and suicidality/self-injurious behavior.

CDER Clinical Review Template 15 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Review of the Safety Database

Lilly evaluated the safety of galcanezumab in 6 clinical studies in patients with EM or CM and 4 clinical pharmacology studies in healthy subjects. The phase 2 and 3 clinical studies are described in Table 1 and Figure 1 of this review. Patients received investigational product (GMB 120, GMB 240 mg or placebo) once monthly, at the study site. The study design of the phase 3 studies is summarized in Appendices 13.2.1 of this review. For additional details about the study design, objectives and conduct of the migraine studies the reader is directed to Dr. Kasim’s review. A schema of the phase 2 and 3 studies is presented below, reproduced from Lilly’s ISS.

Figure 1. BLA 761063. Phase 2 and 3 studies of Galcanezumab for the prevention of migraine

Source: Applicant’s ISS.

The Safety Population was defined as all patients who had received at least one dose of GMB for the treatment of migraine. Lilly presented the safety analyses in 5 main “sets” as follows:

Set A – Double blind period of the three phase 3, placebo-controlled, pivotal trials (two 6- month trials in EM [CGAH and CGAG] and one 3-month trial in CM [CGAI]); includes 1 month of post-treatment washout follow up for studies CGAH and CGAG. (Patients who completed CGAI were offered to continue an open label extension)

CDER Clinical Review Template 16 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Set B – All phase 2 and 3 placebo-controlled trials for the prevention of migraine (CGAH, CGAG, CGAI, ART-01 and CGAB), including 1-month post-treatment follow-up for CGAH and CGAG, and 3-months post-treatment follow-up for ART-01 and CGAB.

Set C – 4-month post-treatment follow-up for studies CGAH and CGAG. At the time of the original submission the post-treatment period was ongoing. At the time of the SUR they were complete.

Set D – Post-treatment follow-up for all four phase 3 studies (CGAH, CGAG, CGAI and CGAJ. At the time of the original submission the post-treatment phase of all four studies was ongoing. (As of the SUR, study CGAI is still ongoing).

Set E – All patients who received GMB in phase 2 and 3 studies for the prevention of migraine (treatment and post-treatment period) (ART-01, CGAB, CGAH, CGAG, CGAI and CGAJ). At time of the original submission, CGAH, CGAG and CGAJ had completed the DB period but post-treatment washout was ongoing; for study CGAI both the open label and washout phase were ongoing. (As of the SUR, study CGAI is ongoing).

This product has a half-life of 27 days and PD effects can be detected up to 134 days. At the time of the original submission none of the phase 3 studies had completed the post- treatment period of the protocols. At the time of the SUR, Lilly submitted updated analyses for Sets C, D and E but did not submit analyses of the complete placebo- controlled trials (Set A+C). These analyses were submitted later, at the FDA request. My review will focus on sets A+C, and E. See additional discussion under 8.2.2 (Adequacy of the data in this application).

- Randomization dose versus Modal dose

Some patients in this development program were randomized but did not receive treatment (mostly because of identification of a protocol violation/lack of fulfillment of eligibility criteria, before treatment). The datasets included a variable called “ACTARM” indicating the dose to which the patient was randomized to, and had received at least one dose of. Of note, some patients in the GMB 120 group received a single loading dose of 240 mg without receiving 120 mg, or received one of each. Also, the OL period of study CGAI allowed flexible dosing (120 or 240 mg at the investigator’s discretion). Therefore, rather than using the ACTARM dose, Lilly conducted analyses by modal treatment (the dose most commonly used: “TRMOD01” for set A and “TRTPG1” for set E). When a patient received the same number of treatments for the 120 mg and 240 mg doses, he/she was included in the 240 mg dose group.

Analyses by modal dose are acceptable. The tables presented in this review refer to the modal dose unless noted otherwise. As per the ADSL datasets, 18 patients randomized to GMB120 received the GMB240 modal dose, and 1 patient randomized to placebo was CDER Clinical Review Template 17 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

treated with GMB120 modal dose, making a total of 705 patients on the GMB120 modal dose, and 730 on the GMB240 modal dose. Although the use of the modal dose is not ideal for evaluating dose response, other possible approaches (e.g. the dose the patient was receiving at the time of the adverse event) would not solve the problem of a patient receiving both 120 and 240 mg dosing. I was able to reproduce the Applicant analyses in Set A+C in the pooled individual study SDTM datasets (which included an EPOCH variable), and in the SUR ADAE datasets (by excluding AE that occurred in CGAI after 120 days).

In addition to the phase 2 and 3 studies, this BLA application includes 4 clinical pharmacology studies in healthy volunteers, a complete study report of GMB in patients with osteoarthritis (CGFA) (b) (4) Information from these studies is included in Appendix 13.2.4 of this review.

Overall Exposure

The overall exposure in the Galcanezumab program is summarized below at the time of the original submission and at the time of the SUR.

Table 2. BLA 761063. Safety Population, Size, and Denominators. Original submission Galcanezumab Placebo Clinical Trial Groups (n=3156) (n=1801) Healthy volunteers 419 27 Controlled trials conducted for this indication 1815 1698 All other trials for this indication1 771 0 Controlled trials for other indications2 151 76 1 Includes patients who switched from placebo to galcanezumab in the open-label treatment phase. 2Study in osteoarthritis was submitted but not integrated with the safety from migraine studies. (b) (4) Source: Table 2.5.1.1. of Clinical Overview.

CDER Clinical Review Template 18 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

(b) (4) Table 3. BLA . Duration of Exposure to GMB in Set E (original submission) Dosage >=3 monthly >=6 monthly 12 monthly doses (modal dose, monthly) doses doses Any dose1 2380 1647 279 120 mg2 902 677 111 240 mg3 1190 970 168 Total number exposed to 120 2092 1647 279* or 240 mg 1All doses in phase 2 and 3 studies (includes 136 patients at <120 mg monthly and 230 patients at doses of 150-300 mg every 2 or 4 weeks).2 GMB 120 mg includes 1 loading dose of 240 mg followed by ≥2, ≥5, or 11 doses of 120 mg, respectively. 3GMB 240 mg includes ≥3, ≥6, and 12 doses of 240 mg, respectively. * Only 25 patients had completed 4-month post-treatment follow up. Source: Extracted from Table 2.5.1.2 of Clinical Overview. Exposure to treatment was similar in all groups in Set A. The mean and median duration of exposure was 134 and 169 days on placebo and 136 and 169 on GMB pooled 120+240, with 532 and 536 patient years (PYRs) of exposure in placebo and GMB pooled, respectively.

As per information submitted on 11/1/17, at the time of the original submission only 25 patients had been exposed to 12 monthly doses and had completed the 4-month post- treatment follow up. However, Lilly estimated that >250 patients would have completed 12 months of treatment plus follow up by the time of the SUR. Exposure at the time of the SUR is shown below.

Table 4. BLA 761063. Patient Exposure in GMB trials. Set E, Safety Update Report.

Dosage >=3 monthly >=6 monthly 12 monthly (modal dose, monthly) doses doses doses Any dose1 2446 1920 526 120 mg2 878 735 167 240 mg 1280 1185 359 Total at the 120 or 240 2158 1920 526 Completed 4-months of 1104 266 post-treatment FU 1 All doses in phase 2 and 3 studies. 2 GMB 120 mg includes 1 initial loading dose of 240 mg. Source: Safety Update Report submitted 1/23/18 (cutoff 8/17/18) and response to informational request submitted 2/15/18.

In set E at the time of original submission the mean and median duration of exposure were 177 and 175 days, respectively, with 1251 PYRs of exposure. In set E of the SUR, the mean and median duration of exposure were 210 and 183 days, respectively, with 1487 PYRs of exposure. No patient was exposed to GMB beyond 12 doses. (A summary table with modal doses and exposure by dose is included in Appendix 13.2.2 of this review).

Exposure fulfills minimum ICH Guidance’s recommendations. [13.1.10] See additional CDER Clinical Review Template 19 Version date: September 6, 2017

Reference ID: 4327093

Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

who had a TIA), should have been categorized as discontinued because of AEs and but the total of patients WD because of subject’s concerns with study procedures or perceived risks is small (0.6%). Categorization of the reasons for discontinuation was appropriate, in general.

Relevant characteristics of the safety population

In general, baseline demographics and disease characteristics were similarly distributed among treatment groups in all studies. Patients in the phase 3 controlled studies (Set A) were predominantly female (85%) and White (77%). The mean age at baseline was 41 years (median 41 years on GMB and 42 years on placebo); 47% of patients were ≤40 years in the GMB 120+240 pooled group as compared to 42% in the placebo group and 26% were ≥ 50 years in the GMB pooled group as compared to 28% in the placebo group. On average, duration of disease was approximately 20 years. In the EM studies (CCAG and CGAH) the number of mean baseline migraine headache days (MHD) was 9, and mean the Migraine Disability Assessment (MIDAS) was 33. In the CM studies, the mean baseline MHD was 19.4 and the MIDAS was 67.2. Baseline demographics in set A are summarized below, from Lilly’s ISS submission.

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Table 7. NDA 761063. Baseline demographics in placebo-controlled trials

Source: Reproduced from Table 2.6 of ISS. Baseline demographics and disease characteristics were balanced among treatment groups, except that patients were slightly younger in the GMB treatment groups. Analyses by gender, race and age will be limited by the small number of male (16%), non-White (26%) and elderly population (only fourteen were ≥65 years old, data not shown). See additional comments under 8.2.2 (Adequacy of the safety database).

- Comorbidities

As per the original ISS, preexisting conditions occurring in at least 10% of patients in Set A were seasonal allergy (20%), drug hypersensitivity (17%), insomnia (12%), anxiety (11%), (12%) and back pain (10%).

Because of the potential deleterious CV effects of CGRP inhibition, the applicant conducted analyses of baseline CV risk factors in the GMB database. Search terms included the following: - Ischaemic heart disease (2 subSMQs below) o Myocardial infarction (subSMQ, Narrow terms only) o Other ischaemic heart disease (subSMQ Narrow terms only) - Hypertension (SMQ narrow terms only) - Cardiac failure (SMQ narrow terms only); Cardiomyopathy (SMQ Narrow terms only) CDER Clinical Review Template 23 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

- Ischaemic CNS vascular conditions (subSMQ under CNS vascular disorders, Narrow) - Dyslipidaemia (SMQ, Narrow) - Hyperglycaemia / new onset diabetes mellitus (SMQ Narrow terms only)

If a patient did not have any of the PTs in the above SMQs as a pre-existing condition or medical history event, the patient’s baseline cardiovascular disease risk group was “no”.

Per Lilly’s analyses the percentage of patients with CV risk factors was 18.5% for placebo and 17.2% for GMB pooled in set A, and 17.7% for GMB all doses pooled in Set E (source: APP 1.4 and 1.7 of ISS).

The preferred terms included for identification of CV risk are appropriate, but the list is missing current smoking and obesity. The following table presents analyses of patients with CV risk factors as per MO analyses of Medical history, Vital signs and ADSL ISS datasets.

Table 8. Patients with CV risk factors at baseline in placebo-controlled trials Total

N=2886 n (%) Hypertension 1 247 (8.6) Diabetes-related 2 74 (2.6) CV ischemic/thrombotic 3 17 (0.6) Hypercholesterolemia 101 (3.5) Dyslipidemia 4 266 (9.2) Smoker (per ADSL dataset) 396 (13.7) BMI ≥ 30 kg/m2 (per ADVS dataset) 851 (29.5) MO analysis of ADMH, ADSL and ADVS datasets. One patient may have had more than one risk factor. 1 Includes HTN, Essential HTN, BP increased, gestational hypertension, prehypertension. 2 Includes diabetes mellitus, hyperglycemia, glucose tolerance impaired, diabetic retinopathy, diabetic neuropathy, diabetic ketoacidosis, Type 1 and Type 2 diabetes mellitus. 3Includes Mi, stroke, angina, cerebrovascular accident, cerebral infarction and TIA.4 Includes hypercholesterolemia, high , hyperlipidemia, dyslipidemia. Patients with a history of CV ischemic thrombotic events in the phase 3 trials, by dose are summarized below.

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Table 9. Patients with a history of myocardial infarction, stroke, angina, TIA or peripheral arterial occlusive disease in placebo-controlled trials

Source: MO analysis ADMH dataset. * One patient had TIA and peripheral occlusive disease.

The percentage of patients with baseline CV risk factors shown in Table 8 appeared balanced between treatment groups (data not shown). Very few patients had a history of an ischemic/thrombotic event (N=17 [0.6%]), and most were in the placebo group (1%) as compared to the GMB pooled group (0.2%). See additional comments in Section 8.2.2, below.

- Baseline concomitant medications

Analyses of baseline concomitant medications by indication were submitted on 2/2/18, in response to a DNP request for information. CV medications in Set A, are summarized below.

Table 10. BLA 761063. Baseline cardiovascular medications, placebo-controlled trials

Source: Applicant’s summary table of baseline concomitant medication submitted 2/1/18. *Includes acetylsalicylic acid and clopidogrel. Overall, a small number of patient was receiving treatment for HTN, diabetes, lipid disorders or ischemic/thrombotic events at baseline. A higher percentage of patients was

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receiving anti-hypertensive treatment in the placebo group as compared to GMB pooled treatment (7% vs. 5%). A higher percentage was receiving cholesterol lowering agents in the GMB group (3% vs. 1%). The impact of these small differences is unclear.

Adequacy of the safety database

The database fulfills minimum ICH guidances for premarketing evaluation for medications for chronic use. However, the size and duration of exposure in the database are insufficient for evaluation of cardiovascular safety, particularly in patients with pre-existent cardiovascular morbidity, which is the main theoretical concern with CGRP inhibition. (See Section 4 and Section 8.5.1 of this review). As of the SUR, 526 patients received 12 doses of GMB 120 or 240 mg, of whom 266 completed the protocol-mandated 4-month post-treatment follow up. No patient has received >12 doses of GMB in this development program.

Patients with migraine are thought to be at increased risk of cardiovascular conditions as compared to the general population, particularly women with migraine with aura.[13.1.3, 13.1.6, 13.1.9 ] The baseline demographic characteristics and cardiovascular risk factors in the GMB database do not seem to reflect those of the population who will be using this product, such as those in the American Migraine Prevalence and Prevention (AMPP) study. The AMPP is a longitudinal study with cross-sectional surveys in patients with migraine representative of the US population. Results of the surveys have been published over the years.[ 13.1.3, 13.1.7, 13.1.8] In the GMB placebo-controlled trials, 8%, <3%, <9% and 14% had hypertension, diabetes mellitus, dyslipidemia or were smokers, as compared to 33%, 12%, 33% and 16%, respectively in the overall AMPP 2008 survey in patients with all types of migraine. [3.1.5] In this survey, 20% were men and 43% were <40 years (not very different in terms of gender and age from the GMB database).

In the AMPP 2009 survey, in patients with episodic migraine (EM) only, the prevalence of hypertension, diabetes mellitus, dyslipidemia and smoking was slightly higher than in the 2008 survey (35%, 15%, 40%, 17%, respectively). Patients were older (only 22% were <40 years) and the percentage of men was 22%.[13.1.7] Of note, approximately 6% of women and 14% of men in the <40 year-old group had a history of at least one CV event or condition [13.1.8] as compared to <1% in the GMB database.

In summary, the GMB database - as most NDA/BLA databases - is not powered to assess cardiovascular safety, particularly among patients at increased CV risk in whom CGRP inhibition would be potentially more likely to show deleterious effects. Additionally, while differences in the demographic characteristics and ascertainment methodology preclude direct comparisons between the GMB database and the AMPP population, the GMB database does not appear to reflect the US migraine population in terms of cardiovascular risks. See additional discussion under Section 4 (Significant issues from other review disciplines) and Section 8.5 (Analyses of Submission Specific Safety issues).

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Adequacy of Applicant’s Clinical Safety Assessments

Issues Regarding Data Integrity and Submission Quality

The application was well organized and information was easy to find. The narratives were generated by an automatic software.

At the time of BLA submission, the treatment period of studies CGAG, CGAH, CGAI (double- blind phase only) and CGAJ, were completed, but the open label phase of CGAI and the post- treatment period of all phase 3 studies were ongoing. At the pre-BLA meeting DNP had requested that all the data needed to support evaluation of safety be submitted. The applicant stated that the information was sufficient and the BLA was filed. At the time of the SUR (1/23/18), the applicant submitted study addenda for the pivotal studies and for study CGAJ, containing information from the post-treatment period only. The SUR analyses did not include integrated analyses of the completed treatment + post-treatment placebo-controlled trials. While these analyses were not specifically requested at the Pre-BLA meeting, they were expected, given that the post-treatment period was part of the protocols.

Presenting separate data from the treatment and post-treatment period did not allow appraisal of whether the adverse events (or ECG or vital sign changes) occurred in the same or different patients. In retrospect, partial data from the incomplete pivotal studies should not have been accepted, because all analyses had to be re-done once the full datasets were available. Moreover, the SUR submitted on 1/23/18 failed to include the datasets. Upon FDA request, updated SUR ISS and individual study datasets were submitted on 2/5/18 and 2/8/18 respectively, and tables with selected safety analyses for the complete placebo-controlled studies (Set A+C+ post-treatment phase of CGAI patients who did not enter the OL phase) were submitted on 2/14/18.

Categorization of Adverse Events

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The protocols defined a treatment emergent adverse event (TEAE) as an event that first occurred or worsened in severity after baseline on or before the date of the last visit within the treatment phase of interest. Adverse events were classified based on MedDRA version 19.1 in the original submission, and MedDRA version 20.0 in the Safety Update Report. As per Lilly’s explanation, the main impact of the new version is that the LLT Common cold, Cold symptoms, Cold, Common cold syndrome, Febrile cold, Head cold, and Pyrexial cold were previously coded to the PT of nasopharyngitis but are now coded to viral upper respiratory tract infection in v.20.0.

Categorization of AEs was acceptable, in general, although in my opinion, some important medical events should have been coded as SAE, such as one non-SAE of hypertension with BP of 202/134 mmHg requiring initiation of antihypertensive treatment (CGAI-(b) (6) . Additionally, several patients reported “chest pain” (including the following LLTs: chest pain, chest pain unspecified, intermittent chest pain, intermittent precordial pain); “chest discomfort” (including chest discomfort, chest tightness, chest pressure-non cardiac, intermittent chest tightness, worsening of tight chest LLTs) and “non-cardiac chest pain” (including atypical non-cardiac chest pain, chest pressure sensation, mechanical chest pain, intermittent left sided chest pain, among others) the etiology of which remains unknown (see Section 8.4.4 of this review).

Routine Clinical Tests

Scheduled safety assessments were appropriate. Visit 1 (screening) included medical history and physical examination (including neurologic examination, weight, height, waist and hip circumference measurement, sitting BP, pulse and temperature), ECG and laboratory measurements (hematology, chemistry, urinalysis, serum pregnancy tests or FSH and urine drug screen), along with the C-SSRS questionnaire. Visit 2 (baseline) re-evaluated eligibility, concomitant meds and specific migraine history. The prospective baseline assessment period lasted 30-40 days. Study drug administration started at Visit 3 (month 0). Routine chemistries, hematology and vital signs were done at baseline (Visit 2), Month 3, 6, 10 and End of study. Adverse events, vital signs and C-SSRS were evaluated every month until month 6, and every 2 months thereafter until the end of study visit. ECG was done at baseline, month 6, 10 and end of study. ECG, labs and vital signs were to be done before dosing. Urine pregnancy test was done monthly until month 5. In addition to outcome measures, Lilly collected data for immunogenicity assays, biomarker storage sample, CGRP plasma sample, PK blood sample, pharmacogenetic sample, and RNA.

Of note, CGRP is involved in the regulation of insulin release. Lilly evaluated parameters related to insulin/glucose metabolism (HbA1c, fasting insulin/fasting C-peptide) at month 0, 6 and End of study. Weight was also measured at month 6, 10 and end of study. Evaluation of CV safety appears appropriate (evaluation of adverse events, ECG and BP measurements). Measurement of orthostatic BP would have been desirable. CDER Clinical Review Template 28 Version date: September 6, 2017

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Safety Results

Deaths

(b) (4)

CGAQ- (b) (6) (galcanezumab 240 mg). A 36 year-old male healthy volunteer in a PK/PD study (CGAQ) received a single dose of GMB on Day 1. Past medical history was unremarkable. Physical examination, vital signs, ECG and labs at screening were normal. He was not taking any concomitant medication. He did not report any AEs during the outpatient visits he had as part of the protocol (Days 3, 5, 6, 8, 10 and 12). On day 15, the subject was “found face down in water next of a yacht slip.” There was no information as to why the subject was in the area, or why he and his vehicle ended in the water. The report speculates that the yacht slip was dark and that the subject may have been backing in the area prior to ending submerged in water. He had no signs of trauma. Toxicology results were negative for and common drugs of abuse. As per the autopsy, there was “blood stained fluid within the nares and oral cavity” and “pulmonary congestion” but there no mention of water in the lungs. As per the autopsy report, he died of accidental drowning. The investigator determined that it was not related to study drug. In my opinion, this death cannot definitively be called an accidental drowning. Since there was no water in the lungs, he could have been already dead when he fell into the water. An could be a possible explanation. I would say that the cause of death is undetermined.

In summary, (b) (4) the relationship to study drug is unknown.

Serious Adverse Events

- SAE in Placebo-controlled trials In the PC trials 52 patients reported 60 SAEs (33 [2.3%] patients on GMB pooled doses and 19 [1.3%] patients on placebo). Approximately two thirds of SAE occurred in the treatment period and one third in the post-treatment period (data not shown). Most SAE occurred in a single

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Swelling face 0 0.0% 1 0.1% 1 <0.1% Urticaria 0 0.0% 2 0.1% 2 0.1% Surgical and medical procedures 0 0.0% 1 0.1% 1 <0.1% Uterine leiomyoma embolization 0 0.0% 1 0.1% 1 <0.1% Vascular disorders 1 0.1% 0 0.0% 1 <0.1% Varicose vein 1 0.1% 0 0.0% 1 <0.1% Source: ADAE SUR ISS submitted 2/5/18.

Approximately 4% of patients presented at least 1 SAE. The SOC with the highest incidence of SAE was the GI disorders (0.6%) followed by Infections and infestations (0.5%) and Neoplasms (0.5%). Again, most SAE occurred in only one patient and there was no suggestion of a dose response. SAE that occurred in 2 patients in the pooled GMB group were myocardial infarction, congestive heart failure, acute pancreatitis, small intestinal obstruction, non-cardiac chest pain, cholelithiasis, intervertebral disc protrusion, uterine leiomyoma, seizure, nephrolithiasis and urticaria. Migraine occurred in 3 patients.

Selected narratives for SAE among GMB-treated patients are discussed below

Cardiac, Cerebrovascular and Vascular SAE

Placebo-controlled period

CGAH- (b) (6) on GMB240mg. SAE acute MI in the PC trial. 55 F with history of hypothyroidism and Raynaud’s phenomenon of unknown duration and a “family history of cardiac disease.” BP at baseline was 110/70. At subsequent visits her BP was on the low side (103/60 mmHg). She reported sleep disorder of mild severity starting the day of the first dose. On Day 79, she went to the ER with severe headache, chest pain “and high blood pressure.” ECG was normal. Pain responded to isosorbide dinitrate and . Labs showed elevated troponin. Coronary angiography showed non-significant coronary disease, decreased blood flow and ectasia in the coronary arteries. The patient was diagnosed with acute myocardial infarction and treated as such. She was discharged 5 days later. The investigator considered the event not related to drug. This is a 55 F without known CV risk factors who presented myocardial infarction without evidence of significant coronary obstruction, but “decreased flow” and “ectasia.” The event occurred approximately 2.5 months into treatment, 1.5 weeks after the 3rd dose, The narrative mentions high blood pressure, but this was not reported as an AE in the datasets. In isolation, it is not possible to determine causality for this event of MI. See discussion on CGRP and CV safety in Section 4 and Section 8.5.1 of this review.

CGAG- (b) (6) on galcanezumab 240 mg. SAE Inverted T wave, congestive heart failure and cardiomyopathy diagnosed during the follow up period of the PC trial. A 51-year-old female

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non-smoker with hypothyroidism, pituitary tumor, obesity, and reported 1 to 2 drinks per day had baseline ECG showing PR interval <120 msec. Otherwise was normal. One month after the 3rd dose of GMB presented a non-SAE of left bundle branch block (LBBB). Three months after the last dose of galcanezumab, an ECG showed non-specific T wave abnormality. A cardiologist diagnosed her with dilated cardiomyopathy with moderate left ventricular systolic dysfunction. The patient was prescribed carvedilol and sacubitril valsartan. Unclear if she had hypertension at the time. At the last study visit on (b) (6) the ECG findings showed anterior and septal T wave abnormality, considered a manifestation of ischemia. On (b) (6) she had improved left ventricular systolic function. 51 F with CV risk factors and possible alcohol abuse had no ECG signs of ischemia at baseline. She developed LBBB, dilated cardiomyopathy with diastolic dysfunction and T wave changes consistent with ischemia. Although she had risk factors, a role of GMB cannot be ruled out (See Sections 4 and 8.5.1 of this review).

A SAE of TIA was reported in the Neurologic system disorders SOC, and one of pulmonary embolism (PE) was reported in the Respiratory, thoracic and mediastinal disorders SOC, but are included here, along with other CV ischemic/thrombotic events.

CGAH- (b) (6) on GMB240. SAE transient ischemic attack (TIA). 54 F with hypothyroidism for 10 years, presented non-SAE of HTN 54 days after starting GBM 240, 26 days after the 2nd dose and SAE of TIA on Day 59, 2 days after the 3rd dose in the PC trial. At baseline the BP was 120/92 mmHg and BMI= 33. At visit 5, BP was 120/92. On day 54 she had a headache of moderate intensity described as “related to HTN”. BP not provided, but she started 5 mg/day. HTN resolved on the same day. On Day 59 while having a blood tests, she presented weakness and decreased sensation of right arm and leg, diagnosed as TIA. At that time BP was 140/90. At the ER, her BP was 100/70 mmHg. She was hospitalized and treated with and atorvastatin. MRI and MRI angiography were reported as normal. She was discharged home after 5 days. The investigator considered the event not related to study drug, but discontinued the patient from the study because of this AE on Day 70 (the reason for discontinuation was “physician’s decision”). Two months later, her BP was 100/72. 54 F with hypothyroidism and obesity presented new onset HTN and a TIA while on treatment with GMB. In isolation a TIA cannot be attributed to study drug. However, given the theoretical concern, I would not rule out an association. See Sections 4 and 8.5.1 of this review.

CGAI- (b) (6) on GMB240. SAE acute bilateral pulmonary embolism. 24 F presented bilateral pulmonary embolism 61 days after starting DB treatment with GMB 120 mg a month, and 4 days since the 3rd dose during the DB period. The patient had recent airline travel. No history of smoking. Concomitant medications at before the event included propranolol, ketorolac, and intravaginal (ring) hormonal contraception for 2 years prior. On Day 58, 3rd dose, the patient’s blood pressure was 91/61 mmHg. On Day 62 she was admitted to the hospital with acute bilateral pulmonary embolism preceded by 4 days of chest pain and nausea. The

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event resolved with appropriate treatment and she was discharged on Day 66. She completed the DB portion of the study on Day 86 and continued in the open label treatment period. The investigator considered the event not related to GMB. On Day 86, her weight had increased to 77 kg. 24 F on estrogen ring presented bilateral PE after 3 doses of GMB, almost 3 weeks after air travel. The estrogen containing ring may have increased the risk of PE in this young patient. In isolation the event cannot be attributed to GMB, particularly that she continued GMB treatment without further PE. Of note, there was one SAE of PE in the placebo group too.

Additionally, one patient treated with GMB 150 mg every 2 weeks (a dose not proposed for marketing) presented severe peripheral vascular disease in a PC phase 2 trial, as follows.

ART (b) (6) 41 F with history of uncontrolled diabetes mellitus, smoking, obesity and hyperlipidemia, with a prior history of right ankle fracture presented left hip and foot pain approximately 3 months into treatment. Concomitant meds included metformin and insulin, oral contraceptive, analgesics and flexeril. On Day 94 of treatment, she complained of left leg claudication and pain at rest. On Day 112 (43 days after the 6th dose of GMB), an ultrasound showed complete occlusion of the arterial blood supply below the left knee reported as severe “peripheral vascular disease.” CT angiogram of the abdominal aorta and chest revealed filling defect in a branch of the right lower lobe pulmonary artery suggestive of pulmonary embolism, distal abdominal aorta thrombus predominantly on left side with near complete occlusion of the common left iliac artery, femoral artery, and distal aspect of the left popliteal artery. On (b) (6) , an inferior vena cava filter was placed and the patient underwent thrombectomy of the left femoral, popliteal, and posterior tibial arteries. The procedure was complicated by compartment syndrome and the patient required an above knee amputation. The investigator considered the event of peripheral vascular disease as not related to study drug. I believe that given the multiple risk factors that this patient had for thromboembolic events, the event of peripheral vascular disease could have occurred in the absence of study drug. On the other hand, few patients in this database had the combination of risk factors that this patient had, and given that CGRP is involved in the regulation of vascular homeostasis, a possible role of blocking CGRP with GMB cannot be ruled out. See Sections 4 and 8.5.1 of this review.

Open label period of studies CGAI and CGAJ

CGAI- (b) (6) on GMB240mg. SAE of myocardial infarction and unstable angina. 55 M. No significant medical history. Non-ST elevation acute myocardial infarction occurred on Day 210 of treatment, 10 days after 5th dose of GMB, followed by and unstable angina. Baseline ECG showed normal sinus rhythm with nonspecific T-wave abnormality. Concomitant meds: aspirin and sertraline; started treatment for hyperlipidemia first day of OL. AE during DB included

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anxiety and dizziness. Diarrhea starting 10 days before the MI. No mention of BP or electrolytes at time of MI. In isolation, it cannot be attributed to GMB, but given that CGRP is involved in the regulation of vascular homeostasis, I would not rule out an association. See Sections 4 and 8.5.1 of this review.

CGAI- (b) (6) on GMB240mg. SAE of Cardiac congestive failure. 38 F, Started GMB 240 on (b) (6) . She was obese (BMI 35 kg/m2) and had a family history of heart disease (brother died of cardiomyopathy; mother died of HTN and diabetes at age 56). BP at screening was 125/99 mmHg (high diastolic BP). ECG at baseline showed left atrial abnormality with poor R wave progression (PRWP). She presented a non-SAE of peripheral edema on Day 70 of treatment. On (b) (6) she went to the ER with “cough and congestion” treated azithromycin and furosemide. She completed the DB period on Day 89. ECG showed non-specific T-wave abnormality. HR at that visit was 100 bpm. Her BP during treatment had been SBP 104-122 mmHg, and DBP 83-87 mmHg. On (b) (6) , 25 days after starting the OL phase, she was admitted to the hospital with shortness of breath, palpitations and peripheral edema, diagnosed as congestive heart failure (CHF). ECG showed sinus tachycardia. Echocardiogram showed severe LV dysfunction with EF<20%, moderate mitral and tricuspid regurgitation and pulmonary hypertension. Troponin was normal, TSH was mildly increased. Cardiac catheterization showed no significant coronary disease but elevated left ventricular end diastolic pressure. She was treated with carvedilol, sacubitril/valsartan and furosemide and discontinued from the study. She did not enter the follow up period. Investigator considered the event not related to drug. This 38 F with family history of cardiac disease, developed severe CHF, moderate valve regurgitation and pulmonary HTN, without significant coronary artery disease. She had borderline high blood pressure at screening and during treatment. The diagnosis of CHF was made during the open label phase, but symptoms started earlier, approximately 2 ½ months into treatment with peripheral edema on Day 70. As per the patient profile, pulse at screening was 78 bpm, and increased slowly to 83 bpm on (b) (6) , to 93 bpm on (b) (6) and 100 bpm on (b) (6) (Day 89). In my opinion, inhibition of GCRP could potentially have interfered with BP regulation and worsen diastolic dysfunction in this patient.

CGAI (b) (6) on GMB120mg. SAE Orthostatic intolerance after treatment of diastolic HTN 44 F Started GMB 120 mg on (b) (6) and continued with OL treatment starting (b) (6) . Preexistent conditions included Raynaud’s phenomenon and thoracic outlet syndrome. SAE of orthostatic intolerance occurred on (b) (6) , 161 days after starting the OL period and 12 days after the 6th dose of GMB 240 in the open label phase. At the end of study for the DB phase she reported an AE of postural dizziness lasting minutes. All VS were in the normal range at all visits. The patient’s baseline and double-blind period ECGs showed left atrial abnormality with PRWP, although these abnormalities were not seen in the open-label ECG at Visit 10. On (b) (6) , 11 days after Visit 12, the patient experienced diastolic hypertension treated with /hydrochlorothiazide. On (b) (6) the patient was admitted to the hospital due to severe orthostatic intolerance. Cardiac evaluation, ECG, Holter and tilt test were normal. MRI

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showed no evidence of cerebrovascular disease. She received hydration during hospitalization. The event of orthostatic intolerance resolved after 9 days (b) (6) The investigator and Lilly determined the event not to be related to study drug. As per updated narrative in the SUR, the patient did not receive further treatment and withdrew from the study one month after this event because of “concerns about study procedures and perceived risks.” This 44 F with Hx of Raynaud’s phenomenon who apparently had postural dizziness during the DB phase, presented an episode of diastolic hypertension on Day 161 of the OL period, treated with amiloride/HCTZ. HTN was not entered to the CRF as an AE, but orthostatic requiring hospitalization occurred upon the use of amiloride/HCTZ for treatment of HTN. She did not have a history of HTN before using GMB. In my opinion the role of GMB cannot be ruled out. Additionally, the event of orthostatic intolerance should have been categorized as leading to drug withdrawal.

The following cases identified in the ADAE datasets (one in the PC period and one in the OL period) were reported as CV non-SAE. In my opinion they should have been categorized as a SAE (important medical event).

CGAG- (b) (6) . 56 F who presented non-SAE of angina pectoris in the PC period. As per Empirica Study tool, concomitant medication was aspirin/caffeine/ paracetamol as needed. She received GMB on Days 1, 30, 59, 86, 114 and 156. She had 3 events of angina pectoris categorized as severe on Days 52, (associated with dyspnea), 156 (day of last dose) and 180 (24 days after last dose). Each event resolved the same day without apparent treatment. On day 1 she presented nausea and vomiting. She was treated intermittently with antiemetics through day 215. She had a last visit on Day 185 and withdrew from the study on Day 248 (withdrawal by patient because of moving). ECG on Day 1 (baseline) showed heart rate of 53 bpm, PRWP and no evidence of ischemia/infarction. PR 168 msec, QTcB 434 msec. ECG on Day 185 was mostly unchanged. QTcB values not provided. Lab evaluations were normal, except for one measurement of mild CK elevation on Day 86 (that was normal on Day 185 and 248) and elevated C-Peptide elevated Day 248. It is unclear who made the diagnosis of angina pectoris and how the diagnosis was made. As per additional information submitted on 5/9/18, ECG and stress test showed no evidence of ischemia, significant arrhythmia, or abnormal blood pressure response and the diagnosis was changed to muscle strain causing angina-like symptoms.

CGAI- (b) (6) (galcanezumab 240 mg) Coronary artery stenosis in the OL period. 62 yo M had pre-existent arrhythmia treated with . At baseline he was obese (BMI >30 Kg/m2) and had BP of 159/109 mmHg. ECG was normal. On Day 116, the same day of the 5th dose of GMB he had an AE of hypertension (202/134 mmHg) categorized as non-SAE of moderate intensity. Treatment with lisinopril, HCTZ and candesartan was initiated. He received 12 monthly doses. Last dose was on Day 312. As per the SUR, on Day 392, 81 days after the last dose of GMB, a coronary angiogram showed narrowing of coronary blood vessels of moderate

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severity. He was treated with diazepam, glyceryl trinitrate and heparin, along with hydrochloride for hypertension. The patient completed the post-treatment follow-up period. This 62 M had hypertension and obesity, and a history of arrhythmia. The non-SAE of HTN should have been categorized as a SAE, because of the values and the need for initiation of treatment. As per information submitted on 5/9/18, the patient was referred by a family physician to a heart center for further evaluation, but he did not have any additional symptom.

In addition to CV SAE in the migraine trials, one event occurred in an osteoarthritis trial as follows:

Patient CGAF 113-8210A 62 year-old female smoker with no other known CV risk factors presented angina pectoris and myocardial infarction 26 days after the 3rd dose of GMB 300 (Day 117 of study). Diagnostic catheterization showed “mild blockages” but no stent was necessary. She was treated with aspirin and atorvastatin. The investigator and Lilly assessed the case as not related to GMB. In my opinion, a relationship cannot be ruled out.

In summary, cardiovascular SAE in the placebo-controlled trials included 1 myocardial infarction, 1 congestive heart failure (CHF)/cardiomyopathy, 1 TIA and 1 bilateral PE in the GMB 240 group (0.5% of GMB240-treated patients [0.3% of all GMB-treated]; and 1 MI, 1 PE and 1 deep venous thrombosis on placebo (0.3%). There were no CV SAE on GMB120. The open label period of studies CGAI and CGAJ included the following CV SAE: 1 MI followed by angina pectoris, 1 CHF, 1 coronary artery stenosis on GMB240, and 1 orthostatic intolerance on GMB120. There were no reported SAE of hypertension but 1 patient had BP of 202/134 mmHg during GMB treatment, that should have been considered a SAE. Additionally, hypertension was mentioned in a patient who had a MI, the patient who had a TIA, and the patient with orthostatic intolerance after being treated for hypertension. Two patients presented SAE with GMB 300 mg monthly (one peripheral vascular disease with leg amputation in a phase 2 study and one myocardial infarction in an osteoarthritis study).

Gastrointestinal SAE

Two events of acute pancreatitis were reported, in the PC period, one in each GMB group (summarized below). A SAE of alcoholic pancreatitis was also reported on placebo (narrative not included).

CGAG- (b) (6) on GMB120mg. SAE acute pancreatitis. 57 M (B) DB started (b) (6) Event occurred (b) (6) , 4 days after starting GBM 120. Medical history included hypercholesterolemia, HTN, obesity, GERD and cholecystectomy. He did not report alcohol abuse. Concomitant meds included lisinopril, omeprazole, hydrochlorothiazide. On Day 4 he went to ER with pain and tenderness in upper abdomen radiated to the back and nausea diagnosed as pancreatitis.

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Lipase was normal. Abdominal CT showed colonic diverticulitis but did not mention the pancreas. On (b) (6) he went to the ER again and was hospitalized for “pancreatitis.” Creatinine was 1.5 mg/dL, GFR was 46 ml/h (normal >59). He also had hyperglycemia (111 mg/dL, normal up to 106), LDL was high, lipase was 411 (range 73-393 mg/dL). CT scan showed mild partial distal small bowel obstruction. He was treated with hydration and analgesics and discharged on (b) (6) . On (b) (6) started treatment with sucralfate; lisinopril dose was decreased. No action was taken with GMB. The event resolved on (b) (6) . He completed treatment on (b) (6) and is still in the post-treatment fu period. The event of pancreatitis was considered by the investigator not to be related to drug. As per Lilly, there is insufficient info to determine causality. Abdominal pain might be related to CGRP, but I am not clear as to what the basis for the diagnosis of pancreatitis was, particularly the first time, when lipase was normal, amylase was not available, and the CT scan did not mention the pancreas. The second time there was a very mild increased in lipase along with increased creatinine, decrease GFR and hyperglycemia, and small bowel obstruction. As per information submitted on 5/9/18 the diagnosis was supported by a history of a prior episode of abdominal pain and pancreatitis (years earlier).

CGAI (b) (6) on GMB240mg. SAE Acute Pancreatitis. 57 F started GMB on (b) (6) , presented acute pancreatitis 5 days after the first dose of GMB leading to study discontinuation. Medical hx included multinodular goiter. Meds included topiramate, flunarizine, ergot derivative. Baseline triglycerides were 271 (normal not provided); other labs were normal. Two days after the first dose she presented abdominal pain. On (b) (6) , he had an upper respiratory infection treated with amoxicillin/clavulanic, and pseudoephedrine. On the same day she presented to the ER with epigastric pain, which was reportedly ongoing since (b) (6) (before starting GMB). She was diagnosed with sludge gallbladder, and pancreatitis with pseudocyst. She underwent cholecystectomy and event resolved. Recurrent pancreatitis and pseudocyst appear to be related to cholelithiasis. The use of topiramate may have contributed to the pancreatitis. Although pancreatitis was diagnosed 5 days after the first dose of GMB, abdominal pain preceded the use of GMB, and the event resolved after .

I am not persuaded that GMB is associated with increased risk of acute pancreatitis. The first case has insufficient information for diagnosis; the second appears related to cholelithiasis. There was a case of alcoholic pancreatitis in the placebo group, with a second event in the OL phase in study CGAI.

Other SAE in the PC trials included 1 case each of gastritis, rectal polyp, small intestinal obstruction and vomiting in the GMB 120 treatment group.

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A case of small intestinal obstruction occurred in CGAG- (b) (6) in the PC period. 36 M in DB treatment period (GMB 120) 16 days after starting GMB. Pre-existing conditions included abdominal pain testicular cancer, small bowel obstruction and hernia repair. Dx was made based on clinical symptoms and CT scan. Admitted to the hospital for 5 days. The event resolved. Drug was discontinued. This event appears related to previous surgery and unlikely to be related to GMB

A second case of small bowel obstruction occurred in the OL period as follows. CGAI- (b) (6) (on GMB 240). SAE Small bowel obstruction in OL period. 53-year old female, 269 days after the first dose and 9 days since the last (10th) dose, she was hospitalized for abdominal pain. Medical history included hypothyroidism. A computerized tomography (CT) scan and blood work were normal. The patient was diagnosed with a small bowel obstruction and treated with dicycloverine. Cause of the obstruction was unknown. The event resolved in 2 days and she was discharged from the hospital. In the opinion of the investigator, the event was not related to study drug. The narrative includes limited information to support the diagnosis. It is unclear why this is called small bowel obstruction, vs. ileus or constipation.

A third case of small intestinal obstruction would be the case identified in a patient with acute pancreatitis (CGAG- (b) (6) ). These cases of small intestinal obstruction do not appear related to GMB.

General Disorders and Admin site conditions CGAH (b) (6) on GMB240 during the placebo-controlled period. SAE Pyrexia and disorientation. 55 M. Started treatment on (b) (6) . No significant medical history. No prior history of allergies. Concomitant meds included aspirin, paracetamol, , ketorolac and . On Day 7 after starting GBM240 he had mild pruritus (site not specified) treated with corticosteroids. On Day 97 of GMB treatment, 12 days after the last dose, he was diagnosed with skin ulcers of 1-2 mm on fingers, left elbow and left gluteus. The left elbow was swollen; he had a skin biopsy and cultures. On Day 100 of GMB treatment 15 days after the 4th dose, he had pyrexia and disorientation. Blood cultures were negative. He was treated with mupirocin and prednisone. These events lasted for 3 and 1 days, respectively. The event of pruritus lasted for 96 days until it resolved on (b) (6) , the same day as pyrexia. On (b) (6) , the event of skin ulcers was reported as resolved and he was discharged from the hospital. The patient discontinued from the study on (b) (6) (Visit 8) and he is currently in the post-treatment follow up period. The investigator considered all events but the skin ulcers as possibly related to GMB. The sponsor assesses that there is insufficient evidence to conclude a relationship to study drug and that skin ulcers “are relatively common in the population, and in view of the patient’s occupation, which may be associated with aquatic infections.” It appears that disorientation was related to fever, and fever related to infected ulcers. As per clarification submitted on 4/12/18, the patient was a fisherman; results of biopsy showed unspecific inflammation.

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Infections and Infestations SOC

There was only one SAE of infection (influenza) on GMB in the PC trials, as compared to 2 on placebo (appendicitis and pyelonephritis with urosepsis). Patients with SAE of infections in Set E are summarized below.

Listing of patients with SAE of infections with GMB in Set E

ID GMB PT Rel Day Action Outcome dose Start/End (b) (6) CGAI GMB120 Osteomyelitis 142/193 Mod none Recovered CGAI GMB120 Cellulitis 168/183 Mod none RECOVERING CGAI GMB240 Appendicitis 244/246 Sev none Recovered CGAI GMB240 Diverticulitis 319/335 Sev none Recovered CGAI GMB120 Appendicitis 344/348 Sev none Recovered CGA GMB240 Influenza 145/154 Sev NA Recovered CGAJ GMB240 Pneumonia 287/488 Sev none RECOVERING CGAB GMB120 Appendicitis 126/156 Sev NA Recovered CGAI GMB120 Upper resp tract 125/132 Sev none Recovered infection CGAI GMB240 Urinary tract 176/186 mild none Recovered infection CGAJ GMB120 Endocarditis & 440/- Sev WD RECOVERING (see narrative after Infective table) aneurysm Source: ADAE SUR datasets. NA=Not applicable= occurred during post-treatment follow up. WD= withdrawn. Mod= moderate. Sev= severe.

Individually each of these cases appeared unrelated to GMB. The case of endocarditis is described in more detail below.

CGAJ- (b) (6) . 33 F presented intracranial mycotic aneurysm secondary to aortic valve endocarditis with subarachnoid hemorrhage in the uncontrolled study. These events occurred 122 days after the last (12th) dose of GMB120 mg, when the patient had severe headache and numbness of the right hand. Apparently, she had undetected aortic insufficiency of unknown etiology, which increases the risk of endocarditis. She did not have any recent dental procedure and was not known to be immunocompromised (e.g. diabetes, immunosuppressors). Blood cultures were negative. She was treated with antibiotics and surgical clipping, and was discharged from the hospital. At the time of the SUR, the event was resolving. The event of mycotic aneurysm appears unrelated to GMB. Metabolism and nutritional disorders SOC

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CGAI- (b) (6) on GMB240mg during the placebo-controlled period. SAE hypokalemia and nephrolithiasis. 41 M with history of HTN, recurrent nasal congestion and irritable bowel syndrome. Started GMB240 on (b) (6) Concomitant meds included hydrochlorothiazide (HCTZ), fluticasone, and pantoprazole. HCTZ was started 2 months prior to entry; its dose was increased 5 ½ weeks into the study. The patient experienced influenza like illness of mild severity from (b) (6) , treated with ibuprofen and paracetamol. Approximately 2 months into treatment he experienced a renal colic lasting for several hours, treated with diclofenac. He was hospitalized with kidney stones and hypokalemia (K= 2.8 mmol/L, reference 3.3-4.7), treated with hydration and analgesics. The stone was excreted and he was discharged after 3 days. Hypokalemia was thought to be related to HCTZ. The patient completed the DB study on (b) (6) (Day 86) and entered the OL phase. On Day 86, BUN and creatinine were mildly elevated but at the following visit were normal. Event of hypokalemia appears related to HCTZ and nephrolithiasis may have been related to dehydration. The HCTZ dose increase, suggests he had worsened HTN but this was not reported as an AE.

CGAI-(b) (6) on GMB240. SAE Diabetic Ketoacidosis during the open label period. 24 F, DB started (b) (6) . OL started (b) (6) . DKA occurred on (b) (6) , 89 days after starting open-label treatment with galcanezumab and 5 days after the 4th open-label dose. Pre-existing conditions included type 1 diabetes mellitus for 10 years, with episodes of hypoglycemia and DKA in (b) (6) Concomitant meds included insulin. The patient’s fasting serum glucose at screening (Visit 1) was high at 267 mg/dL (reference range: 70-101 mg/dL). On (b) (6) (Visit 3), the patient’s serum glucose was normal at 110 mg/dL and on (b) (6) (Visit 7), the patient’s serum glucose was low at 56 mg/dL. Hemoglobin A1c was high at baseline and subsequent visits (ranging from 6.6% to 7.3%[reference range: 0-6.4%]). The patient was discharged on (b) (6) No laboratory details were available during hospitalization. The event was considered not related to GMB. I agree, an isolated event of DKA in a patient with known DM that is not well controlled is likely not related to GMB.

Neoplasm benign, malignant and unspecified

Seven neoplasms occurred in the placebo-controlled studies including 5 malignant neoplasms and 2 uterine leiomyomas, all on GMB120. No neoplasms were reported on placebo or GMB240. Four additional SAE were reported in the OL period of GCAI and CGAJ. The cases are listed below.

Age Rel ID Sex PT Day Comment Placebo controlled trials (b) (6) CGAG 63F Tubular breast carcinoma 29 Drug WD CGAH 38F of the cervix 185 Drug WD

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Drug WD upon diagnosis, after 332

(b) (6) days of treatment. Lesion was present CGAI 43F Malignant nipple neoplasm 12 since day 12* CGAI 53F Colon cancer 31 None CGA 40F Uterine leiomyoma 236 None (hysterectomy, during FU) CGA 63M Tonsil cancer 246 None CGA 30F Uterine leiomyoma 238 None Open label

(b) (6) none (started with cough 42 days after CGAJ 48F Lung neoplasm malignant 337 the 12th and last dose) none (On GMB240) CGAI 61M neoplasm malignant 134 CGAI 41M Squamous cell carcinoma 190 Drug WD CGAJ 55M Malignant melanoma 359 not applicable (during FU) Source: ADAE datasets SUR. *GMB120 in controlled phase and 240 in OL phase.

Eleven SAE of neoplasm occurred in 4M/7F ages 40 to 63 years. All but 1 of the 11 cases occurred in patients receiving GMB120 modal dose. The lack of cases at the highest dose and the early onset for most cases (<1year) support that they are not drug related.

Nervous system disorders

One SAE of seizure occurred in the PC period, and 2 in the OL period as follows.

CGAH (b) (6) . 21 F with medical hx of depression and panic attacks presented tonic-clonic seizure on the day of the first dose of GMB 240 (b) (6) in the PC period. Concomitant meds included and APAP. Vital signs before the first injection were BP 110/76, pulse 90 bmp. After the second injection on the first day, she presented sweating, light-headedness and fainted, with possible vasovagal syncope, followed by tonic-clonic seizure for 30 seconds with no incontinence, followed by postictal state. Supine BP was 112/75, pulse 102. Taken to the ER, the event resolved on the same day. She continued in the trial without further seizures. She developed depression. Six months after the first dose she had stress induced panic attack and was hospitalized for 3 days. She completed the follow up period. The investigator considered the events not related to drug. There is insufficient information to confirm that she had a seizure vs. a seizure-like activity related to vasovagal syncope.

CGAI- (b) (6) 38 F with SAE of seizure during the OL phase on GMB240, leading to drug discontinuation. She had a medical history of seizure (pseudoseizures and generalized tonic- clonic seizures but had been seizure free for 11 months prior to the first dose of GMB), allergy to insect sting and hypersensitivity to diazepam. She presented non-SAEs of fatigue and injection site reactions with of most doses; swelling of hands (reported as “potential hypersensitivity”) 12 days after the first dose, lasting 52 days; and sneezing and cough 1-2 days after the 6th and 7th doses, associated with fever, myalgia and nasal congestion. Two weeks

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after the 7th dose she presented bronchitis, treated with azithromycin, which resolved after a few days. On the day of the 9th dose of GMB one hour after the dose, she experienced flu-like symptoms, cough, fever nausea, bad taste in her and migraine. On the same day approximately 8 hours after dosing, she had a seizure. It was not witnessed; the patient was unconscious and woke on her own. She stated that all the symptoms she previously had, disappeared after the seizure. The following day she started topiramate treatment. Two weeks after the last dose she experienced a non-SAE of dyspnea of moderate severity, associated with chest pain, dizziness, nausea and decreased appetite, and cognitive impairment. She was seen in the ER with chest pain/tightness, radiated to the right shoulder, intermittently for several hours, worse with a deep breath. ECG was normal. There is no mention of blood pressure values. Cognitive impairment resolved after 5 days. The event of dyspnea lasted 64 days. She completed the post-treatment follow up without additional AEs. The investigator attributed the seizure and potential hypersensitivity to study drug. Lilly stated that there is insufficient evidence that the seizure was related to GMB. In summary, this 38 year-old female presented injection site reactions and episodes suggesting hypersensitivity (cough, sneezing, flu-like symptoms, fatigue) 1-2 days after most injections of GMB 240. On the day of the 9th dose, 8 hours after dosing she had a seizure with loss of consciousness. She had a history of seizures but had been seizure- free for 1 and ½ years. Two weeks after the last dose the patient developed unspecified chest pain/tightness and dyspnea, that resolved after 2 months. In isolation, it is difficult to attribute the seizure to GMB but the seizure seems to be part of a complex hypersensitivity reaction. There is limited information as to the workup done for the chest pain and dyspnea. The constellation of symptoms is consistent with an anaphylactic-type reaction but does not fulfill criteria for classic anaphylaxis because not all of them occurred within hours. In my opinion, a relationship to GMB is possible for all these events.

CGAI (b) (6) on GMB120mg in the OL period. SAE of seizure, motor vehicle accident, occipital laceration. 30 F, DB GMB120 started (b) (6) , OL started (b) (6) . Medical history included non-epileptic psychogenic seizures since (b) (6) , and post-traumatic stress disorder. Concomitant meds included for seasonal allergies. The patient had a seizure while driving, lost consciousness and hit a tree, 7 days after starting the OL phase (Day 89, 4th dose of GMB 120 mg). There were no witnesses. She denied emotional stress, sleep deprivation, alcohol use, recreational drug use, fever, change in diet, headache, or other possible triggers for seizure. A CT of the brain, spine, abdomen and pelvis, as well as chest x- rays were reported as normal without acute injury. Labs were normal. Toxicology screen was negative. The patient was treated with and while in the hospital. Topiramate was started on (b) (6) led to study discontinuation because of “protocol violation” (use of prohibited med). The investigator considered “worsening seizure” not related to drug. This patient had a history of “psychogenic seizure” but it is unclear how this diagnosis was made, how often he had this type of seizures and when was her last seizure before

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starting GMB. Given that this is the second case of seizure in this database, I would consider the possibility that GMB may have played a role in this seizure. Additionally, there were 2 non-SAE of seizure that in my opinion should be categorized as SAE because they are important medical events, one in the DB and one in the OL periods, as follows.

CGAG- (b) (6) on GMB 240. 52F SAE of tonic-clonic seizure, on day 63 of the study, 8 days after the 3rd dose in the PC period. Medical history included head injury (>15 years prior), depression, hypertension, COPD, spinal stenosis and “white matter lesion in both frontal lobes.” Concomitant meds included amlodipine, , paroxetine and telmisartan. Two episodes of seizure occurred and resolved the same day. The patient reported heavy alcohol consumption prior to the seizures. CT of head did not identify significant changes. GMB was not discontinued. She completed the DB study and entered the post-treatment period. The investigator considered the seizure not related to drug. The event is confounded by use of bupropion, and alcohol. Individually, it does not appear to be drug related but I would not rule out an association.

CGAI- (b) (6) on GMB240. 30 F with a history of febrile convulsion 16 years prior, had a febrile seizure of moderate severity along with fever of 102-103 F, on Day 209 of GMB treatment (25 days after the 4th dose of GMB), during the OL period. The seizure resolved on the same day. The following day she was diagnosed with streptococcal pharyngitis. Patient had a history of prior febrile seizure, but was seizure free for 16 years. Individually it does not appear to be related to GMB but I would not rule out an association.

There were 3 SAE of seizure with GMB (one in the DB, 2 in the OL period), including one after the first GMB dose and one 8 hours after the 4th dose. One of them was not confirmed (it could have been vasovagal syncope); one of them occurred in a patient with a prior history of psychogenic seizures. Additionally, 2 non-SAE of seizures were reported with GMB. And one SAE of seizure was reported in a patient receiving placebo in one of the phase 2 studies (study CGAB).

Other SAE in Neurologic system disorders SOC in more than one patient was migraine. Three patients presented SAE of migraine, one in the placebo-controlled period, and 2 in the open label period (CGAJ- (b) (6) , CGAI- (b) (6) and CGAI- (b) (6) ). Two occurred after 3 doses of GMB240 and 1 after 8 doses of GMB240. All improved after 5-7 days hospitalization and treatment with analgesic and corticosteroid. These cases represent lack of efficacy and do not appear causally related to GMB.

Pregnancy, puerperium and procedural complications

CGAG- (b) (6) . On GMB 240 in the PC period. SAE Missed abortion. 22 F, presented missed abortion on Day 69 of GMB treatment, 30 days after the 2nd dose. Prior medical history

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included spontaneous abortion 3 and 5 years prior. Current conditions included anxiety and dysfunctional bleeding. She admitted to smoking 10 cigarettes daily. On (b) (6) a pregnancy test was negative; On (b) (6) she had positive HCG testing. She had been bleeding for 2 weeks prior to positive testing. A transvaginal ultrasound on (b) (6) showed abnormal embryo consistent with embryonic demise and abortion in progress. The GCRP family of peptides including CGRP play a role in trophoblast implantation, proliferation and fetal organogenesis. CGRP inhibition could interfere with normal trophoblast/placental development. The patient had risk factors (prior abortions, smoking) but the role of GMB cannot be ruled out.

CGAG- (b) (6) (GMB 120) –24 F presented a SAE of pre-eclampsia on Day 382 after initiation of GMB, 102 days after completing the in the PC trial post-treatment period. The patient also presented SAEs of incarcerated incisional hernia and seroma 50 and 104 days after starting GMB treatment respectively. Last dose of GMB was given in (b) (6) . A pregnancy test was positive in (b) (6) . As per the SUR, on (b) (6) she was hospitalized with pre- eclampsia. She underwent a C-section and delivered a premature male infant without complications. The narrative shows diastolic BP values of 71-95 mmHg during the study up to (b) (6) . There are no values for SBP in the original narrative or any BP value after (b) (6)

CGRP is reported to have a role in the regulation of placental pathophysiology, but a causal relationship between pre-eclampsia and GMB in this case is unlikely because it occurred 8 months after the last dose of GMB.

Psychiatric disorders SOC The following SAE occurred during the placebo-controlled studies CGAG- (b) (6) on GMB240mg. SAE: Adjustment disorder with mixed anxiety and depressed mood on Day 238 of treatment, 84 days after the last dose. She was also diagnosed with borderline personality disorder. The patient reported suicidal thoughts in the CSSRS at month 8, (3.5 months after the last dose), and not suicidal thoughts at month 10. CGAH (b) (6) on GMB240. SAE Panic attack and seizure, summarized above. CGAH (b) (6) on GMB240. SAE of Post-traumatic stress disorder. 37 F, PTSD on day 301 of GMB treatment, 149 days after the sixth dose after someone broke into her house. Medical history included neurocardiogenic syncope, mitral valve prolapse and general anxiety. She completed the post-treatment follow up and at the last visit she reported she had suicidal ideation and thoughts, and a failed suicidal attempt. Because of the prior history of anxiety and more than 5 half-lives after the last dose, the events appear unrelated to GMB. CGAH-(b) (6) on GMB240. SAE Disorientation. 55 M, presented disorientation along with pyrexia, discussed in the General disorders SOC section. Additionally, a SAE of suicidal ideation occurred in the PC trials at the GMB 300mg dose. CGAB- (b) (6) was a 51 F who discontinued from the trial because of protocol violation (use of excluded medication during treatment phase). She received only one dose of GMB300 on (b) (6) . Approximately 3 weeks later, she was hospitalized with suicidal ideation. She had a

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prior history of major depression and suicide attempts. The event does not appear related to GMB.

The following SAE occurred during the Open label period: CGAI- (b) (6) onGMB240. SAE of Confusional state. 54 F experienced a transient confusional episode while engaging in intense physical activity, 11 days after the first dose of GMB in the OL phase (she had received placebo in the DB phase). The event lasted 30 minutes. At the ER, no abnormalities were found. She also had 2 non-SAE of injection site hypersensitivity and rash. Treatment was still ongoing at the time of the data cutoff for the original submission.

In summary, SAE in the Psychiatric SOC, included 2 patients with suicidal thoughts in the PC period (3 weeks and 3.5 months after the last dose of GMB, likely unrelate to drug). There was also one suicide attempt on placebo. One patient presented disorientation probably related to fever and infection, and one presented a brief confusional episode while exercising. These events do not appear related to GMB.

Respiratory, thoracic and mediastinal disorders

There were 2 cases of pulmonary embolism (PE) in the placebo-controlled studies. One of them was on placebo. The other (on GMB240) was described earlier along with SAE of CV and vascular events. One SAE of dyspnea and one of hemoptysis were reported in the OL phase, as follows.

CGAI (b) (6) on GMB240. Dyspnea. 45 M. The patient received placebo in the PC period. On Day 88 of GMB treatment 11 days after the 4th dose he presented severe dyspnea and dizziness during physical therapy. Medical history included “chronic chest discomfort” and tobacco use. Ongoing pre-existent conditions included bronchitis, cough, sleep apnea and 3 weeks of moderate exertional dyspnea and seasonal allergies. Chest X-Ray and ECG were normal. He was discharged from the hospital on the same day. As per the SUR, dyspnea did not resolve and at visit 12, 29 days after the 5th dose of GMB, he presented worsening dyspnea along with ALT and AST elevation 3xULN and CK of 12549 U/L (normal up to 308 U/L), leading to treatment discontinuation. Apparently, he had a pre-existent condition of hepatic steatosis and had recently used an amino acid dietary supplement with testosterone, diclofenac and ibuprofen. As per the narrative, 3 weeks after stopping dietary supplements, AST and CK values were normal, and ALT was still elevated <2xULN. Both the increase in CK and liver enzymes could be explained by dietary supplements. Apparently, the patient had a pre-existent condition of chest discomfort, dyspnea and hepatic steatosis before starting the OL period, in which case, the events of dyspnea and liver enzyme elevation are not related to GMB.

CGAI (b) (6) on GMB240. Hemoptysis. 61 M, presented hemoptysis and swollen face (left side “lump”) in association with tongue malignant neoplasm, 51 days after starting GMB

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treatment (22 days after the second GMB dose). He had received placebo in the PC period. The event of hemoptysis does not appear related to GMB.

Skin and subcutaneous tissues disorders

There were no SAE in this SOC in the placebo-controlled trials. Two SAE of urticaria were reported in the OL period of CGAI as follows.

CGAI-(b) (6) on GMB240. SAE urticaria. 51 F. Presented generalized a SAE of urticaria of moderate severity 54 days after the 5TH dose of GMB (3 in PC period and 2 in OL period). She had a history of Rheumatoid arthritis. She discontinued GMB on Jan 3, 2016 because of protocol deviation (insufficient washout of prohibited migraine preventive medication). She was treated with ciprofloxacin for urinary tract infection from (b) (6) , and with norfloxacin for keratitis from (b) (6) he had generalized urticaria, which got worse on (b) (6) requiring hospitalization and prednisolone treatment. At the time of hospital discharge the event was improved but not resolved. The investigator considered the event of urticaria as not related to drug. I believe the event is confounded by recent use of antibiotics but would not rule out a relationship to GMB.

CGAI- (b) (6) on GMB240. SAE urticaria (led to DC). 41 F presented SAE of severe urticaria 38 days after starting the OL treatment, 6 days after the 5th GMB dose. She received GMB240 in the DB period, and GMB120 in the OL period. Preexisting conditions included asthma, allergic rhinitis, drug hypersensitivity to , metronidazole, sulfa and penicillin. On (b) (6) she went to the ER and treated with and methylprednisolone followed by oral prednisone. On (b) (6) she was worse, requiring treatment with epinephrine and diphenhydramine. She had no prior exposure to biologics and did not have any food allergies. A skin biopsy was done. Event lasted 24 days and resolved on (b) (6) she had mild eye swelling. She did not continue treatment and had a short post-treatment follow up because of conflicting schedules. The sponsor states there is insufficient evidence to support a relationship to drug. I believe there is a possible association.

In summary, evaluation of SAE did not identify significant safety issues with GMB. The overall risk of SAE was 2.3% on GMB 120+240, and 1.3% on placebo. There was no dose response between GMB 120 and 240. The most common SAE were in the Neoplasms SOC and the GI SOC. All but 1 of the SAE of neoplasm occurred in the GMB 120 treatment group. There were 2 cases of pancreatitis among GMB treated patients (one in each group) but there is limited information about the cases and a relationship is unclear; there was 1 SAE of alcoholic pancreatitis on placebo. There was no imbalance in the percentage of cardiovascular SAE events as compared to placebo. There were no reported SAE of hypertension in the database, but hypertension is mentioned in the

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Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Lilly’s Table identified 8 AE that are not flagged as leading to WD in the SUR datasets (tongue discomfort, malaise, non-cardiac chest pain, viral upper respiratory infection, gastroenteritis viral infection, infection, and spinal osteoarthritis), while I identified 14 AE flagged as leading to WD, not included in Lilly’s table (autoimmune thyroiditis, eye pruritus, ocular hyperemia, chest pain, fatigue, CPK increased, AST increased, cognitive disorder, TIA, agitation, mental fatigue, pulmonary mass, pruritus and abortion induced). Some of the events I identified, occurred in a patient with another AE causing WD (e.g. (b) (6) patient CGAI_ was WD because of ALT elevation but the datasets also include AST elevation, CPK elevation and worsening dyspnea as causing withdrawal). The narrative for the patient with a SAE of TIA states that the reason for discontinuation was “physician decision.” And the narrative for a patient with fatigue, pruritus and possible hypersensitivity is listed as “WD by subject” (concerned about study procedures).” Overall, the discrepancies are minor and do not change the conclusions.

Selected narratives for patients with AE that led to DC and were non-SAE on GMB 120 or 240 mg during the double blind or open label studies are presented below.

Cardiac and vascular disorders SOC

The following AE was reported in the General disorders SOC, but I believe that it may potentially be cardiac pain.

CGAH- (b) (6) GMB240. In the PC trial. Chest tightness/discomfort. 37 F started treatment (b) (6) . Stopped (b) (6) . Pt presented non-SAE of chest tightness on Day 90 of GMB treatment, 6 days after the 4th dose. Preexisting conditions were GERD, drug hypersensitivity with and penicillin, and HTN. Concomitant meds were HCTZ, ibuprofen, sumatriptan omeprazole and prednisone (for urticaria preceding study treatment). She was obese. BP at baseline was 136/98, HR55. Between baseline and visit 8 (b) (6) her SBP ranged from 120-141 and DBP 81 – 98 mmHg. At visit 8 her weight had increased >7% from baseline; BP was 141/92. ECG showed prolonged QT >30 msec as compared to baseline. Corrected QTc was 444 msec. The AE of chest discomfort was ongoing at the time of discontinuation of treatment. The investigator considered the AE not related to drug, but the patient did not have a cardiologic evaluation. An obese patient with history of HTN presented chest tightness starting 6 days after the 4th dose. She discontinued from the study without apparent cardiologic workup. At the time of discontinuation, the discomfort had not resolved and there is no available follow up. As per 4/16/18 response, workup, corrective treatment and other associated events were not reported. I believe this chest tightness/discomfort could be angina pectoris.

Ear and labyrinth disorders CGAJ- (b) (6) . On GMB240. Uncontrolled study.

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47 F with history of hypersensitivity to penicillin and sulfa drugs, received GMB on Days 1, 29, 57, 89 and 121. On Day 122 of the study, the day after the 5th dose of GMB she presented that led to drug discontinuation. On day 123 she had an injection site rash/pain. The patient had 2 prior episodes of vertigo, one on Day 18, that resolved the same day, and one on Days 89 to 92. The event of rash was treated with diphenhydramine and resolved on Day 134. BP on Day 89 was normal. BP on Day 122 is not available. She completed the post-treatment FU. This patient had 3 episodes of vertigo. The first was 18 days after the first dose, the second on the day of the 4th dose, and the 3rd the day after the 5th dose. Vital sign values at the time of the third episode are not available. Analyses of all AEs (serious and non- SAE) suggest an increased in vertigo on GMB as compared to placebo. Vertigo in this patient may have been related to drug.

Endocrine disorders CGAI (b) (6) . GMB240. Autoimmune thyroiditis in OL period. 21F with a history of goiter and seasonal allergies, presented injection site reaction characterized by erythema and pain the day after the 7th dose of GMB, and on the same day of the 8th dose of GMB (Days 183 and 211 of treatment). She received 3 more doses without reported site reaction (Dose 11th on Day 308 of study). Concomitant meds included , oral contraceptives and naproxen. As per the SUR, the patient withdrew because of “patient-concerned thyroid issue” (categorized as “withdrawal by subject”). She was diagnosed with autoimmune thyroiditis on Day 312 of the study. It is unclear whether the patient had any symptoms. Laboratory values were within normal. ECG at baseline was normal. ECG at Visit 7 (end of placebo-controlled phase) showed left atrial abnormality and non-specific T wave changes. ECG at Visit 10 (day of 7th dose) and Visit 15 (a month after last dose), ECG showed same findings from Visit 7 and poor R wave progression. This patient was diagnosed with autoimmune thyroiditis. There is no information about the symptoms or laboratory data that let to that diagnosis.

Eye disorders CGAJ- (b) (6) GMB240 (uncontrolled study). Eye pruritus, ocular hyperemia associated with rash and hypersensitivity, 16 days after the 4th dose of GMB.

Gastrointestinal disorders Ten patients presented GI symptoms leading to drug discontinuation, including 4 during the DB phase and 6 during the open label/non-placebo phase. The events were abdominal pain/tenderness/ distension (n=4), nausea (n=3), gastritis, dyspepsia, diarrhea, acute pancreatitis and Crohn’s disease. Except for the case of pancreatitis (described in the SAE section), all were non-SAE. Three were severe (nausea, gastritis and acute pancreatitis). The onset ranged from Day 3 to Day 318. One had nausea, diarrhea and abdominal pain lasting for 1 week. Except for one case of nausea and one dyspepsia listed as outcome not recovered, all resolved after 1 to 111 days. Cases are listed below.

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Relative day ID Dose PT Onset / End Action Outcome Placebo-controlled (b) (6) CGAG GMB240 Dyspepsia 3 85 Led to study WD NR CGAG GMB120 Abdom. distension 54 116 Drug WD R CGAH GMB120 Gastritis 35 119 Led to study WD R CGAI- GMB240 Pancreatitis acute 5 116 Drug WD R Open label CGAI and CGAJ Nausea, diarrhea, abdominal pain (also (b) (6) CGAJ GMB120 lethargy) 141 148 Drug WD R CGAI GMB240 Nausea 86 203 Drug WD NR CGAI GMB120 Abdom. pain lower 182 195 Drug WD R CGAI GMB120 Crohn's disease 318 348 Drug WD R CGAI GMB240 Abdom. tenderness 303 303 Led to study WD R CGAI GMB240 Nausea 251 314 Drug WD R Source: SUR ADAM dataset. WD= withdrawal. R=resolved. NR= did not resolve.

GI symptoms could potentially be associated to CGRP inhibition. A relationship to study drug is possible, although individually most do not appear drug related and there was no difference with placebo in the rate of GI AE leading to DC in placebo-controlled trials.

A non-SAE of “tongue discomfort” was reported in the OL period as follows. CGAJ- (b) (6) (GMB 240) 56 F. Tongue discomfort, on Days 75 to 203 in association with hypertrophy of tongue papillae. Started 7 days after the 3rd dose. The patient withdrew consent. The event resolved without specific treatment. Other than the tongue discomfort she had injection site pain/burning. The event to tongue discomfort does not appear related to drug.

General disorders

Fourteen patients discontinued because of injection site reactions, as follows (6 in the PC and 8 from the open label period of CGAI and in study CGAJ (with not placebo), as listed below.

Relative day Out PT Onset / End come Placebo-controlled (b) (6) CGAG 27 M GMB240 Injection site reaction 92 93 Mod R CGAG 36 F GMB240 Injection site swelling 120 122 Mod R CGAH 46 F GMB240 Injection site reaction 58 79 Mod R CGAH 56 F GMB240 Injection site reaction 121 130 Mod R CGAG 46 F GMB120 Injection site erythema 30 44 Sev R CGAH 27 F MB120 Injection site reaction 60 120 Mod R

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Open label CGAI and CGAJ (b) (6) CGAJ 47 F GMB240 Injection site rash 123 134 Mod R CGAJ 27 F GMB240 Injection site reaction 261 264 Mod R Injection site erythema, CGAJ 41 F GMB120 pruritus and pain 150 155 Mod R CGAJ 28 F GMB120 Injection site reaction 272 279 Sev R CGAJ 27 M GMB120 Injection site reaction 183 199 Mod R CGAI 35 F GMB240 Injection site pruritus 181 186 Mod R CGAI 51 F GMB240 Injection site erythema 169 190 Mod R CGAI 45 F GMB120 Injection site reaction 117 131 Mod R Source: SUR ADAM dataset. WD= withdrawal. R=resolved. Mod= moderate. Sev= severe.

None of the injection site reactions was a SAE. Most were moderate or severe, and occurred on the day of or the day after the 2nd or 3rd doses (none after the first dose). Some occurred with more than one dose, on at more than one site, and/or associated with other local reaction. For instance, CGAH- (b) (6) had multiple injection site reactions after the 3rd, 4th and 5th dose associated with itching and local rash, non-SAE, not leading to WD, until day 120. All events resolved with no or minimal intervention. There were no discontinuations because of injection reactions on placebo.

Other than injection site reactions, events that occurred led to treatment discontinuation from The General disorders SOC are listed below.

Relative day Out Age/Sex Dose PT Onset / End come Placebo-controlled (b) (6) CGAH 37 F GMB240 Influenza like illness 61 64 Sev R Fatigue (also hypersensitivity and CGAG 27 F GMB240 confusional state) 2 4 Sev R CGAH 55 M GMB240 Pyrexia 100 102 Sev R CGAG 58 F GMB120 Peripheral swelling 65 78 Mod NR Chest discomfort CGAH 37 F GMB240 (tightness) 90 113 Mod NR Open label CGAI and CGAJ (b) (6) CGAJ 35 F GMB120 Pain 141 148 Mod R CGAI- 52 F GMB240 Malaise 85 113 Mod R CGAI- 31 F GMB240 Peripheral swelling 264 278 Mod R CGAI- 38 F GMB240 Chest pain (unspecific) 251 314 Mod R Source: ADAE SUR dataset.

Three patients presented general symptoms (influenza-like illness, fatigue and malaise), leading to drug discontinuation within the first 3 months of treatment. Two patients were coded as

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having “peripheral swelling”; in one case code was inappropriate, because it referred to joint swelling of psoriatic arthritis (described below, with the musculoskeletal disorders).

As per the AE datasets, two patients withdrew from the study because of chest-related symptoms. One was Chest discomfort/tightness (CGAH- (b) (6) , discussed in the Cardiac SOC); the other was chest pain and dyspnea two months after an episode of seizure (CGAI- (b) (6) consistent with a hypersensitivity reaction, discussed in the SAE section of this review). There are several cases of chest pain that were non-SAE and did not lead to study discontinuation in this application. (See section on Significant AEs 8.4.4.)

Additionally, patient CGAJ- (b) (6) discontinued treatment because of “pain” (generalized body aches) discussed under the Immune system disorders SOC, because of a possible hypersensitivity reaction. The only SAE leading to drug DC in the General disorders SOC was pyrexia (in a patient who also had a SAE of skin ulcers).

Immune disorders SOC One case of hypersensitivity and one of dyspnea (in the Respiratory, thoracic and mediastinal disorders SOC, but consistent with drug hypersensitivity), led to drug DC from the PC trials. A case of Type IV hypersensitivity and one of dyspnea consistent with hypersensitivity led to WD in the OL period of CGAI. Cases are summarized below.

CGAG- (b) (6) GMB240mg in PC trial. Hypersensitivity. 27 F started DB GMB on (b) (6) stopped on (b) (6) . She presented severe, non-SAE of rash on extremities and groin, and pruritus 2 days after starting GMB treatment; 2 days later she experienced a severe “possible allergic reaction” coded as “hypersensitivity” but there is no description of what the evented consists of. She also had agitation, fatigue and confusional state up to Day 4. Preexisting conditions included seasonal allergy and PTSD and allergy to . She was treated with diphenhydramine and . Pruritus lasted 3 days, “hypersensitivity” lasted 2 days. The narrative includes a few BP measurements. An average diastolic BP increased from 101 mmHg at baseline to 114 mmHg 2 weeks later. On (b) (6) (visit 13) she discontinued from the study because of “withdrawal by subject” (concerns with study procedures/perceived risks). The investigator considered the events to be not related to drug. The patient appears to have had a hypersensitivity reaction associated with confusional state starting 2 days after the first dose of GMB, but the exact nature of the reaction is not well described. BP values at the time of the event of hypersensitivity were not provided. Apparently, she did not require corticosteroid treatment. She appears to have had an increase in diastolic BP, but full BP values are not included.

CGAI- (b) (6) . On GMB240, open label period. Patient presented a “Type IV hypersensitivity reaction” on Day 199 to 204 of the trial. The patient had received placebo during the double- blind phase of the study. There is very limited information about the case. Apparently, she did not require corticosteroid treatment.

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The following AE of dyspnea are consistent with hypersensitivity reactions

CGAG- (b) (6) (GMB240) Shortness of breath/Dyspnea in PC trial. 27 M started DB on (b) (6) . He had a prior history of asthma and seasonal allergy and had presented injection site pain with the first 2 doses, but not rash. He was not receiving treatment for asthma. He developed injection site reaction on both arms on (b) (6) , 62 days after starting treatment, associated with itching and rash, and resolving on the same day. On Day 92, after the 4th dose, he again had bilateral injection site reaction of moderate intensity, along with shortness of breath. He discontinued treatment because of dyspnea that improved on the same day, after treatment with diphenhydramine.

CGAI-(b) (6) (GMB 240). 32 M discontinued because of non-SAE of dyspnea in OL trial. He received placebo in DB phase. On the day 92 of the study, on the day of the 4th dose of GMB he presented dyspnea along with skin rash of moderate intensity. Ongoing pre-existing conditions included anxiety, urticaria and allergic rhinitis. He had a history of an “unspecified immune system disorder” five years prior to study entry and as well as allergy to aspirin and ibuprofen. WBC was normal at baseline but slightly low at the visit prior to entering the OL study. As per the site, dyspnea was likely related to anxiety, and the location of the rash was in the face and upper trunk. He was treated with chlorpheniramine and IV fluids. Dyspnea resolved the same day; rash lasted 3 days. In my opinion, these two cases of dyspnea associated with skin rashes in patients with a prior history of allergies are consistent with a mild hypersensitivity reaction.

Additionally, CGAJ (b) (6) , a 35 F on GMB 120, discontinued treatment because of “pain” (generalized body aches coded to the General disorders SOC) and “lethargy.” As per the narrative, the patient had several reports of injection site reaction/erythema/pruritus/ induration during the study. Pre-existing ongoing conditions included asthma, drug hypersensitivity (penicillin), latex allergy and seasonal allergy. Medications received during the study included pseudoephedrine, cetirizine, fluticasone and loratadine. She received GMB on Days 1, 30, 58, 85, 112 and 140. In (b) (6) , Day 141 of GMB treatment the patient presented injection site reaction/erythema/pruritus, abdominal pain, diarrhea, nausea, body pain and lethargy, the day after the 6th dose. This was the 3rd episode of lethargy, leading to drug discontinuation. The event lasted 8 days. She discontinued treatment in (b) (6) (visit 9) and completed the post treatment fu on (b) (6) (visit 17). The investigator considered the episode of lethargy related to drug. In my opinion, the clinical picture is consistent with a hypersensitivity reaction or some type of immunologic reaction to GMB, in a patient with a history of drug allergies and asthma. There is no information on vital signs on Day 141 when she presented injection site reaction, lethargy and GI symptoms. In the absence blood pressure data, an event of anaphylaxis cannot be ruled out.

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Of note Lilly’s search of potential hypersensitivity AE included the latter 3 cases. Upon medical review Lilly concluded that the first 2 (dyspnea) were likely hypersensitivity, but the 3rd was not because it involved several unspecific terms.

Infections and infestations SOC Two patients discontinued GMB because of non-SAE of infections (a common cold and an “infection” both on GMB240). The “infection” is presented below.

CGAH- (b) (6) GMB240 Infection. 43 M had non-SAE of nasopharyngitis, on Day 41, 10 days after second dose. And a second event of infection was reported on Day 161, 17 days after the 6th dose. The event was coded as “infection” and led to drug discontinuation. The patient had a fall and leg wound, that became infected. The wound and infection resolved after 29 days. The event does not appear related to GMB. This should have been coded as wound infection.

Investigations SOC

Seven GMB-treated patients had AE that led to study WD, including 4 in the placebo-controlled period. PT Relative day ID Dose Onset/ End Outcome Placebo-controlled Hepatic enzyme increased. ALT x5ULN, AST 2xULN, on day of 4th dose. Concomitant med: ketorolac (b) (6) CGAH 36 F GMB240 (suspected culprit). 86 191 R Hepatic enzyme and CK increased. CGAI- 36 M GMB240 (See narrative below) 64 190 R CGAG 49 F GMB120 Weight increased 54 209 NR CGAI- 20 F GMB120 Weight increased 31 139 NR CGAI OL (b) (6) ALT & AST increased. CK also CGAI- 37 F GMB120 increased. See narrative. 203 280 NR ALT, AST, CK increased. Full CGAI- 45 M GMB240 narrative in SAE section (Dyspnea) 239 253 R CGAI- 52 F GMB120 CT thorax abnormal 141 289 NR Source ADAE SUR datasets. R= Resolved. NR=did not resolve

CGAI- (b) (6) . Patient had ALT, AST and CK increased <2x ULN at screening. ALT and AST were normal at baseline (before dosing), and CK was mildly elevated (363 U/L (normal up to 308). At visit 6, 33 days after the second dose of GMB, the patient reported non-cardiac chest pain that began 3 days after the second dose. The patient decided to withdraw from the trial. Lab evaluations on that day showed ALT and AST 3xULN, and CK >10xULN (4128 U/L). After

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appropriate workup, an hepatologist diagnosed rhabdomyolysis related to high intensity sports. The patient was asymptomatic other than the non-cardiac chest pain. Concomitant medication was citalopram, for depression for many years. Liver enzyme elevation was reported as the reason for drug discontinuation. Investigator considered the event possibly related to GMB. At the last available measurement 4 months after the last dose, ALT and AST were normal; CK was still elevated (507 U/L) and creatinine was just above normal (1.3 mg/dL; normal up to 1.2). This is a case of liver enzyme and CK elevation in a patient with pre-existent elevated values and a negative hepatic workup, suggestive of rhabdomyolysis. In my opinion, increased liver enzymes and CK do not appear related to GMB. Rather than liver enzyme elevation, the reason for discontinuation appears to be non-cardiac chest pain.

CGAI- (b) (6) . At the end of DB (placebo) period had mild ALT elevation <2xULN. In (b) (6) , on day 203 of the study 14 days after 4th GMB dose, presented ALT and AST elevation (6x ULN and 3xULN, respectively). One month later, ALT and AST were still elevated leading to drug WD. BR, ALP and CK were normal. She was asymptomatic. Concomitant meds: medroxyprogesterone and diazepam. Prior med ciprofloxacin and fluconazole for urinary infection. Testing was negative for hepatitis A, B, C and E. ANA and F-actin ab negative at al times. Anti-smooth muscle (ASMA) ab was 1:20 in (b) (6) . CMV IgG was positive; CMV IgM was not collected. In (b) (6) , ALT & AST were improved but slightly above normal. CK was also slightly above normal. At time of the cutoff of the SUR, the event was not resolved and the patient was still in the follow up period of the study. The investigator considered the event not related to drug. This patient had slight ALT & AST elevation before starting GMB treatment, with increase up to 6xULN and 3xULN respectively, without increase in BR and ALP. She also presented slight elevation of CK. Liver workup was negative, except for a ASMA titer of 1:20 which is of undetermined value. Because her liver enzymes started to increase before starting GMB, I agree that they are unlikely related to GMB, but the reason for the increase remains unknown.

CGAI- (b) (6) . The events of liver enzyme and CK elevation appear related to dietary supplements. See discussion under SAE of dyspnea.

CGAI- (b) (6) . 52F. CT thorax abnormal led to drug DC on Day 56 of the OL treatment 27 days after the 5th dose of GMB 120 mg. Preexistent condition included seasonal allergies and tobacco use. She started GMB on (b) (6) . Non-SAE were herpes zoster (on day 42, treated with ), bronchitis (starting on day 49, treated with salbutamol, that did not resolve) and injection site reactions (on day 115, itching, hardening). On Day 140 she went to the ER with acute shortness of breath and chest pain. WBC was 13.7 x10^9 cells/L (normal up to 10.7 x10^9 cells/L) and glucose was 133 mg/dL (normal up to 101; she did not have a history of diabetes mellitus; glucose at baseline was normal). A CT scan showed a pulmonary mass. She was diagnosed with influenza and treated with oseltamivir. As of the cutoff of the original submission the pulmonary mass had not resolve and she was still in the post-treatment period.

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This narrative is insufficient to characterize what happened to the patient. She had chest congestion and bronchitis for 4 months, she went to the ER with acute dyspnea, was found to have a lung mass and was treated for influenza. As per additional information submitted on 5/9/18 the primary physician reviewed the CT scan and assessed the findings to likely be scar tissue because of chronic bronchitis but recommended the patient have a repeat scan in 6 months. The patient was lost to follow up.

CGAG-.(b) (6) 49 F. Started DB treatment with GMB 120 in (b) (6) Baseline weight and BMI were 55k and 22.5 kg/m2. In (b) (6) , 27 days after the second dose she had an AE of weight gain along with abdominal distension. The abdominal distension resolved on the same day. In (b) (6) (visit 7) she discontinued treatment because of increase in weight of 3.5 kg. She completed the post-treatment FU in (b) (6) (visit 14). The AE was still ongoing. On that day, glucose was slightly elevated (104 mg/dL, normal up to 101). Potassium was also elevated (5.7 mmol/L, normal up to 5.4). ECG was unchanged from baseline. CGRP is involved in the regulation of insulin secretion. In the absence of another explanation, an increase in weight of 3.5 kg over 2 months may be drug related. There is also a mild increase in glucose and potassium at the last visit. Ideally, these labs should have been repeated at least once.

CGAI- (b) (6) . 20F. Started GMB120 in (b) (6) . Discontinued treatment 3 days after the second dose of GMB. Pre-existing conditions included irritable bowel syndrome, depression and anxiety. Baseline weight and BMI were 67.1 kg and 26.3 kg/m2. Concomitant meds included oral contraceptive. She had recently stopped sertraline. She took prednisone for 5 days in (b) (6) , for worsening of migraine. An AE of weight gain was reported first in (b) (6) (weight not reported). On (b) (6) , 2 months after initiation of GMB treatment her weight was 80.2 kg (a gain of 23 kg, which represents 19.5% increase from baseline). There were no clinically relevant laboratory findings. The patient was subsequently lost to follow up during the post-treatment FU period. The patient took prednisone for a few days, and may have been depressed because of stopping sertraline but that does not explain a weight gain of 23 kg over 2 months. In my opinion this AE may be drug related.

Metabolic One patient discontinued because of hypokalemia in the OL phase of study CGAI, as follows. CGAI- (b) (6) . 52 F presented one instance of low potassium levels (3.2 mmol/L) during placebo treatment. During GMB120 treatment she had lower potassium levels (2.5mmol/L) at 2 and 3 months after starting treatment, leading to drug DC. Low potassium level preceded use of GMB.

Musculoskeletal and Skin disorders CGAG- (b) (6) GMB120mg in controlled study. Psoriatic arthritis. 58 F discontinued treatment because of peripheral swelling (verbatim: “swelling of left foot second toe of

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unknown etiology”) after the 3rd dose of GMB. She also had swelling of the right index finger and left hand digits. A rheumatologist diagnosed psoriatic arthritis based on a medical history of psoriasis. Investigator considered event possible related to drug. This is wrongly coded under General disorders and administration. The primary SOC is Musculoskeletal; alternative SOCs are Immune system disorders and Skin and subcutaneous tissue disorders. An isolated AE of psoriasis is unlikely related to drug.

Nervous system disorders Five patients discontinued from GMB treatment because of worsening migraine or headache in the placebo-controlled period of the studies, as compared to 4 on placebo. Four patients discontinued during the OL period. Eight of the 9 on GMB were females; the age was 19 to 59 years (mean 39.7 years). Only one was taking baseline prophylaxis. They were moderate to severe in intensity. Two were SEA (CGAI-(b) (6) and CGAJ- (b) (6) ). Of the patients in the PC period, the time to onset of migraine leading to WD was 17 days (3 to 39 days). Two did not resolve CGAG (b) (6) and CGAG- (b) (6) ). These cases appear to represent lack of efficacy rather than an adverse event.

Other non-SAE leading to DC from this SOC were dizziness (n=2), hemiparesis, hypoesthesia, and lethargy, as follows.

CGAI- (b) (6) . 31F presented dizziness described as “dizzy spells” from day 1 of the trial, until day 232 of GMB240 in the PC trial. Medical history included anemia. Ongoing conditions included anxiety and recurrent respiratory infections and irritable bowel syndrome. Per the site, dizziness was not postural and lasted for 4 days after the injection, but it was not reported by the patient until she decided to discontinue from the study, after 8 monthly injections. The AE of dizziness appears related to drug. There were no orthostatic measurements.

(b) (6) CGAI- 38F presented dizziness from Day 251 to 314 of GMB240 of GMB exposure; she also had cognitive impairment on Day 251 to 256. This patient also presented non-SAE of peripheral swelling of the hands, 3 episodes of injection site reaction/erythema/induration, bronchitis and a SAE of seizure 8 hours after dosing, consistent with a hypersensitivity reaction. Case was discussed in the SAE section of this review.

(b) (6) CGAI- 37F hemiparesis in the OL study, on GMB120. Presented nasopharyngitis during DB phase of the study. As per the SUR, she presented orthostatic hypotension on Day 215 of the OL treatment, 14 days after the 8th dose of GMB120. She discontinued the OL treatment because of non-SAE of right sided weakness of moderate severity that started 21 days after the 8th dose of GMB. Medical history included right sided numbness and iron deficiency. The patient was borderline obese (BMI 29.8 kg/m2); vital signs and ECG were normal. On (b) (6) she experienced orthostatic hypotension, hypovolemia, dizziness and confusional state of mild severity. She was hydrated and all the AE resolved on the same day. On (b) (6) she discontinued treatment because of hemiparesis.

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The etiology of these events is unknown. As per additional information submitted on 5/25/18, a CT scan and lab evaluations in the ER were within normal, except for anemia.

CGAI-(b) (6) As per SUR datasets, 36 F presented bilateral upper extremity pain and numbness (coded as hypoesthesia) in the OL phase of study CGAI, on Days 294 to 365 of the study. She had received placebo in the controlled phase. The events were non-serious, did not resolve and led to drug discontinuation. As per additional information submitted 5/9/18, she received prednisone for 5 days and saw a chiropractor. Subsequently, all symptoms resolved. The cause of this event is unclear. It does not appear related to GMB.

CGAJ- (b) (6) 35F lethargy in the uncontrolled study, discussed in page 58 of this review, consistent with a hypersensitivity/immunologic reaction.

Respiratory, thoracic and mediastinal disorders SOC

(b) (6) CGAH- on GMB120mg. Bronchiectasis. 45 F discontinued treatment because of non- SAE of bronchiectasis of moderate severity 9 days after starting treatment and 9 days since 4th dose. Pre-existent condition included alveolitis allergic, and seasonal allergy. Labs at 3rd and 4th month visits showed moderately increased neutrophil count. Patient discontinued the post- treatment period because “WD by subject”, concern with study procedures/perceived risks). The AE had not resolved at the last visit. Bronchiectasis does not appear related to drug.

Skin and subcutaneous tissue disorders Fifteen GMB-treated patients presented AE leading to drug or study WD in this SOC including 6 in the controlled phase of the studies. AE in the controlled phase included 5 allergic reactions (rash/pruritus and/or urticaria) and skins ulcers of unclear etiology on GMB, as compared to 1 case of alopecia and 1 of eczema on placebo. All but one were moderated to severe in intensity (one was mild). All but one were non-SAE, and all but one had resolved at the time of last follow up. Time to onset of these events was Day 1 to 184 of the study (although some patients had received placebo in the DB phase). Duration of the events was 1 day to 3 months. The SAE of skin ulcer (CGAH- (b) (6) ) was discussed in the SAE section of this review. Non-SAE leading to WD in this SOC are summarized below. In my opinion, they are all related to GMB.

Patients with non-SAE leading to drug or study withdrawal from Skin and SC tissue disorders SOC in galcanezumab database ID Age/ Dose PT Relative Comments Sex study day Onset/End Placebo-controlled

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CGAG- (b) (6) 27 F GMB240 Rash & 2 4 Severe. Also reported as Hypersensitivity. Also pruritus reported fatigue and confusional state (pg.61 of this review) ART01 (b) (6) 54 F GMB300 Rash 20 43 Moderate. Narrative not found. (b) (6) CGAG- (b) (6) 48 F GMB120 Rash 36 128 Mod. 8 days after 2nd dose. Also had “scalp and generalized ears psoriasis vulgaris” that started 4 days after the 2nd dose and lasted 3 months, treated with topical steroids. CGAH- (b) (6) 31 F GMB120 Rash 75 178 Mild rash started 2 days after 3rd dose. Hx of pruritic asthma and seasonal allergy. Concom meds: cetirizine, diphenhydramine, salbutamol. Treated with oral prednisone 30 mg taper over 1 week. CGAI (b) (6) 19 F GMB120 Urticaria 30 134 Mod. hives started after the 2nd dose. Hx of allergy to cat & fruits and eczema. Patient reported suicidal ideation on first day of OL treatment (day 88, 4th and last dose). A month later he reported dyspnea and anxiety. CGAI OL and CGAJ CGAI (b) (6) 43 F GMB120 Urticaria 114 117 Mod hives after the 2nd dose of GMB (he had received placebo in DB). Treated with oral prednisone 20mgQD x5. CGAI (b) (6) 50 F GMB120 Urticaria 123 123 Mod hives started 12 days after 1st dose of GMB (after placebo) treated with Diphenhydramine, lasted 4 days. A second episode occurred 23 days after first dose. 2 more episodes of hives occurred 3 days and 6 days after the 2nd dose. No hx of allergies. Treated with s/c dexamethasone x1. CGAI- (b) (6) 32 F GMB120 Urticaria 152 153 Mod Hives-Allergic Reaction day of 3rd dose of (b) (6) GMB (he had been on placebo). No hx of allergies. Treated with Diphenhydramine. CGA (b) (6) - 32 M GMB240 Rash 184 186 Mod rash Face and trunk. Associated with (b) (6) (and dyspnea, on the day of 4th dose. See page 62 of dyspnea) this review. Treated diphenhydramine. CGAI- (b) (6) 41 F GMB240 Urticaria * 125 138 Severe. Serious AE after 6th dose. Required (b) (6) epinephrine. Described in pg. 50 of this review CGAI (b) (6) 58 F GMB240 Rash 99 132 Mod rash on the abdomen. Two weeks after 4th dose of GMB (during OL). Also had nasopharyngitis. Skin bx showed allergic/ hypersensitivity reaction. It was treated with topical treatment. Listed as WD by subject. CGAI (b) (6) 47 F GMB120 Rash 115 119 Mod thigh Rash, same day of the 5th dose (during OL). No hx of allergies. Lasted 5 days. CGAI- (b) (6) 63 M GMB120 Urticaria** 136 169 Mod urticaria, a few hours after the 6th dose. (b) (6) Prior AE was upper resp. viral infection on day 82-104. Urticaria was treated with topical and systemic treatment, not corticosteroids. Ongoing at the time of last fu. CDER Clinical Review Template 69 Version date: September 6, 2017

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CGAJ- (b) (6) 58 M GMB240 Rash & 1 2 After fist dose. Mod skin rash/itchy hands pruritus No narrative. Source ADAE datasets SUR. * SAE. ** Did not resolve.

In general, these skin reactions leading to drug WD did not occur immediately after dosing and occurred throughout the study. Two occurred after the first dose (one on the same day, and one 12 days after, followed by other episodes); most occurred after the 2nd, 3rd and 4th dose; one each occurred after the 5th or 6th dose. Most were treated with topical treatment, and diphenhydramine or other antihistaminic or antipruritic drug. Only 3 mention treatment with a short course of systemic corticosteroids.

In summary, there was no difference in the risk of AE leading to discontinuation in the placebo-controlled trials (approximately 2% in each group). The only SOC with a rate of AE leading to drug discontinuation with a difference of at least 0.5% greater than placebo in any GMB group was the General disorders and administration site conditions (0.4%, 1.1% and 0.1% in the GMB120, 240 and placebo groups, respectively), driven by non-serious injection site reactions.

In Set E, 4% of GMB patients discontinued drug because of treatment emergent AEs. There was no evidence of a dose response between GMB120 and 240. In addition to injection site reactions, GMB is associated with hypersensitivity. At least 14 patients discontinued GMB because of AE of urticaria, rashes, pruritus or hypersensitivity, and some patients discontinued because of AE consistent with hypersensitivity (dyspnea, unspecific symptoms [body pains/abdominal pain/dizziness/lethargy], malaise, fatigue and chest pain/tightness). There were no reported cases of or anaphylaxis leading to drug discontinuation.

Significant Adverse Events

This section discusses important medical events or lab abnormalities that were not categorized as serious AE and did not lead to drug discontinuation.

- Severe AEs

The percentage of patients with severe AEs on GMB was similar to placebo in the placebo- controlled trials (7.5% in each group and placebo). The SOCs with a percentage of severe AE that was at least 0.5% greater than placebo were the General Disorders and Administration site conditions (the difference driven by injection site pain) and the Nervous system disorders SOC (the difference driven by migraine).

Table 17. BLA 761063. Severe AEs by SOC in Set A+C that occurred in at least 1% of patients and ≥0.5% greater than Placebo

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Table 18. Patients with Non-cardiac Chest Pain* in Set A.

Source: MO analysis of ADAE datasets. *Non-cardiac chest pain includes the following PTs: non-cardiac chest pain, chest discomfort and chest pain. N = number of patients in the analysis population; n = number of patients with events.

In Set E, non-cardiac chest pain was reported in 1.5% and 1.6% of patients in the GMB120 and GMB240 groups (data not shown).

The incidence of non-cardiac chest pain in the placebo-controlled trials was 5-fold on GMB as compared to placebo. The incidence of chest pain on GMB 120 and 240 in Set E was slightly higher than in the 3-6 month PC period. Selected cases of chest pain are summarized below.

Table 19. Selected patients with chest pain, non-cardiac chest pain, chest discomfort and chest tightness in the GMB database.

PT Age/ GMB Rel onset/ ID Sex Dose Rel end day Comment Intermittent, radiated to R shoulder, worse with deep ; dizziness, nausea and dyspnea, chest tightness, 13 days after 9th dose. ECG was normal. “Potential hyper- sensitivity events,” cough, sneezing, fatigue, myalgia, after doses. Seizure led to drug DC on same day of the 9th dose. No mention of BP or cardiac enzymes. Discussed in page 47. Etiology and relationship to drug is unclear. Consistent with CGAI- (b) (6) 38F 120 Chest pain drug hypersensitivity. Hx of asthma, cardiac murmur and GERD. Concomitant meds: cetirizine and salbutamol. 7 days after 3rd dose had intermittent, left sided chest and abdominal pain. No workup Non-cardiac Chest of treatment reported. Completed 6 injections. CGAG- (b) (6) 47F 120 pain Unclear etiology. Unlikely related to drug. Hx of asthma. Day of 1st dose reported mild intermittent fleeting chest pain which lasted 24 days. Treated with Non-cardiac Chest . Also, reported nausea 2nd day after 1st dose, pain lasting for 15 days. Completed 12 doses. Unclear etiology. CGAI- (b) (6) 35F 120 1/25 Unspecific symptoms. It resolved and did not recur. Hx of asthma. 2 days after 3rd dose associated with dyspnea. Chest discomfort lasted 7 days; dyspnea lasted 54 days. No Chest discomfort ECG changes. Completed 6 injections. Suggestive of CGAH- (b) (6) 45F 120 63/69 hypersensitivity but resolved and did not recur.

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PT Age/ GMB Rel onset/ ID Sex Dose Rel end day Comment Hx of asthma and seasonal allergy. Intermittent chest tightness 2 weeks after first dose, along with cough and lower respiratory tract infection. No cardiac workup. Event resolved 20 days after 5th dose. Completed 6 doses. Appears related to Chest discomfort respiratory infection but lasted 4 months. Relationship to drug CGAG- (b) (6) 45F 120 14/132 is unlikely. Hx of Depression, hypertension and GERD. On citalopram and Chest tightness/ HCTZ. Chest tightness 6 days after 4th dose. Did not resolve Discomfort led to study WD. In my opinion it could be angina. Discussed CGAH- (b) (6) 37F 240 90/- Not resolved in page 54 of this review. Hx of asthma and multiple sclerosis. 11 days after 6th dose had moderate chest pain, dizziness and syncopal episode. Seen in ER, no cardiac pathology was found. Patient completed 12 months of treatment. No mention of BP. CGA (b) (6) 42M 240 Chest pain Unclear etiology and relationship to drug. Hx of asthma and recent airline travel. On estrogen Chest pain preparation. 1 day after 3rd dose moderated chest pain and CGA (b) (6) 24F 59/63 nausea, diagnosed as pulmonary embolism. Unlikely related. Hx of seasonal allergy and drug hypersensitivity. 20 days after 3rd dose had chest tightness lasting 1 day. No treatment Chest discomfort reported. She received a total of 10 doses without CGAI- (b) (6) 30F 240 98/98 recurrence. Unclear etiology and relationship to study drug. Hx of myocarditis. Day of 2nd dose reported chest pressure. Chest discomfort Day of 3rd dose reported short lasting non-cardiac chest pain. (29/29) No vital signs, workup or treatment provided. Completed Non-cardiac chest remaining 3 months without recurrence. Unlikely to be CGAH (b) (6) 44F 240 pain (57/57) cardiac in origin. Hx of anxiety, asthma, COPD, GERD, HTN, obesity. Three hours after 1st dose had increased heart rate, intermittently for 22 days. Day of 2nd dose had atypical chest pain, hypo- tension, hypoesthesia oral, mild dyspnea and diarrhea (all intermittent). Hospitalized. Treated with nitrate, , metoprolol, albuterol, simethicone and aspirin. Normal CK, troponin, ECG and stress test. WD from study because of non- cardiac chest pain. Atypical chest pain of unclear etiology. CGAJ- (b) (6) 54F 240 Chest pain Consistent with angina, hypersensitivity or anxiety. Chest pain following sumatriptan use, 3 days after the 2nd dose, associated with palpitations. Pain lasted 1 hour; palpitations lasted 4 months. Completed 6 treatments. BP and pulse were within normal at baseline and throughout the study. Abnormal ECG with poor R wave progression at baseline, and at 2 subsequent visits. The patient had ECG was monitored for 2 weeks without evidence of cardiac pathology. The ECG at Visit 14 was normal with no R-wave Chest pain progression noted. No other AEs were reported. No evidence of Non-cardiac cardiac origin, however, there was no further use of sumatriptan CGAH (b) (6) 41F 240 30/30 during the study. Source: ADAE datasets and 4/16/18 response to FDA informational request.

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Review of the cases of chest pain/tightness/discomfort confirms that most were likely non-cardiac, although the great majority did not have a cardiac workup. Overall, this AE was not associated with a single common etiology. Eight of the 39 patients with chest pain on GMB had a history of asthma; 11 had CV risk factors (mostly hypertension, high cholesterol or obesity). Three appear to be cardiac in origin but are confounded or contain insufficient information (CGAH- (b) (6) , CGAJ- (b) (6) , CGAH- (b) (6) . Some reports are consistent with a hypersensitivity reaction but are also consistent with anxiety (they were transient and did not recur on repeat exposure).

- Raynaud’s phenomenon

On case of Raynaud’s phenomenon was identified by review of severe AE in the datasets. ART01- (b) (6) . As per the dataset, a 52 F presented worsening Raynaud’s on Days 17 to 22 of GMB 150 mg every 2 weeks treatment. The event was severe, non-serious, did not lead to study WD, and resolved. The patient completed treatment. There were no additional cases of Raynaud’s phenomenon in the entire GMB database.

- Designated Medical Events (DME)

A search for DMEs that were non-SAE and did not lead to drug DC in the ADAE datasets identified the following AE

Neutropenia Two cases of neutropenia on GMB240 (no cases on GMB 120) were reported for patients (b) (4) CGAH- (b) (6) and GAI- There are no narratives for these cases. As per information submitted on 5/9/18 both patients had below normal neutrophil counts at baseline before receiving GMB. One returned to baseline levels at the end of the treatment phase; the other increased values to normal levels 2weeks into treatment. None present absolute neutropenia or fever. These events do not appear related to GMB.

Pancreatitis Two cases of pancreatitis in GMB treated patients were discussed in the SAE section of this review. There is limited information to support GMB causality. There was also one case of alcoholic pancreatitis on placebo.

Seizures There were 7 reports of seizure in the GMB database. In set A there was 1 seizure on GMB and none on placebo. Four more cases occurred in the OL phase of CGAI or CGAJ. Additionally, there were 2 seizures in patients receiving placebo (1 on study ART-1 [Set E], and 1 in study CGAF (an hyperglycemic seizure in a clinical pharmacology study). The cases are listed below,

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from Lilly’s 10/31/17 response.

Table 20. BLA 761063. Patients with seizures in GMB database.

Patient ID Treatment PT Rel Day SAE or Outcome onset/end DC Placebo controlled trials (b) (6) CGAG- GMB240 Seizure 63 no Recovered Hyperglycemic Seizure 171 (during post- ART01 (b) (6) Placebo no treatment) Recovered Open label period CGAI or CGAJ CGAI- (b) (6) GMB240 Febrile Convulsion 209 no Recovered CGAI- (b) (6) GMB240 Seizure discussed in 238 SAE, DC SAE section of review. Recovered CGAI- (b) (6) GMB120 Seizure (worsening) 95 SAE R with sequelae Generalized Tonic- 1 SAE CGAH (b) (6) GMB240 Clonic Seizure Recovered Phase 1 trials Placebo (worsen) Generalized CGAF-137-8006 DC Seizure/Convulsion 33 Recovered Source: Response to FDA request for information submitted 10/31/17.

There was a small number of seizures (total=7) with no imbalance in the phase 2 and 3 placebo-controlled trials (1 on GMB, 1 on placebo). There were 3 SAE of seizure in the entire database. One was associated with fever in a patient with a previous history of febrile convulsions, one occurred on Day 1 but did not have a definitive diagnosis of seizure (the patient continued treatment without further seizure events), and one occurred in a patient with a potential hypersensitivity reaction to GMB (previously discussed in pages 41 and 42 of this review). Other narratives contained limited information. There does not appear to be a signal for increased risk of seizures with GMB.

In summary, evaluation of AE of severe intensity and DMEs did not identify a new safety signal.

Treatment Emergent Adverse Events and Adverse Reactions

A summary of all treatment emergent AE by SOC is presented below, for sets A+C and E.

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disorders (18%), Gastrointestinal (16%), Nervous system disorders (12%), Injury, poisoning and procedural complications (11%) and Respiratory, thoracic and mediastinal disorders (10%). There is a suggestion of a dose response for infections and infestations between GMB 240 and 120 (43% vs 38%) but for most SOCs the difference was 1%, in either direction.

Adverse events with an incidence ≥2% on any GMB group and ≥1% versus placebo are summarized below, using a MedDRA HLT grouping approach.

Table 23. AE by MedDRA HLT with incidence of at least 2% on GMB and ≥1% higher than placebo in Completed Placebo-controlled Studies (Set A+C) Placebo GMB120 GMB240 GMB pooled N=1451 N=705 N=730 N=1435 n % n % n % n % Any Injection site reaction1 183 12.6% 129 18.3% 166 22.7% 295 20.6% Upper resp. tract infections2 134 9.2% 78 11.1% 80 11.0% 158 11.0% Upper resp. tract signs & 27 1.9% 16 2.3% 23 3.2% 39 2.7% symptoms3 Upper resp. tract S&S and 153 10.5% 91 12.9% 98 13.4% 189 13.2% Infections General signs and symptoms4 11 0.8% 12 1.7% 11 1.5% 23 1.6% Pain and discomfort NEC5 16 1.1% 9 1.3% 14 1.9% 23 1.6% Pruritus NEC 6 4 0.3% 9 1.3% 12 1.6% 21 1.5% Gastrointestinal and 13 0.9% 10 1.4% 16 2.2% 26 1.8% hypomotility disorders7 MO analysis of ADAE SUR datasets submitted 2/5/18. These HLTs include the following PTs in order of frequency: 1 Injection site pain, reaction, erythema, pruritus, swelling, rash, discomfort, hematoma, induration, irritation, hemorrhage, hypersensitivity, mass, papule, urticaria, inflammation, edema, discoloration (General disorders and Administration site conditions SOC). 2 Upper respiratory tract infection*, sinusitis*, , rhinitis, pharyngitis, laryngitis, nasopharyngitis, acute sinusitis, pharyngotonsillitis (Infections and infestations SOC) (* >1%) 3Oropharyngeal pain, rhinorrhea, paranasal sinus discomfort, sneezing, upper respiratory tract congestion, dysphonia, increased upper airway secretion, throat irritation, upper-airway cough syndrome, catarrh, laryngeal pain, nasal discomfort, rhinalgia, snoring, upper respiratory tract inflammation. (Respiratory, thoracic and mediastinal disorders SOC). Few patients with upper respiratory signs and symptoms also had an infection. 4 Influenza like symptoms, peripheral swelling and swelling. 5 Pain, non-cardiac chest pain, facial pain, discomfort, chest discomfort. 6 Pruritus, pruritus allergic, pruritus generalized, rash pruritic, brachioradial pruritus. (Skin and subcutaneous tissue disorders SOC) 7 Constipation, gastroesophageal reflux disease (Gastrointestinal disorders SOC). Constipation occurred in 7 (1%),12 (1.6%) and 9 (0.6%) of GMB 120, 240 and placebo, respectively. GERD occurred in 0.3-0.5% of all groups.

The great majority of these events were non-SAE, were mild to moderate in severity and resolved without drug discontinuation. SAE and AE leading to discontinuation have been discussed earlier. Of the Upper respiratory infections, 75% and 80% occurred during the

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72 days for placebo (4 to 210). The PT driving the difference was menorrhagia (5 on GMB 240, 3 on GMB 120 and 1 on placebo, See Appendix 13.2.4 of this review). The number of events is small and does not allow drawing conclusions.

- Vertigo, vestibular dysfunction

The risk of vertigo and vestibular dysfunction was 1.4%, 1.6% and 0.6% on GMB120, GMB240 and placebo respectively. The FDA customized MedDRA query included the following PTs: vertigo, vertigo labyrinthine, vertigo positional acute vestibular syndrome, labyrinthitis, Meniere's disease, tinnitus vestibular disorder, vestibular neuronitis, vestibulitis and viral labyrinthitis. Most were non-SAE and did not lead to WD. Mean time to onset of vertigo and vestibular dysfunction AE was 69 days (range 1-230) on GMB and 106 days on placebo (range 17 to 228). Most had resolved at the time of last follow up. Three events did not resolve on placebo and 4 did not resolve on GMB. The most common PT driving the difference in percentage was vertigo (9 on GMB240 and 4 on placebo), suggesting an increased risk of vertigo in the GMB240 group as compared to placebo.

In summary, common AE with a risk of at least 2% (rounded) and at least 1% greater than placebo in any GMB group were injection site reactions, upper respiratory tract infections, dysfunctional uterine bleeding, vertigo and vestibular disorders and pruritus.

Common AE in Set E were consistent with those observed in set A+C (data not shown).

Laboratory Findings

Analyses of changes from baseline and shift analyses for hematologic (Hb, HTC, platelet count, neutrophils, basophils, eosinophils, WBC, monocytes, lymphocytes), chemistry (fasting cholesterol, fasting glucose, HDL, ALT, AST, albumin, ALP, AST, Bilirubin, BUN, creatinine, calcium, cholesterol, CK, glucose, uric acid) and urinary measurements, showed no significant findings as compared to placebo in the placebo-controlled studies (Set A or Set A+C), or between the GMB 120 and 240 mg doses in the OL studies (data not shown).

Liver enzyme outlier analyses are shown below.

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Table 25. BLA 761063. Risk of ALT >3x ULN in placebo-controlled trials

AST ≥5xULN - none. ALT or AST ≥10x ULN: none BR ≥2x ULN - none on GMB, 1 on placebo. Source: Table Submitted on 2/14/18 in response to FDA request.

There were no Hy’s law cases. The risk of ALT and AST >3xULN in the placebo-controlled trials was approximately 1% for all treatment groups. GMB is does not appear to be associated with liver toxicity. The relative risk of ALT or AST elevation is 2-3 fold in GMB treated patients, but there were few events, and the absolute difference is <0.5%.

Treatment emergent lab abnormalities in set E show that approximately 8% and 5% of patients had abnormal high ALT or AST; 10% had abnormal high creatine kinase; 2% had abnormal high creatinine; 7% had abnormal low glucose and 1% had abnormal high glucose, at least once during the trials (treatment and post-treatment). There was no evidence of a dose response (data not shown). All these percentages were higher in studies CGAI and CGAJ, with 1-year treatment. Regarding urinalyses in pool E, 35% had abnormal levels of protein present in urine, and 17% were leukocyte esterase positive, suggesting a urinary infection (data not shown).

Analyses of laboratory values outside normal ranges, show no major differences between GMB and placebo (data not shown). Very few patients had potentially clinically significant laboratory abnormalities (PCSA)(see outlier analyses below, using mostly Grades 2 or 3 NCI CTACAE).

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Table 26. Patients with potentially significant laboratory values in Set A+C (SUR)

Source: Response to FDA IR, submitted 5/25/18. Table 27. Patients with potentially clinically significant laboratory values in Set E

Source: Table APP 1.55. SUR.

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The only lab with >1% of patients having a PCS abnormality in Set E was creatine kinase. Adequate interpretation is not possible in the absence of a comparator group. There were no reported SAE or dropouts related to these labs.

Four patients presented abnormally low potassium on GMB pooled as compared to none on placebo in Set A+C, using a threshold of K <3.0 mmol/L (the normal range for K was 3.4 to 5.4 mmol/L). There was no difference in the number of patients with K>6 mmol/L (1 in each). As per the SUR lab datasets, the four patients with K<3.2 mmol/L received GMB120; one presented an AE of “mild hypokalemia” without other AEs, and one was taking a diuretic and already had a K level of 3.2 mmol/L before entry.

On 6/15/18 at the FDA request, Lilly provided normal range laboratory values for routine measurements (data not shown), and on 6/25/18 provided additional analyses using NCI Grade 2 CTAEC for neutrophils and platelets. Analyses showed no difference in the percentage of patients with neutrophil count <1.0 x 109/L or platelet count <75 x 109/L between GMB and placebo groups.

- Fasting glucose, C PEPTIDE and insulin

GMB did not appear to have a clinically significant impact on laboratory evaluations when looking at mean changes from baseline, shift analyses and available PCSA evaluations for fasting glucose, insulin and C peptide in Set A+C and Set E (submitted on 5/25/18 and 6/25/18, at the FDA request. Except for one patient who had a SAE of diabetic ketoacidosis (CGAI- (b) (6) 5 days after the 4th dose of GMB) no patients with abnormal lab levels related to glucose metabolism had SAE or AE leading to study withdrawal. Glucose-related analyses are presented in Appendix 13.2.3 of this review.

Vital Signs

Analyses of changes from baseline for pulse, BP (sitting systolic and diastolic), temperature and weight showed no significant findings as compared to placebo or between GMB 120 and 240 in the entire database (Set A, Set A+C and Set E, data not shown). There were no measurements of orthostatic BP).

Shift analyses of sitting systolic and diastolic did not show a difference with placebo in the 3 to 6-month placebo-controlled trials (Set A+C, submitted on 2/14/18; data not shown).

Outlier analyses of BP (SBP≥140 mmHg or DBP≥ 90 mmHg) in Set A and of Set A+C, submitted at the FDA request on 5/9/18, did not show a difference with placebo. For SBP ≥140 mmHg, the percentage was 12%, 13% and 13% for GMB120, 240 and placebo, respectively; for DBP≥ 90 mmHg, the percentage was 19%, 17% and 17% for GMB120, 240 and placebo, respectively) (data not shown).

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BP outlier analyses in Set E are shown below.

Table 28. BLA 761063. Outlier analyses of Blood Pressure measurements as per FDA pre- defined categories in Set E. SUR.

Source: Table APP 1.58. SUR

There was a suggestion of a dose response in BP outlier analyses between GMB120 and GMB240 in pool E. The difference seems to be more marked during the treatment period (16% vs. 12% for SBP; 21% vs. 18% for DBP) as compared to the complete treatment + post-treatment period (16% vs. 14% for SBP and 22 vs. 21% for DBP). In the absence of a control group and of an increased risk of hypertension related AEs between GMB120 and 240, this apparent effect on BP cannot be interpreted. There does not seem to be an increase in BP for the 300 mg dose but the number of patients exposed is small and inadequate for comparison to the 120 and 240 mg doses.

Analyses of Weight

Analyses submitted on 5/25/18 for set A+C showed similar percentage of patients with weight decrease ≥7% (5%) on GMB and placebo, and a 1% higher percentage of patients with weight increase ≥7% on GMB as compared to placebo (10% and 9%, respectively). There was no dose

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response between GMB 120 and 240. As per analyses submitted in the SUR, weight increase ≥7% from baseline in set E was reported in 6% of patients on GMB 120 and 7% of patients on GMB 240.

In summary, GMB did not appear to have a clinically meaningful impact on vital signs, except for a suggestion for increased risk of weight gain, but the differences are small.

Electrocardiograms (ECGs)

There were no changes from baseline in mean HR, PR interval, QRS interval or QTcF as compared to placebo in the placebo-controlled trials. The percentage of patients with changes in ECG parameter (HR, PR interval, QRS interval and QTcF) was similar in patients treated with GMB and placebo. No patient experienced a QTcF value >500 msec. More galcanezumab- treated patients (n=8; 0.6%) met the criteria for QRS high (≥120 msec) compared to placebo (n=1, 0.2%) (Source: response to FDA informational request submitted 2/14/18). However, 6 of the 8 had a pre-existing condition of a complete or incomplete bundle branch block at study entry, and 5 of those patients also had a QRS ≥120 msec prior to dosing. One of the 8 patients discontinued treatment due to the AE of mild dyspepsia. The other 7 patients completed the treatment phase without AEs.

There was no difference with placebo in the overall rate of treatment emergent qualitative changes in ECG in Set A (treatment only period) (Source APP.1.7.6. original submission) or A+C (response to request for information submitted 2/14/18), including conduction, morphology, rhythm, ST segment, T waves, or signs of ischemia (submitted 2/20/18). There was a suggestion for a slightly higher percentage of patients with treatment emergent left axis deviation on GMB (0.9% on GMB120, 0.6% on GMB240 and 0.4% on placebo) but the differences are small and unlikely to be of clinical significance. In terms of rhythm, a slightly higher percentage of patients presented sinus bradycardia with sinus arrhythmia on GMB (0.8% on GMB120, 0.5% on GMB240 and 0.3% on placebo); and sinus tachycardia (0.8 on GMB120, 0.6% on GMB240 and 0.2% on placebo), again of unclear clinical significance. One inverted T wave consistent with ischemia was discussed under CV SAE (131-04523). In set E, some patients presented small changes from baseline in HR, PR interval and QTcF interval, and conduction abnormalities (data not shown). Definitive conclusions cannot be drawn in the absence of a control group, but there is no obvious signal for ECG abnormalities.

In summary, GMB did not have a clinically meaningful impact on ECGs.

QT

There was no Through QT study. QTcF changes were discussed above.

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Immunogenicity

Immunogenicity was assessed in the “Immunogenicity available population.” In response to a FDA request for information, on 5/9/18, Lilly clarified that this population consisted of a subset of patients from the controlled and uncontrolled phase 3 studies, including 1388 patients from the placebo-controlled pivotal trials (Set A+C), and 2142 patients from Set E. Lilly’s analyses of the risk of immunogenicity (Anti-Drug Antibody [ADA]+ and Neutralizing Antibody [NA]+) in these two populations are summarized as follows.

- In the placebo-controlled trials, 7-11% of the immunogenicity available population was ADA+ and 4-6% was NA+ at baseline. Treatment emergent ADA+ was observed in 14-15% of patients on GMB and 2% of patients on placebo. NA were present in almost 99% of GMB patients who became ADA+, and 2/3 of placebo patients who became ADA+.

- In the overall population, 9% and 6% of the immunogenicity available population was ADA+ and NA+, respectively, at baseline; 17% became ADA+ during treatment or post-treatment period, and most of these patients also became NA+.

Lilly’s analyses are included in Appendix 13.2.3 of this review. For additional information, the reader is referred to the Clinical pharmacology review.

On 5/25/18, in response to another FDA request for information, Lilly provided tables of treatment emergent AEs among patients who became treatment emergent ADA+ in Set A+C and Set E. The kind of adverse events among TE ADA+ patients were similar to those in the overall safety populations as presented in the SUR, but the percentages of AE were higher among ADA+ patients as compared to the overall safety populations (data not shown)(AE tables for patients in the immunogenicity available population who were not ADA+ were not submitted).

The Applicant concluded that ADA positivity did not have an impact on the safety of GMB. However, available data is not adequate to support that conclusion. Approximately 300 GMB- treated patients became ADA+ in the database. Moreover, duration of the immunogenicity evaluations is relatively short (1 year) for a product that takes several months to reach maximum concentration.

Of note, no patient has been re-exposed after GMB treatment in any migraine or non-migraine study. This is an important potential safety issue, if a patient were to stop GMB and re-start treatment. This issue could be addressed with a PMR (e.g. submission of reports of anaphylaxis after interruption and reinitiation of treatment).

Analysis of Submission-Specific Safety Issues

Potential safety issues identified during GMB development included cardiovascular safety, hepatic safety, AEs related to injection sites, hypersensitivity, upper respiratory tract infections,

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and suicidality/self-injurious behavior. Additionally, the potential increase on the risk of seizures was identified during this review.

8.5.1 Cardiovascular safety

CGRP is a potent vasodilator (although only one of multiple factors involved in the regulation of vascular homeostasis). Theoretical concerns exist that blocking of CGRP’s vasodilatory effects, might increase the risk of ischemia, particularly in patients with pre-existent increased cardiovascular risk. Because of these concerns, the Applicant and myself conducted extensive analyses of the cardiovascular safety profile of this product.

Cardiovascular SAE in the PC trials, included 1 myocardial infarction and 1 congestive heart failure/cardiomyopathy (later diagnosed with inverted T wave), 1 TIA and 1 PE in the GMB 240 group, and one MI, 1 PE and one DVT on placebo (0%, 0.5% and 0.2% on GMB120, GMB240 and placebo, respectively). In the OL period there was one additional case each of MI and CHF. There were no such SAE on GMB120.

SAE during the uncontrolled period of studies CGAI and CGAJ included one patient with angina and non-ST elevation MI; one congestive heart failure on GMB 240 (making a second case of CHF on GMB240); and one SAE of orthostatic intolerance (after treatment for diastolic hypertension) on GMB 120. Additionally, one patient on GMB240 in the OL period, had non- SAE of coronary artery stenosis (an important medical event). Most of these patients had some CV risk factor. None of the cases individually appear to be unequivocally related to GMB but given the theoretical concerns, I would not completely rule out a relationship to drug.

There were no SAEs of hypertension in the controlled period but the narratives of the MI, TIA and coronary artery stenosis on GMB240 mention that the patients had high blood pressure at the time of or prior to the events. One patient on placebo WD because of HTN.

Patients with cardiac, vascular and ischemic-thrombotic events that were SAE or led to drug discontinuation in the migraine prevention trials are listed below.

Age ID Sex PT Treatment Comment Placebo controlled trials 55 F Family Hx of cardiac Dz. Hx of Raynaud’s.

(b) (6) Myocardial infarction (S) 3 Angiogram: Decreased blood flow CGAH At hospital also had HTN GMB240 without significant coronary artery Dz. 51F Cardiomyopathy 3 months into trial. Treated with carvedilol and valsartan. Dilated cardiomyopathy/ 3 (Unclear if she had HTN). T wave congestive heart failure (S) 6 inversion (ischemia) diagnosed during CGAG- (b) (6) Inverted T wave on ECG GMB240 post-treatment follow up

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54F TIA (S) preceded by new onset 3 Hx of hypothyroidism, obesity, (b) (6) CGAH- HTN GMB240 hyperlipidemia 24F Bilateral pulmonary 3 Recent air travel and on estrogen ring. CGAI- (b) (6) embolism (S) GMB240 Open label CGAI and CGAJ 55M Myocardial infarction (S) 5 (b) (6) CGAI- and unstable angina GMB240 Hyperlipidemia. 44F Orthostatic intolerance (S) after diuretic use for 9 CGAI- (b) (6) diastolic hypertension GMB120 ECG, Holter, Tilt test normal. 38F Family Hx of heart Dz. Baseline PRWP and borderline high BP. Dx with LV dysfunction EF<20% after 4 doses. Angiogram: no significant coronary Congestive heart failure 3 disease but elevated left ventricular end CGAI- (b) (6) (S) GMB240 diastolic pressure. 62M Preexistent arrhythmia treated with flecainide. BP was elevated at baseline (without a diagnosis of HTN). After dx of HTN was made, started treatment with Lisinopril, HCTZ and candesartan. Non-SAE of HTN 12 Angiogram showed coronary artery CGAI- (b) (6) Coronary artery stenosis* GMB240 narrowing 81 days after last dose (S)= serious adverse event. *In my opinion, an important medical event. Additionally, 5 patients had cardiac or vascular SAE or dropouts on placebo (1 MI, 1 deep venous thrombosis, 1 PE were SAE; one patient withdrew because of HTN; one patient had congestive heart failure that should be considered an important medical event). Source: ADAE SUR datasets.

There was no difference in the percentage of CV SAE or dropouts in the placebo-controlled trials (0%, 0.6% and 0.3%, on GMB120, 240 and placebo, per the table above [0.5% for pooled GMB120+240]).

Of note, two 62 F presented 1 SAE each of peripheral vascular disease leading to leg amputation and myocardial infarction, respectively, while receiving GMB 300 mg monthly (ART (b) (6) (b) (6) , in a phase 2 study and CGAF- in an osteoarthritis study [page 37 of this review]). The former had multiple CV risk factors including uncontrolled diabetes mellitus, smoking and obesity, and the later was a smoker without other known CV risk factors. The investigator and Lilly considered the cases not related to drug, but in my opinion the role of GMB cannot be ruled out. Few patients have been exposed to doses above 240 mg monthly (150 mg twice a month or 300 mg monthly) (174 in set E, and 37 in the osteoarthritis study), and few patients had the underlying CV risk factors that this patient had. No conclusions can be drawn regarding the CV safety of GBM at the 300 mg monthly dose.

Exploratory analyses of all AE (serious and non-serious) by HLT and SMQs that involve CV events in placebo-controlled trials showed no difference between GMB pooled 120+240 doses and placebo (approximately 3% in GMB and placebo groups; data not shown). The only HLT in CDER Clinical Review Template 88 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

which there was a suggestion for an increased risk on GMB as compared to placebo was the Peripheral vascular disorders NEC, which includes flushing and hot flashes (0.9%, 0.7% and 0.3% on GMB120, 240 and placebo, respectively). For all other CV HLTs the risk was the same or higher on placebo, including Hypertensive disorders (1.1% on GMB, 1.5% on placebo) and Hypotensive disorders (0.5% each). It is unclear if AE of flushing (reported under the Vascular disorders SOC) are drug related. They occurred at any time during treatment, mostly in women above 40 years (only one patient was a 32 M). None was serious.

There were no significant findings from analyses of ECG changes or use of CV (anti- hypertensive, anti-arrhythmic, anti-anginal, anti-thrombotic) medications in the galcanezumab PC trials (data not shown). In set E, a small percentage of patients increased the use of CV medications (shown in Appendix 13.2.3). No definitive conclusions can be drawn regarding the use of concomitant CV medication in patients exposed to GMB for up to 1 year in the absence of a control group.

Blood pressure analyses did not show meaningful changes from baseline in mean systolic or diastolic pressure, in shift analyses of BP or relevant findings in outlier analyses of pre-specified values (SBP ≥140 or DBP ≥90 mmHg) in Set A or A+C. Outlier analysis in set E suggested a possible dose response for increased BP between GMB240 and 120, but this finding in isolation does not allow drawing definitive conclusions.

In summary, extensive review of the GMB safety database including adverse events, ECG, vital sign measurements and analyses of concomitant CV medications did not identify an increase in cardiovascular risk with galcanezumab. However, the size and duration of the database are not powered to adequately rule out cardiovascular safety concerns. Moreover, the demographics and underlying CV risk of patients in the clinical trials do not seem to represent those of the migraine population.

As per Dr. Lois Freed, FDA supervisory pharmacologist, summary dated 9/27/18, the Agency has conducted an independent evaluation of available published literature, to investigate the potential for antagonism of CGRP to induce vasoconstriction or adversely affect coronary vessel size, blood flow, or coronary infarct size under ischemic conditions. The results of this evaluation suggest that regulation of vascular tone in healthy patients and those with cardiovascular risk factors involves multiple endogenous factors, of which CGRP is only one, and that there is limited understanding of the role of CGRP in normal hemodynamic processes or response to ischemic events. It was, therefore, concluded that there is insufficient information to dismiss the original concerns but that additional basic research is needed to further understand the role of CGRP in these processes. Without a better understanding, it is unlikely that nonclinical studies of galcanezumab could be designed and conducted that would provide useful information; therefore, no post-marketing study to further assess the cardiovascular safety of galcanezumab is recommended.

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8.5.2 Hepatic safety

Hepatotoxicity has been raised as a potential concern based on small molecules CGRP inhibitors (“gepants”). Review of adverse event and laboratory data in this database, did not suggest an increased risk of liver toxicity with galcanezumab. The risk of ALT and AST >3xULN in the placebo-controlled trials was approximately 1% (rounded), for both GMB groups and placebo. There were no Hy’s law cases. SAE and AE dropouts because of liver-related PTs did not appear to be drug related.

8.5.3 Injection site reactions

As per analyses using MedDRA High level term (HLT) 18% and 23% of patients in the GBM120 and 240 groups presented injection site reactions as compared to 13% in the placebo group in set A (up to 6 months). Of the patients who had ≥1 injection site reactions, 33% had a single event. Approximately 40% had ≥4 events in both active treatment and placebo-treated groups. The most frequently reported injection site PTs were injection site pain, injection site reaction, injection site erythema, and injection site pruritus. Excluding the injection site pain PT, the rate of injection site reactions was 10% on GMB 120, 15% on GMB 240 and 4% on placebo. Most events were mild to moderate in severity, occurred on the day of treatment administration and resolved within 2 weeks. Most injection site reactions occurred on the day of administration and could occur with any dose over the course of therapy. There were no SAEs of injection site reaction. The rate of discontinuations related to injection site reactions was low (<0.5%). The findings in set E are consistent with Set A. There seems to be a dose response in the overall percentage of administration site reactions between GMB240 and GMB120.

8.5.4 Hypersensitivity

Galcanezumab is a humanized monoclonal antibody expected to carry some risk for hypersensitivity reactions. By evaluating SAE, discontinuation due to AE, severe and all AE throughout this review, I identified several cases that in my opinion were consistent with systemic hypersensitivity (non-site hypersensitivity), some which were coded under the Immune system disorders SOC (e.g. “hypersensitivity”) or the Skin and subcutaneous tissue disorders (e.g. urticaria, rash) and some that were not straight forward cases of an allergic reaction such as CGAG- (b) (6) and CGAI- (b) (6) who discontinued because of non-SAE (b) (6) of dyspnea and CGAJ- who had eye pruritus and ocular hyperemia. (Lilly’s evaluation agrees with my assessment that these three AEs are consistent with hypersensitivity reactions.) Additionally, CGAJ- (b) (6) had injection site reactions accompanied by abdominal pain, (b) (6) nausea and lethargy, and CGAI had injection site reactions accompanied by cough, sneezing, fatigue, myalgia, with an episode of chest tightness, dizziness, nausea and seizure, and CGAG- (b) (6) reported a confusional state along with hypersensitivity. Narratives for these cases were included in Section 8.4.3 of this review. Analyses of potential cases of hypersensitivity (excluding injection site reactions) in the placebo-controlled trials and Set E are

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The percentage of these events in Set E for GMB120 and 240 was approximately 6%, without evidence of a dose response. Two patients treated with GMB120 or 240 (0.3%) had SAE (b) (6) (urticaria, CGAI-(b) (6) and CGAI- . Twelve patients (0.6%) had potential (b) (6) hypersensitivity AEs that led to drug discontinuations. Including CGAG- CGAJ- (b) (6) and CGAI- (b) (6)who in my opinion had AE consistent with an allergic reaction, there would be at least 15 patients with potential hypersensitivity reactions causing drug discontinuation (0.7%). Most of the hypersensitivity events were transient and mild or moderate in severity. Nine patients (0.4%) treated with GMB presented hypersensitivity AE categorized as severe.

There were no reported cases of angioedema or anaphylaxis. However, as noted above, several patients reported a combination of signs and/or symptoms suggestive of a complex allergic (b) (6) reaction. As per the datasets, one patient with face swelling (CGAI- was coded under the Angioedema HLT, in study CGAI but it was an isolated event that occurred during the follow up period to the PC phase, was non-serious, did not lead to discontinuation and resolved after 1 day. The case does not sound like true angioedema.

The Applicant identified potential treatment emergent hypersensitivity using several queries followed by medical evaluation of each case. The analyses found a statistically significant increase in the risk of Hypersensitivity for GMB as compared to placebo using the Hypersensitivity (Narrow) SMQ (4.6% on GMB pooled and 2.8% on placebo, including local and systemic, immediate and non-immediate reactions). The statistical difference was observed for both immediate (on the day of the injection) as well as and non-immediate (beyond the first day) reactions (see Appendix 13.2.3 of this review). A similar analysis using the Hypersensitivity (Narrow SMQ) in set E submitted on 8/6/18 at the FDA request showed that 6.5% on GMB120 and 6.7% on GMB240 reported PTs consistent with hypersensitivity (data not shown). Hypersensitivity should be included in the Warnings and Precautions section of labeling.

8.5.5 Upper respiratory tract infections

Analyses by HLT in the placebo-controlled trials showed that upper respiratory infections (URTI) were more frequent on GMB as compared to placebo. Table 31. BLA 761063. Incidence risk and rate of Upper respiratory tract infections HLT in Set A+C Placebo GMB120 GMB240 GMB pooled N=1451 N=705 N=730 N=1435 PYRs=533 PYRs=268 PYRs=269 PYRs=537 n n n n 134 78 80 158 9.2% 11.1% 11.0% 11.0% 25.1 per 100 PYRs 29.1 per 100 PYRs 29.7 per 100 PYRs 29.4 per 100 PYRs Source: estimated by MO.

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None of the URTIs in Set A+C were SAE or led to drug discontinuation. Seven were severe (3 on placebo, 3 on GMB120 and 1 on GMB240). Mean time to onset of first event was similar for GMB and placebo (112 [1-299] and 116 [range 2-280] days, respectively).

Looking at individual PTs, the only PT with percentage of at least 2% and 1% greater than placebo was Upper respiratory tract infection (5%, 5.8% and 5.5% on placebo, GMB120 and GMB240, respectively). The next common PT was sinusitis (2.8%, 3.3% and 3.2% on placebo, GMB120 and GMB240, respectively).

The risk of URTI HLT in set E was 415 patients with at least 1 event among 1487 PYRs= 27.9 per 100 PYRs, about the same as in the original application (29.4 per 100 PYRs). Again, the most common PTs were URTI and sinusitis. Only 1 was a SAE (CGAI- (b) (6) ) and 1 led to drug (b) (6) discontinuation (CGAI (both URTIs).

Analyses of URTI conducted by Lilly based on time at risk exposure in Sets A and E in the original application indicates a higher rate for the URTI PT (but not other PTs in the URTI HLT) in Set E as compared to Set A (15.7 vs. 12.8 per 100 PYRs, respectively), which is expected because of the longer duration of treatment in set E (1 year, vs. 6 months). The rate of URTI events in set E in the SUR (13.9 per 100 PYRS) was lower than in the original application (data not shown).

There is a suggestion for an increased risk of upper respiratory tract infections with GMB in this database, but I am not persuaded that it is a true signal. There is a small difference in the incidence risk and rate as compared to placebo. Only 1 event was a SAE and 1 led to drug discontinuation in the entire database

8.5.6 Suicidality and self-injurious behavior

Patients with migraine headaches are at a greater risk for suicidality than the general population. [13.1.11] As per FDA guidance Lilly evaluated suicidal ideation and behavior in the galcanezumab clinical program using the Columbia Suicide Severity Rating Scale (C-SSRS). There was no difference in the number of AE of ideation or behavior in the placebo controlled trials in the original submission. (Source Table 2.84, APP1.268 and 1.269, original ISS, data not shown). There was 1 SAE of attempted suicide on placebo. One patient discontinued from GMB because of suicidal ideation (CGAH- (b) (6) ) and one had an AE of suicidal thoughts at the last visit of the treatment phase that was resolved at the post-treatment follow up (CGAG- (b) (6) (b) (6) .

As per clarification submitted on 5/25/18 (APP.3.3), 0.8% of patients presented treatment emergent suicidal ideation in Set A+C as assessed by the C-SSRS, on both, GMB and placebo. As per Table APP 1.207 of the SUR, 1.3% of GMB treated patients reported treatment emergent suicidal ideation and 0.1% reported suicidal behavior in set E, as assessed by the C-SSRS in Set E (data not shown).

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There is no signal for an increased risk of suicidality with GMB.

Safety Analyses by Demographic Subgroup

The majority in the galcanezumab database were women (85% of patients in Set A; 86% in Set E). Analyses by gender did not identify any new/unique safety signals (data not shown). Analyses by race were not done because of the small number of non-White patients (23% in Set A, including Black [8% ], multiple [7% ] Asian [6%] American Indian or Alaska native [2%] and native Hawaiian or other Pacific islander [<1%] races). Analyses of AE by age were not done. There were only 14 patients age 65 years or older in Set A.

Specific Safety Studies/Clinical Trials

Not applicable.

Additional Safety Explorations

Human Carcinogenicity or Tumor Development

Evaluation of SAE and discontinuations due to AE in the Neoplasm SOC for the placebo- controlled trials and the overall safety database did not suggest that GMB increases the risk of tumor development. There were 7 neoplasms, including 5 malignancies on GMB and none on placebo in the placebo-controlled trials, and 4 additional malignancies in the open label periods. All but one of those was at the lower dose (GMB120). All occurred within 1 year of treatment. The clinical database is not adequate to evaluate human carcinogenicity (maximum exposure to GMB was 1 year). However, the published literature does not suggest that CGRP inhibition may affect carcinogenesis.

Human Reproduction and Pregnancy

There are very limited safety data on the use of galcanezumab in pregnant women or in women exposed via a male partner treated with galcanezumab. Pregnant and lactating women were excluded from entering the clinical studies. Subjects with reproductive potential were required to use a reliable method of birth control during the clinical studies and for 5 months following last dose. Pregnancy was a criterion for permanent discontinuation in all galcanezumab studies.

As of the SUR 16 pregnancies occurred with exposure to GMB via mother, and 2 with exposure via father. Thirteen of the women were exposed to GMB during their first trimester of pregnancy; 3 pregnancies occurred after completion of treatment. As per information submitted on 5/25/18, the outcome of the pregnancies via mother was reported as follows: 8 normal; 1 premature birth; 1 spontaneous abortion; 1 missed abortion; 1 elective termination; 4 unknown/lost to follow up. Of the 8 babies who were carried to term, one who was born of a mother with gestational diabetes had low blood glucose at birth, which resolved on an unknown date. The other 7 are reported to have no complications. One of the pregnancies that

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occurred after completing treatment (10 weeks after the last dose of GMB) ended ion spontaneous abortion/miscarriage. The mother was 38 years old and had a history of fibroids.

The premature birth (34 weeks) occurred in a 24 year-old patient who became pregnant during (b) (6) the post treatment period (CGAG- GMB120 group). A SAE of pre-eclampsia was reported on Day 382 of the study, 102 days after completing the post-treatment period (244 days after the 6th dose). She underwent a C-section and delivered a premature male infant without complications. The narrative shows diastolic BP values of 71-95 mmHg during the study. CGRP is reported to have a role in the regulation of placental pathophysiology [13.1.12], but a causal relationship between pre-eclampsia and GMB in this case is unlikely because it occurred 8 months after the last dose of GMB.

Of the 2 pregnancies in which exposure to GMB was via the father, one was normal and the other was a baby with ankyloglossia (short frenulum). During pregnancy, the mother had gestational hypertension and 1 vasovagal syncopal episode, and the father had a chlamydial infection. Ankyloglossia is a common disorder, likely unrelated to GMB. There is limited information on the effects of GMB during pregnancy. This issue can be addressed with a postmarketing Pregnancy Registry.

Pediatrics and Assessment of Effects on Growth

Not applicable.

Overdose, Drug Abuse Potential, Withdrawal, and Rebound

According to the sponsor, non-clinical studies indicate that GMB does not penetrate the blood brain barrier in a significant manner. As per agreement with FDA, no specific studies were conducted to assess GMB potential for abuse. However, Lilly conducted a search for AE consistent with abuse potential in the clinical program, using the MedDRA Drug abuse and dependence SMQ and additional terms not included in the SMQ.

No patients from any of the treatment groups reported any events from the MedDRA Drug abuse and dependence SMQ and a similar percentage of patients presented the additional non- SMQ PTs in set A, including terms such as somnolence, dizziness, memory impairment, disturbance in attention, mood altered, and others (overall 7-8% on GMB treated groups, as compared to 9% on placebo, data not shown). One patient (CGAG-104-01700) reported a mild euphoric mood on Day 1 of GMB120 treatment; it resolved the same day and did not occur again. Concomitant meds included . Analyses of potential for abuse in Set E showed similar findings (data not shown). Most cases were transient, mild, and confounded by comorbid conditions or concomitant medications (e.g. antihistaminic drugs).

GMB does not seem to be associated with an increased risk of abuse.

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Safety in the Postmarket Setting

Safety Concerns Identified Through Postmarket Experience

Not applicable. Galcanezumab is a new biologic agent.

Expectations on Safety in the Postmarket Setting

The GMB database fulfilled minimum ICH guidances for exposure for a new product for use in the chronic setting. Additional adverse reactions will likely be identified after a larger group of patients is exposed to the product, particularly those with comorbidities who were not allowed to participate in the trials. (See discussion under 8.2. Adequacy of the data, and 8.5.1 Analyses of specific safety issues). One of the populations that might require special postmarketing monitoring is that of patients with underlying cardiovascular risk. Two issues that could be addressed as PMRs are the lack of adequate information on the effects of GMB during pregnancy, and the lack of data on re-exposure after interruption of therapy.

Additional Safety Issues From Other Disciplines

Please see other disciplines’ reviews

Integrated Assessment of Safety

Safety findings from BLA 761063 are summarized below.

Deaths. (b) (4) . One patient was found dead, suspected of drowning, but the cause of death and relationship to GMB is uncertain. SAE. Evaluation of SAE did not identify significant safety issues with GMB. The risk of SAE in the complete placebo-controlled trials was 2.3% on GMB 120+240, and 1.3% on placebo, the difference driven by the Neoplasm SOC. The risk of SAE in Set E (all phase 2&3 trials) was 4%. There was no evidence of a dose response between GMB120 and 240. The most common SAE in the PC trials were in the Neoplasms SOC (no particular neoplasm; all neoplasms were in the lower dose group) and in the GI disorders and Infections SOCs in Set E (without one particular AE driving the difference). AE leading to drug or study discontinuations. The risk of AE leading to DC in the PC trials was 2% in each group. The only SOC with a risk greater than placebo in any GMB group was the General disorders and administration site conditions SOC (0.4%,1.1% and 0.1%, on GMB120, 240 and placebo, respectively) driven by non-SAE injection site reactions. In Set E, 4% of GMB patients discontinued drug/study because of an AE. There was no evidence of a dose response between GMB120 and 240. Significant AEs. Evaluation of severe AEs and DMEs did not identify a new safety signal. Most common AE. The SOCs with the greatest percentage of AE in both the PC trials and in Set

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E and at least 1% greater than placebo in the controlled trials were the Infections and infestations and General disorders SOC. The greatest difference with placebo was in the General disorders SOC (24%, 28% and 17%, in the GMB120, 240 and placebo groups, respectively) driven by injection site reactions (18%, 23% and 13% on GMB120, 240 and placebo, respectively). Other AE with at least 2% risk (rounded) and at least 2% greater than placebo in any GMB group were upper respiratory tract infections (11% on both GBM doses vs. 9% on placebo, driven by sinusitis [5.8% and 5.5% and 5%, GMB120 and GMB240 and placebo, respectively]). Vital sign, laboratory and ECG evaluations did not identify a safety signal. Outlier analyses suggested a dose response for increased DBP between GMB240 and 120 in Set E, but conclusions cannot be made in the absence of a control group. More patients presented increase in weight ≥7% in the GMB treatment groups as compared to placebo (10% and 9%, respectively) in the placebo-controlled trials. Pre-specified AE of interest • CV safety – A small number of patients presented SAE or discontinuation because of cardiac, vascular and cerebrovascular events in this database, some of them associated with hypertension, but there was no imbalance for these events between GMB and placebo (0.5% and 0,3% each, respectively). Most events on GMB (including the OL phase) occurred in the GMB240 group. However, the number of events is small. Analyses of all AE (serious and non-SAE) that involve cardiac or vascular PTs showed no difference between GMB120, 240 and placebo (approximately 3% in each group). There was no evidence that GMB increases the risk of cardiovascular ischemic events or blood pressure related events in this database. However, the size and duration of the database is insufficient for adequate evaluation of CV safety. Moreover, the patients in these trials did not reflect the demographics and CV risk factors as per the published literature. • Hepatic safety- there is no evidence that GMB increases liver toxicity in this database. • Injection site reactions – GMB is associated with injection site reactions (see above, common AE). This should be mentioned in Section 6.1 of labeling. • Hypersensitivity – GMB is associated with hypersensitivity including urticaria, rash, pruritus, and unspecific symptoms such as dyspnea and chest pain/discomfort. In the PC trials, at least 3% had AE consistent with non-site hypersensitivity in the GMB groups as compared to 2% on placebo. In Set E 6% of patients presented some of these events. At least 15 patients (0.7%) discontinued GMB because of AE consistent with systemic hypersensitivity. There were no reported cases of angioedema or anaphylaxis but these events are certainly possible. A handful of patients presented a constellation of signs and symptoms consistent with a complex allergic reaction (dyspnea, unspecific symptoms [body pains/abdominal pain/dizziness/ lethargy], malaise, fatigue and chest pain/tightness). Information regarding the risk of hypersensitivity should be included in the Warnings and Precautions section of labeling. • Upper respiratory tract infections occurred more frequently on GMB as compared to placebo, driven by sinusitis (see above, common AE). None of them were SAE. • Suicidality. There was no evidence of an increased risk of suicidality with GMB.

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Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

• Immunogenicity. 17% of patients became ADA+ during GMB treatment for up to 1 year. Definitive conclusions cannot be drawn regarding ADA positivity and adverse events. No data exist on the immunogenicity of GMB on re-exposure after treatment interruption. Potential new issue: There was a signal for increased menstrual bleeding with GMB, driven by menorrhagia, but the number of events is small for definitive conclusions.

There are no safety concerns that would preclude approval of galcanezumab at the proposed dose of 120 mg monthly, with a loading dose of 240 mg for the prevention of migraines.

9. Advisory Committee Meeting and Other External Consultations

There was no FDA AC meeting.

10. Labeling Recommendations

Prescription Drug Labeling

The Applicant’s proposed GMB labeling is currently under review. I agree that there is no need for a Boxed Warning. I concur with the recommendation by the MPPRC not to include information about the potential CV risk of CGRP inhibition. However, I favor including a description of the population included in this clinical database in terms of age, gender and cardiovascular risk, and making clear that no patient was exposed for more than 1 year.

11. Risk Evaluation and Mitigation Strategies (REMS)

Not Applicable.

12. Postmarketing Requirements and Commitments

This product will be used in women of childbearing potential. I recommend a postmarketing Pregnancy Registry.

Given the concerns raised in the literature about potential CV effects of long-term CGRP inhibition, I am in favor of some type of postmarketing study or monitoring to address this possibility. Upon extensive discussion, the FDA MPPRC concluded that there is not compelling

CDER Clinical Review Template 98 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

evidence that antagonism of CGRP poses a cardiovascular risk, therefore, a PMR will not be requested.

13. Appendices

References F.A. Russell et al. Calcitonin Gene Related Peptide: Physiology and Pathophysiology. Physiol Rev 94: 1099–1142, 2014. MaassenVanDenBrink et al. Wiping out CGRP: Potential Cardiovascular Risks. Trends in Pharmacological Sciences. Vol 37 (9). September 2016. Kezeli et al. Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality and PG2 production by nitrate-induced tolerant rats with acute myocardial infarction. The EPMA Journal (2016) 7:6. Smillie et al. An ongoing role of αCGRP as part of a prospective network against hypertension, vascular hypertrophy and oxidative stress. Hypertension. 2014;63:1056- 1062. M. E. Bigal, T. Kurth, N. Santanello, et al. Migraine and Cardiovascular disease. A population based study. Neurology 2010;74;628-635 Sacco and Kurth. Migraine and the Risk for Stroke and Cardiovascular Disease. Current Cardiology Reports. Vol 16 (9) September 2014. Lipton et al. Framingham-based Cardiovascular risk estimates among people with episodic migraine in the US population: results from the American Migraine Prevalence and Prevention (AMPP) study. Headache 2017;57:1507-1521. Buse et al. Cardiovascular events, conditions and procedures among people with episodic migraine in the US population: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache 207:57:31-44. Vetvik and MacGregor. Sex differences in epidemiology, clinical features and pathophysiology of migraine. Lancet Neurol 2017:15:76. International Conference on Harmonisation (ICH) guidance (“The Extent of Population Exposure to Assess Clinical Safety For Drugs Intended for Long-Term Treatment of Non- Life-Threatening Conditions” (ICH 1995) 13.1.11 Breslau N, Schultz LR, Stewart WF, Lipton RB, Lucia VC, Welch KM. Headache and major depression: Is the association specific to migraine? Neurology. 2000;54(2):308–313. 13.1.12 Yallampalli C et al. Calcitonin gene related family peptides: importance in normal placental and fetal development. Adv Exp Med Biol, 2014, 834:229.

Return to Section 4; Return to 8.2.2; Return to section 8.5

CDER Clinical Review Template 99 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Additional information not included in body of the review

Eligibility criteria for phase 3 studies

- Studies I5Q-MC-CGAI and I5-MC-CGAH in Episodic Migraine

Studies CGAG also referred to as “EVOLVE 1”( or “Study 1” in labeling) and study CGAH also referred to as “EVOLVE 2” (or Study 2 in labeling) included male and female patients 18 to 65 years of age (inclusive) with a diagnosis of migraine as defined by International classification of Headache disorders (ICHD), with or without aura, for at least 1 year prior to Visit 1, and migraine onset prior to age 50. Patients were to have 4-14 migraine headache days per month as confirmed during a prospective 1-month baseline period. In addition, patients had to agree to use an acceptable method of birth control during the study and for at least 5 months after last dose of IP, and be willing to follow study procedures. Patients were allowed to use medication for the acute treatment of migraine, but not for the prevention of migraine. Treatment was given once a month (28 days ± 2 days) (GMB 240 mg, GMB 120 mg with a 240 mg loading dose, or placebo). A schematic of the study design for study CGAG is shown below

Figure 2. BLA 761063. Study design for CGAG in Episodic Migraine

Source: Figure CGAG.9.1, CGAG Study report. Abbreviations: LY2951742 = galcanezumab; SP = study period. * Eligibility period determined between a minimum of 30 days and a maximum of 40 days. Investigators may have had up to 5 additional days (beyond the 40 days) if needed to schedule a patient’s Visit 3 appointment. a Patients randomized to the 120-mg dose received a loading dose of 240 mg at the first injection only (Visit 3).

To preserve blinding throughout the study, patients in all treatment groups received 2 injections of IP at each dosing visit. Patients continued to log in and complete the ePRO diary each day. Patients could continue to take their allowed acute migraine headache medications during the treatment phase, but opioid- and containing medications were limited to

CDER Clinical Review Template 100 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

3 times per month, with only 1 corticosteroid injection allowed at any time during the trial, and no oral corticosteroids. All randomized patients were to enter this 4-month posttreatment phase (washout), including patients who discontinued treatment early in Study Period III. One month after Visit 12, if clinically warranted due to a worsening of symptoms, patients could start migraine prevention medications at the discretion of the investigator. Site personnel and patients remained blinded to their Study Period III treatment assignments.

- Study CGAI (“Study 3”)

CGAI was a study in patients who met ICHD criteria for chronic migraine with ≥15 headache days per month, of which at least 8 had the features of migraine, as confirmed during a prospective 1-month baseline period. It included a 3-month, double-blind, placebo-controlled treatment period of GMB 240, GMB 120 + one 240 mg loading dose, or placebo monthly, followed by an optional 9-month open-label extension with either 120 or 240 mg flexible dosing, and a subsequent 4-month washout period. Patients could use medications for acute migraine. One third of patients could continue stable doses of topiramate or propranolol for prevention of migraine. A schematic of the study is shown below.

Figure 3. BLA 761063. Study design for CGAI in chronic migraine

At Visit 7, all patients who entered the open-label extension received galcanezumab at a dose of 240 mg. At Visit 8, all patients received galcanezumab at a dose of 120 mg. Starting at Visit 9, dosing was flexible (galcanezumab 120 or 240 mg) at the discretion of the investigator.

The pivotal studies evaluated efficacy, health outcomes, immunogenicity, PK/PD and safety. - Study CGAJ

Study CGAJ was an open label study in patients with episodic or chronic migraine, with a one- month baseline period followed by 12 months of treatment at the two doses (b) (4)

CDER Clinical Review Template 101 Version date: September 6, 2017

Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

(b) (4) , followed by a 4-month post treatment phase. Patients received the first dose at the site, but could self-administer GMB via subcutaneous injection thereafter. The study consisted of a mix of office visits and telephone visits.

Exclusion criteria for the phase 3 studies are summarized below (from protocol CGAG). - Current enrollment or participation in another investigational drug study within the last 30 days or within 5 half-lives of the investigational product. Current or prior exposure to GMB or another CGRP antibody. o Use of the following prior or concomitant therapy: therapeutic antibodies, medication or other treatment for the prevention of migraine headaches. - Failure to respond to 3 or more adequately dosed migraine preventive treatments - Known hypersensitivity to multiple drug, monoclonal antibodies or other therapeutic proteins, including GMB. - Headaches other than episodic or chronic migraine; history of head or neck injury within 6 months prior to visit 1 - ECG showing abnormalities compatible with acute CV events and/or serious CV risk, including but not limited to prolonged QTc interval, or have had myocardial infarction, unstable angina (UA), percutaneous coronary intervention, coronary artery bypass graft, stroke, or deep vein thrombosis/pulmonary embolism within 6 months of screening, or have planned cardiovascular surgery or percutaneous coronary angioplasty. - Body mass index ≥40 kg/m2. - Any liver tests outside the normal range at Visit 1 that are clinically significant. Alanine aminotransferase (ALT) >2X upper limit of normal (ULN), or total bilirubin (TBL) >1.5X ULN, or alkaline phosphatase (ALP) >2X ULN must be discussed and judged not clinically significant by Lilly Medical prior to enrollment. - Evidence of significant active or unstable psychiatric disease by medical history - Patients who, in the clinician’s judgment, are actively suicidal and therefore deemed to be at significant risk for suicide - Pregnancy - Patients who have used opioids or barbiturate containing analgesic >2X per month for the treatment of pain in more than 2 of the past 6 months; history of drug or alcohol abuse/dependence within 1 year prior to visit 1 or currently using drugs of abuse. - Have a history or presence of any other medical illness including but not limited to any autoimmune disorder, cardiovascular, hepatic, respiratory, hematological, endocrine, psychiatric or neurological disease, or any clinically significant laboratory abnormality, that in the judgment of the investigator, indicates a medical problem that would preclude study participation. - In the opinion of the investigator have other issues which would interfere with compliance with the study requirements and completion of evaluations required for this study.

- Discontinuation criteria

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Reference ID: 4327093

Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Additional Applicant’s evaluation of selected AE of interest

- Lilly’s evaluation of use of concomitant CV medications in Set E (original and SUR).

Source: Table 2.53 of ISS. GMB = galcanezumab; N = number of patients in the analysis population; n = number of patients within each specific category. Note: Shaded rows contain initial submission data. a GMB-treated patients while receiving GMB treatment b GMB-treated patients while and after receiving GMB treatment c Four patients were re-classified by Cardiovascular Disease Risk Group in this safety update due to the provision of additional medical history during the safety update reporting period; as such, N=458 for the “Yes” subgroup and N=2128 for the “No” subgroup in the initial submission data presented here.

Overall, approximately 2% of patients increased use of antihypertensive medications in set E during the treatment period, and an additional 1% did it in the post-treatment period. The increase in use of CV medications occurred at a higher rate among patients with CV risk factors as compared to patients in the treatment + post-treatment period (e.g. 8% of 460 patients vs. 2% of 2126, respectively, for anti-HTN medications), but higher use of CV medications would also be expected for patients at risk not exposed to GMB.

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Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

- Lilly’s evaluation of Potential hypersensitivity AE in Set A, after medical review

N = number of patients in the analysis population; n = number of patients within each specific category; PBO = placebo; SMQ = Standardized MedDRA Query.* p-value≤0.05 (vs. placebo)**p-value≤.0.01 (vs. placebo). Source: Lilly’s Table 2.1 of response submitted June 15, 2018. Includes analyses of Immediate (on day of drug administration) and Non-immediate (beyond day of drug administration) reactions. Both immediate and non-immediate Hypersensitivity SMQ Narrow reactions were more common on GMB as compared to placebo (Immediate: 14 [1%] vs. 5 [0.3%] respectively; non-immediate: 55 [3.8%] and 35 [2.4%], respectively [both statistically significant, data not shown]). The Hypersensitivity SMQ Narrow search included injection site rash, injection site hypersensitivity, hypersensitivity, rash (various types), dermatitis allergic/contact/atopic, rash pruritic, allergic pruritus/conjunctivitis/rhinitis, bronchospasm and urticaria; the SMQ Broad search included pruritus, asthma and seasonal allergy, among other PTs. None was serious. The Angioedema SMQ Narrow included urticaria. There were no Anaphylaxis SMQ Narrow AEs. (There were some SAE of hypersensitivity in the OL trial).

A similar analysis for set E, submitted 8/6/18 showed that the rate of Hypersensitivity Narrow SMQ for all immediate and non-immediate reactions was 7% for both GMB120 and 140 (Data not shown).

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Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

- Lilly’s evaluation of glucose-related laboratories (fasting glucose, insulin and C-peptide)

Set A+C (Source APP 3.2, 5/25/18)

Set E

Source: SUR. Low and High refer to values below and above normal range. Normal fasting glucose for this lab: 3.8 - 5.6 mmol/L (equivalent to 68 – 100 mg/dl).

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Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

- Lilly’s analyses or new Anti-Drug Antibody and Neutralizing Antibody

Set A+C (Placebo-controlled studies)

Set E (All studies)

ADA= Anti-Drug antibody. N= number of patients in the analysis population; n = number of patients in specified category; TE = treatment-emergent. *a, A patient is TE ADA evaluable if there is at least one baseline assessment and at least one postbaseline assessment of ADA. *b. A TE ADA evaluable patient is TE ADA+ if the patients has a negative baseline result and any subsequent positive postbaseline ADA result with a titer >= 1: 20 (treatment- induced); or a positive baseline with subsequent positive postbaseline ADA result with a >= 4 fold increase in titer (treatment-boosted); A TE ADA evaluable patient is TE ADA Inconclusive if > 20% of the patient's postbaseline samples, drawn pre-dose, are ADA Inconclusive and the patient is not otherwise TE ADA+. A TE ADA evaluable patient is TE ADA- if not TE ADA+ and not TE ADA Inconclusive. (1) Denominator for percent (%) is the number of patients who are TE ADA Evaluable in each treatment group. (2) Baseline for ADA analysis is defined as the last ADA assessment prior to first study drug administration. Source: Response to FDA request submitted 5/9/18.

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Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

Analyses of increased menstrual bleeding in Set A by Preferred Term

Placebo GMB 120 GMB 240 Females exposed N= 1237 N= 599 N= 609 Females with events n % n % n % Any Menstrual Disorder 13 1.1% 12 2.0% 17 2.8% Amenorrhoea 1 0.1% 0 0.0% 1 0.2% Dysmenorrhoea 6 0.5% 2 0.3% 5 0.8% Menorrhagia 1 0.1% 3 0.5% 5 0.8% Menstrual disorder 0 0.0% 0 0.0% 4 0.7% Menstruation irregular 5 0.4% 4 0.7% 1 0.2% Metrorrhagia 1 0.1% 2 0.3% 0 0.0% Oligomenorrhoea 0 0.0% 1 0.2% 1 0.2% Polymenorrhoea 1 0.1% 0 0.0% 1 0.2% Source: MO analysis, ADAE datasets.

Analyses of menstrual disorders in Set A by HLT

Total number of patients: Placebo= 13, GMB 120= 12, GMB240= 17

Return to 8.4.5

Other GMB studies

The galcanezumab program included 4 phase 1 clinical pharmacology studies in healthy subjects (CGAO, CGAQ, CGAA and CGAE), a completed study in osteoarthritis (CGAF) and ongoing, blinded studies in cluster headache (CGAL, CGAM, CGAR). There are also 2 ongoing migraine trials in Japan (CGAN and CGAP).

Phase 1 studies evaluated the PK and PD of the lyophilized versus the solution formulations as well as those of GMB administered via prefilled syringes or via autoinjector. Two of the 2 clinical pharmacology studies (CGAA and CGAE) included triplicate ECGs in healthy subjects treated with GMB or placebo. Overall, the phase 1 population included 446 healthy subjects of whom 419 received at least 1 dose of GMB. The majority were white (55%) and male (58%). Thirty-three percent were African American. Mean age and weight were 36.5 years and 78.5 kg, respectively. The maximum single dose administered in this trial was 600 mg. One death of uncertain cause (suspected drowning) occurred in one of these studies (described under Deaths). Two subjects had 1 SAE each: one atrial fibrillation on 300 mg of GMB, and one

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Reference ID: 4327093 Clinical Review Maria L. Villalba, M.D. BLA 761063 – Emgality (galcanezumab) for prevention of migraines

cellulitis on placebo. No patients discontinued because of AEs. AE were similar to those observed in the Phase 2 and 3 trials.

Study CGAF, included 266 patients, 190 of whom received GMB at the dose of 5 to 300 mg monthly in patients with knee pain associated with osteoarthritis. The trial was designed to include treatment for 16 weeks, with a follow up period of 8 weeks, but was stopped because of futility (as per the CSR, there was inadequate analgesic efficacy at a protocol planned interim Analysis). There were no deaths. Two patients had SAE. One was on placebo (small intestinal obstruction). The SAE on GMB (myocardial infarction) was described in page 37 this review. Two patients discontinued because of AE (one [on placebo [convulsion] and one on celecoxib [pain in extremity]).

(b) (4) (b) (4) (b) (4)

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Reference ID: 4327093 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

MARIA L VILLALBA 09/27/2018

SALLY U YASUDA 09/27/2018

Reference ID: 4327093

Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

ranges from 11-12% and is approximately 3 times more frequent in women than in men. Dr. Villalba provides a list of the 5 products already approved for prophylaxis of migraine in the United States, in addition to the CGRP receptor antagonist, erenumab, approved in May 2018 and the CGRP antagonist, fremanezumab, approved in September 2018. Dr. Villalba notes that other products are used off-label for this indication. She states that because of insufficient response or tolerability issues, a substantial number of patients discontinue preventive treatment within 6 months.

 Regulatory background and marketing history Please refer to reviews by Dr. Suhail Kasim and Dr. Villalba.

2. Product Quality Please refer to the CMC review.

3. Nonclinical Pharmacology/Toxicology Please refer to the nonclinical reviews.

Dr. Lois Freed, supervisory pharmacologist, discusses in her memorandum that because of the potent vasodilatory properties of CGRP, concerns were raised regarding long-term antagonism of the CGRP in humans, particularly in patients with cardiovascular risk factors. The applicant was asked to provide a review of relevant published literature and data available to the applicant. Since this request was made, the Agency has conducted an independent evaluation of available published literature, primarily on a well-established probe (CGRP(8-37)), to investigate the potential for antagonism of CGRP to induce vasoconstriction or adversely affect coronary vessel size, blood flow, or coronary infarct size under ischemic conditions. The results of this evaluation suggest that regulation of vascular tone in healthy patients and those with cardiovascular risk factors involves multiple endogenous factors, of which CGRP is only one, and that there is limited understanding of the role of CGRP in normal hemodynamic processes or response to ischemic events. It was, therefore, concluded that there is insufficient information to dismiss the original concerns, but that additional basic research is needed to further understand the role of CGRP in these processes. Without a better understanding, it is unlikely that nonclinical studies of galcanezumab could be designed and conducted that would provide useful information; therefore, no postmarketing study to further assess the cardiovascular safety of galcanezumab is recommended.

4. Clinical Pharmacology Please refer to the Clinical Pharmacology review. The following information regarding pharmacokinetics and pharmacodynamics is from of the Clinical Overview provided by the applicant and reflects the findings most relevant to safety.

 Peak plasma concentrations occur at approximately 5 days after a dose.

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

 Elimination half-life is approximately 27 days.  Inhibition of capsaicin-induced dermal blood flow lasted for at least 134 days after the last dose of galcanezumab was given (5 half-lives).

5. Clinical Microbiology Not applicable.

6. Clinical/Statistical- Efficacy Please refer to Dr. Suhail Kasim’s review of efficacy.

7. Safety

8.1 Safety Review Approach The safety pools included in the application have the following characteristics, as provided by Dr. Villalba:

Safety cohorts for BLA 761063 Safety Safety Population Analysis Set Description Studies Double blind period of the placebo controlled pivotal CGAH and CGAG trials (includes 1 month post-treatment follow-up for (EM; 6 months) 1435 A CGAH and CGAG) CGAI (CM; 3 months) CGAH and CGAB CGAI Phase 2 and 3 placebo controlled trials (includes 1 ART-01 (EM; proof of 1815 month post treatment follow for CGAH and CGAG concept; 3 months) and 3 months posttreatment follow-up for aRT-01 and CGAB (EM, dose B CGAB ranging; 3 months) C 4 month post treatment follow-up for episodic CGAH and CGAG 1435 CGAH and CGAG CGAI CGAJ (12 month open label safety; fixed dose with 4 month post- Post-treatment follow-up of 4 phase 3 studies (CGAI treatment washout; D ongoing at time of safety update report [SUR]) episodic and chronic) 2586 CGAH and CGAG (Set B plus 771 subjects CGAI who switched from All galcanezumab-treated patients in phase 2 and ART-01 placebo to galcanezumab phase 3 studies (CGAI ongoing at time of the SUR). CGAB in the open label E _ CGAJ extension of CGAI) EM: Episodic migraine. CM: Chronic migraine.

Study characteristics were as follows: Phase 2 study ART-01 used 150 mg every 2 weeks Phase 2 study CGAB used 5, 50, 120, or 300 mg every 4 weeks Phase 3 studies CGAG, CGAH, and CGAI used doses of 120 mg or 240 mg/month

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

The 9- month open label phase of CGAI had flexible doses Phase 3 12-month open label study CGAJ used fixed doses of 120 or 240 mg/month

Study personnel administered the study drug. The primary data (the safety population) in Dr. Villalba’s review and in this memo are from the migraine trials. In addition to these studies, the BLA includes 4 clinical pharmacology studies in healthy volunteers (n=419 on galcanezumab), study CGFA in patients with osteoarthritis (n=151 on galcanezumab), (b) (4)

Dr. Villalba primarily used Sets A+C to evaluate safety signals in the controlled trials and Set E for long-term safety. I agree with her approach. The use of Sets A+C allows for inclusion of AEs that may occur in the washout period of this drug with an elimination half-life of 27 days and pharmacodynamic effects (inhibition of capsaicin-induced dermal blood flow) detected up to 134 days after the last dose in a multiple dose study.

I agree with Dr. Villalba’s use of “modal dose” for evaluation of AEs in the database. Modal dose reflects the flexible doses in the open label portion of CGAI and reflects patients randomized to receive 120 mg monthly who may have received a single loading dose without receiving more than one 120 mg dose. Dr. Villalba notes that 18 patients randomized to receive 120 mg received the 240 mg modal dose, and 1 patient randomized to placebo received the 120 mg modal dose.

I note that worsening migraine was included as an AE. However, my memo does not discuss it as an AE, considering that it may reflect lack of efficacy.

8.2 Review of the Safety Database Adequacy of the drug exposure experience (i.e., the safety database) The exposure to galcanezumab at relevant doses meets ICH criteria. Only 15% of the patients were male. One percent were 65 years of age or older. In addition there was limited exposure overall in patients with cardiovascular risk factors. As noted by Dr. Villalba, the database may not reflect the migraine population in the United States and the database would not address potential cardiovascular safety concerns. Exposure is described in more detail in the following paragraphs.

The table below, extracted from Dr. Villalba’s review, shows duration of exposure in Set E at through the Safety Update Report (SUR). The exposure at relevant doses in the migraine population exceeds ICH guidelines of 1500 patients total, 300-600 patients for 6 months, and 100 patients for 1 year. At the time of the SUR, there were 1487 patient years of exposure. No patient had more than 12 doses. Dr. Villalba notes that 1104 patients had at least 6 doses of galcanezumab followed by 4 months of post-treatment follow-up (that would address 4 half-lives of elimination), but that only 266 patients had 12 doses with 4 months of post-treatment follow-up.

Duration of Exposure in Migraine Trials, through the Safety Update Dosage (modal dose) Number of patients exposed to galcanezumab ≥ 3 monthly doses ≥ 6 monthly doses 12 monthly doses Any dose in Phase 2 and 3 studies 2446 1920 526 120 mg (with loading dose of 240 mg) 878 735 167

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

240 mg 1280 1185 359 Total 120 or 240 mg 2158 1920 526

For the placebo-controlled migraine trials Safety Set A, the median age was 41 years (range 17-66 years2; 1% [14 patients] were 65 years of age or older), 85% of patients were female and 77% were white. Dr. Villalba shows that gender distribution was generally similar across treatment groups; she notes that galcanezumab patients were slightly younger than placebo- treated patients (approximately 47% of galcanezumab patients and approximately 42% of placebo patients were less than 40 years old). Approximately 8% of patients were black, 6% were Asian, and 73% were non-Hispanic or Latino. Most patients were in North America (67%). Dr. Villalba notes that analysis by gender, race, and age will be limited by the small number of men, non-white subjects, and adults older than 65 years.

Dr. Villalba notes that the percentage of patients with cardiovascular risk factors was similar in the galcanezumab (17.2 %) and placebo (18.5%) groups; 0.2% of galcanezumab and 1% on placebo had a history of myocardial infarction, stroke, angina, TIA, or peripheral arterial occlusive disease. Approximately 5% of galcanezumab patients and 7% of placebo patients were taking medications for hypertension and 3% of galcanezumab and 1% of placebo patients were taking medications for hypercholesterolemia at baseline.

Dr. Villalba notes a theoretical concern raised in the literature regarding CGRP inhibition resulting in impaired protective vasodilation in patients in pre-existing cardiovascular morbidity. She notes that the prevalence of cardiovascular risk factors in the galcanezumab development program is less than that in the 2009 American Migraine Prevalence and Prevention longitudinal study in the US in which 35% of migraine patients had a history of hypertension, 15% had a history of diabetes, and 40% had a history of high cholesterol.3 I agree with Dr. Villalba that the galcanezumab database does not have the power to assess cardiovascular safety.

8.3 Adequacy of Applicant’s Clinical Safety Assessments Clinical Safety Assessments appear to have been adequate. Dr. Villalba notes that categorization of adverse events was acceptable in general. Routine clinical tests and testing schedule appear to be adequate, although as Dr. Villalba notes, orthostatic changes in blood pressure would be reasonable to collect but were not evaluated.

8.4 Safety Results Overall, there were slightly more frequent serious adverse events (SAEs), discontinuations due to adverse events (AEs) particularly in the 240 mg monthly group, and treatment emergent adverse events (TEAEs) in patients receiving galcanezumab compared to placebo. Most events of SAEs or AEs leading to discontinuation occurred in only 1 patient.

2 From ISS p. 62, Table APP.1.5. 3 Lipton et al. Framingham-based cardiovascular risk estimates among people with episodic migraine in the US population: results from the American Migraine Prevalence and Prevention (AMPP) study. Headache 2017; 57:1507-1521.

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

In this section I first discuss the deaths in the database. Then I provide a general overview of the safety results regarding SAEs and discontinuations. I discuss Significant Adverse Events, Treatment-Emergent Adverse Events and Reactions, Laboratory Findings and Vital Signs. Next I discuss Submission Specific Safety Issues and then other significant adverse events, incorporating information from SAEs, Discontinuations, TEAEs, and labs, as appropriate. I finish Section 8.4 with a summary of the other issues discussed in Dr. Villalba’s safety review.

Deaths (b) (4)

In clinical pharmacology study CGAQ subject CGAQ-(b) (6) , a 36 y.o. healthy male volunteer with no concomitant medication and unremarkable past medical history and screening received a single dose of galcanezumab 240 mg on Day 1. He did not report any AEs during outpatient visits through Day 12. On Day 15, he was found “face down in the water next to a yacht slip”. He had no signs of trauma and toxicology results were negative for alcohol and common drugs of abuse. According to the autopsy he had pulmonary congestion but Dr. Villalba notes there was no mention of water in the lungs. The autopsy report concluded that he died of accidental drowning. Dr. Villalba states that arrhythmia could be an explanation. This event would have occurred 10 days after the expected tmax of approximately 5 days. I agree with Dr. Villalba that the relationship to study drug is unknown.

SAEs and Discontinuations and TEAEs overall Overall, SAES were few and slightly more frequent in the galcanezumab groups than in the placebo group, with no evidence of dose-relatedness either in controlled trials or in Set E. Discontinuations due to adverse events in the controlled trials were few and were generally balanced across treatment groups and occurred slightly more frequently in Set E than in the controlled trials. Most SAEs and discontinuations due to AEs in Set A+C occurred in only 1 patient. In the controlled trials, TEAEs occurred slightly more frequently in galcanezumab- treated groups than in placebo in general, and slightly more frequently in the galcanezumab 240 mg group than in the 120 mg group. TEAEs occurred more frequently in Set E than in the controlled trials, and in Set E they occurred more frequently in the 240 mg group than in the 120 mg monthly group.

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

Patients with SAEs, Discontinuations Due to Adverse Events, or TEAEs in Migraine Trials Controlled Trials (Set A+C) Placebo Galcanezumab Galcanezumab 120 mg 240 mg (N=1451) monthly monthly n (%) (N=705) (N=730) n (%) n (%) All SAEs 19 (1.3) 16 (2.3) 17 (2.3) Discontinuations4 24 (1.7) 17 (2.4) 14 (1.9) TEAEs 882 (61) 456 (65) 490 (67) Set E (b) (4) Galcanezumab Galcanezumab 120 mg 240 mg monthly monthly (N=926) (N=1350) n (%) n (%) All SAEs 32 (3.5) 50 (3.7) Discontinuations 38 (4.1) 52 (3.9) TEAEs 663 (72) 1031 (76)

Serious adverse events (SAEs) As Dr. Villalba notes, SAEs were not frequent. She notes that in the Phase 3 migraine controlled trials approximately 2/3 of SAEs occurred in the treatment period and 1/3 in the post-treatment period. SAEs occurred at similar rates among galcanezumab treatment groups, and slightly more than placebo in the controlled trials. Dr. Villalba shows that most SAEs occurred only in 1 patient. The SOC with most SAEs were neoplasms (0.5% in total galcanezumab and none in placebo) and GI disorders (0.4% for galcanezumab pooled and 0.2% for placebo). Cardiac disorders SAEs and other vascular or cerebrovascular SAEs are shown in the table below, extracted from Dr. Villalba’s review. These SAEs are described in more detail below. In a Phase 2 trial, there was also a patient with pre-existing risk factors who had thromboembolic events resulting in an above knee amputation.

Placebo GMB120 GMB240 N=1451 N=705 N=730 n % n% n% Cardiac disorders 1 0.1% 0 0.0% 2 0.3% MI, Acute MI 1 0.1% 0 0.0% 1 0.1% Cardiac failure congestive5 0 0.0% 0 0.0% 1 0.1%

4 The Sponsor’s analysis found slightly more discontinuation due to AEs (adding dyspepsia, gastritis, and 2 viral upper respiratory infections) than Dr. Villalba’s analysis. However I agree with Dr. Villalba that this difference does not impact the conclusions. 5 The cardiac failure congestive and cardiomyopathy SAEs were reported in the same patient.

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

Placebo GMB120 GMB240 N=1451 N=705 N=730 n % n% n% Cardiomyopathy5 0 0.0% 0 0.0% 1 0.1% Nervous system disorders 1 0.1% 0 0.0% 2 0.3% Transient ischemic attack 0 0.0% 0 0.0% 1 0.1% Respiratory, thoracic and 1 0.1% 0 0.0% 1 0.1% mediastinal disorders Pulmonary embolism 1 0.1% 0 0.0% 1 0.1% Vascular disorders 1 0.1% 0 0.0% 0 0.0% Deep vein thrombosis 1 0.1% 0 0.0% 0 0.0%

In Set E SAEs occurred at similar rates among the proposed to-be-marketed treatment groups. The most commonly reported SAEs in Set E were in the SOCs of gastrointestinal disorders (0.6% that included 1 case of acute pancreatitis in each dose group, 2 cases of gastritis in the 120 mg group, 1 case of small intestinal obstruction and of vomiting in each dose group, and single cases of other events), infections and infestations (0.5% that included 2 cases of appendicitis in the 120 mg group and 1 in the 240 mg group and single cases of other events), neoplasms (0.5% with 2 cases of uterine leiomyoma in the 120 mg group and other neoplasms that occurred in only 1 patient each) , and nervous system disorders (0.4% including two cases of migraine in the 240 mg group and 1 in the 120 mg group, 1 case of seizure in each group, and single cases of other events). Other SAEs that occurred in more than 1 patient in the (b) (4) Set E were acute myocardial infarction (2 patients on 240 mg), cardiac failure congestive (2 patients on 240 mg), noncardiac chest pain (2 cases on 240 mg), cholelithiasis (1 case on each dose), intervertebral disc protrusion (2 cases on 240 mg), nephrolithiasis (2 cases on 240 mg) , and urticaria ( 2 cases on 240 mg). Set E also included doses of less than 120 mg (in which a SAE of Crohn’s disease was reported in the 5 mg group and a dose of 300 mg monthly with 1 SAE each of peripheral vascular disease, spontaneous abortion, and suicidal ideation.

Selected SAEs are described below.

Cardiac and Cerebrovascular SAEs

Set A+C Dr. Villalba identified 1 patient with myocardial infarction in the controlled trials on galcanezumab and 1 in a placebo patient, (and 1 additional patient in Set E, discussed below under Set E).

Subject CGAH- (b) (6) was a 55 y.o. female with a history of hypothyroidism and Raynaud’s phenomenon and “family history of cardiac disease” with blood pressure at baseline of 110/70, without known cardiac risk factors (other than family history6) who had a SAE of acute myocardial infarction on Day 79 (1.5 weeks after the third dose of 240 mg) with coronary angiography

6 Risk factors reviewed in Narula N, Rapezzi C, Tavazzi L, Arbustini E. Medical Clinics of North America Volume 96, Issue 1, January 2012, Pages 67-86. https://doi.org/10.1016/j.mcna.2011.11.001

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

showing non-significant coronary disease, decreased blood flow, and ectasia in the coronary arteries. Although a contribution of CGRP inhibition cannot be ruled out, there is not strong evidence for a supporting role either.

Subject CGAG- (b) (6) was a 51 y.o. female nonsmoker with a history of hypothyroidism, pituitary tumor, obesity, and reported 1-2 drinks/day with baseline ECG showing PR < 120 msec who had a SAE of inverted T wave, congestive heart failure, and cardiomyopathy diagnosed during the follow-up period of the controlled trial (240 mg monthly). Dr. Villalba notes that this patient had risk factors but states that a role for galcanezumab cannot be ruled out. There is not sufficient information to either rule out or implicate galcanezumab as a cause for these events.

Subject CGAH- (b) (6) was a 54 y.o. female with a 10 year history of hypothyroidism who presented a non-SAE of hypertension 26 days after the 2nd dose of galcanezumab 240 mg and a SAE of transient ischemic attack (TIA) 2 days after the 3rd dose. She had baseline and visit 5 blood pressure with elevated diastolic (120/92) and a BMI of 33 (obese). On day 54 she had a non-SAE of hypertension and started amlodipine. On Day 59 she had a TIA and blood pressure at that time was 140/90. She discontinued from the study on Day 70 and 2 months later her blood pressure was 100/72. This patient had risk factors for elevated blood pressure and subsequent TIA. There is not sufficient information to rule out or implicate galcanezumab as a cause for these events.

Subject CGAI- (b) (6) was a 24 y.o. female using an intravaginal estrogen ring (hormonal contraception) for 2 years with a recent history of air travel approximately 3 weeks prior to the event of bilateral pulmonary embolism on galcanezumab 240 mg monthly. She continued galcanezumab treatment without further pulmonary embolism. Dr. Villalba also notes that there was a SAE of PE in the placebo group too. I agree with Dr. Villalba that this event in isolation cannot be attributed to galcanezumab.

Controlled Phase 2 trial Subject ART (b) (6) was a 41 y.o. female with a history of uncontrolled diabetes mellitus, smoking, obesity, and hyperlipidemia, with concomitant meds including metformin, insulin, and oral contraceptive, with a prior history of right ankle fracture (approximately 3 years prior to the event), presented left hip and foot pain approximately 3 months into treatment with galcanezumab 150 mg every 2 weeks (that began 43 days after the 6th dose). CT angiogram suggestive of pulmonary embolism, distal abdominal aorta thrombus with near complete occlusion of the common left ilia artery, femoral artery, and distal aspect of the left popliteal artery, resulting in thrombectomy and above knee amputation. I agree with Dr. Villalba that although the role of galcanezumab cannot be ruled out, this patient had multiple risk factors for pulmonary embolism and for peripheral vascular disease/thrombus (diabetes, smoking, obesity, hyperlipidemia, and oral contraceptives).

Open label period of CGAI and CGAJ

Subject CGAI- (b) (6) was a 55 y.o. male with no significant medical history but with baseline ECG showing nonspecific T-wave abnormality and concomitant meds of aspirin and sertraline, and started treatment for hyperlipidemia on the first day of the open label study, who developed acute myocardial infarction 10 days after the 5th dose of galcanezumab 240 mg, followed by unstable angina. Anxiety and dizziness in double blind period. Diarrhea started 10 days before the

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

MI. Dr. Villalba notes that there was no mention of blood pressure or electrolytes at the time of myocardial infarction. I agree with Dr. Villalba that a role for galcanezumab cannot be ruled out but in isolation cannot be attributed to galcanezumab.

Subject CGAI- (b) (6) was a 38 y.o. female with a history of obesity and a family history of heart disease (brother died of cardiomyopathy, mother died of hypertension and diabetes at age 56), with blood pressure at screening of 125/99mm had an SAE of cardiac congestive failure, with no significant coronary artery disease, with symptoms beginning with peripheral edema on Day 70 taking galcanezumab 240 mg. Dr. Villalba believes that inhibition of GCRP may have interfered with blood pressure regulation and worsened diastolic dysfunction in this patient. I agree that a role for galcanezumab cannot be ruled out, but the risk of CGRP inhibition is theoretical, and the patient had risk factors, and there is not sufficient information to implicate galcanezumab.

Subject CGAI- (b) (6) was a 44 y.o. female with a history of Raynaud’s phenomenon and thoracic outlet syndrome, taking galcanezumab 120 mg, who had an SAE of orthostatic intolerance 12 days after the 6th dose of galcanezumab 240 mg. The patient, who did not have a history of hypertension (but had an AE of postural dizziness approximately 10 days after the 4th dose), experienced diastolic hypertension 11 days after Visit 12 (Day 246) and was treated with amiloride/hydrochlorothiazide, and 3 days later (Day 249) was admitted to the hospital due to severe orthostatic intolerance. (She had taken naproxyn, 10 mg, and a caffeine- containing medication on Days 242, 243, 244, and 248, and 12.5 mg on Days 244 and 248). She received hydration during the hospitalization and the event resolved after 9 days. The patient withdrew from the study. Dr. Villalba believes that a role for galcanezumab cannot be ruled out. I agree that a role for galcanezumab cannot be ruled out, although amiloride/hydrochlorothiazide may have caused the “orthostatic intolerance”.

Dr. Villalba also comments on the following cases in the datasets that were not reported as SAEs, although she thinks that they should have been: Subject CGAG(b) (6) was a 56 y.o. female who presented with angina pectoris in the placebo controlled period on Days 52 (22 days after the 2nd dose and associated with dyspnea), 156 (day of the last of 6 doses), and day 180 (24 days after the last dose). Each event resolved the same day without apparent treatment. ECG and stress test showed no evidence of ischemia, arrhythmia, or abnormal blood pressure response. The diagnosis was later changed to muscle strain causing angina-like symptoms. The timing of the events, resolution on the same day of the event, and the lack of reproducibility after doses 3-5, do not support a drug-related event.

Subject CGAI- (b) (6) was a 62 yo. male with pre-existent arrhythmia, obesity, and high blood pressure had coronary artery stenosis in the open label period of galcanezumab 240 mg, 81 days after the last of 12 doses. The event is most likely due to his pre-existing condition.

Subject CGAF (b) (6) was a 62 y.o. female smoker with no other known CV risk factors who presented angina pectoris and myocardial infarction 26 days after the 3rd dose of galcanezumab 300 mg in the osteoarthritis study, with diagnostic catheterization showing “mild blockages”. Dr. Villalba believes that a role for galcanezumab cannot be ruled out. However, I note the pre- existing risk factors (age and smoking history) in this patient.

Gastrointestinal SAEs

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

SAEs related to gastrointestinal disorders occurred in 5 patients on galcanezumab 120 mg (0.7%), 1 patient on 240 mg (0.1%) and 3 on placebo (0.2%) in the controlled trials (Set A+C). Two subjects in the galcanezumab group had acute pancreatitis: Subject CGAG- (b) (6) on galcanezumab 120 mg with a prior history of pancreatitis, a lipase level just 1.04X ULN and insufficient information for a diagnosis of pancreatitis who continued to take galcanezumab after the event and who also had small bowel obstruction, and Subject CGAI- (b) (6) who was a 57 y.o. female on galcanezumab 240 mg, with acute pancreatitis 5 days after the first dose, with symptoms beginning before starting galcanezumab, associated with cholelithiasis. I agree with Dr. Villalba that neither case seems to be related to galcanezumab. I note that 1 placebo patient had an SAE of alcoholic pancreatitis.

Other gastrointestinal SAEs were: Subject CGAG- (b) (6) , a 36 y.o. male, with a prior history of small bowel obstruction, with small intestinal obstruction 6 days after starting galcanezumab in in the placebo controlled trial, and Subject CGAI- (b) (6) , a 53 y.o. female on galcanezumab 240 mg diagnosed with small bowel obstruction (but with normal CT scan) in the open label period, 269 days after the first dose and 9 days since the last (10th) dose. I agree with Dr. Villalba that the first case does not appear related to galcanezumab and the 2nd case has limited information to support the diagnosis.

General Disorders and Admin Site Conditions SAEs One SAE in this SOC occurred in the placebo controlled trials. Subject CGAH- (b) (6) , a 55 y.o. male with no prior history of allergies and with concomitant meds of aspirin, paracetamol, ibuprofen, ketorolac, and eletriptan, on galcanezumab 240 mg, had mild pruritus on Day 7 treated with corticosteroids, and skin ulcers on fingers, left elbow and left gluteus on Day 97, 12 days after the last dose. On day 100 he had an SAE of pyrexia and disorientation. Blood cultures were negative, he was treated with mupirocin (indicated for topical treatment of impetigo due to S. aureas and S. pyogenes) and prednisone and the SAEs resolved within 3 days with pruritus resolving on the same day as the pyrexia. The patient was a fisherman. Given the rapid resolution of the SAEs and resolution of pyrexia at the same time, and the occupational risk of staph infections in fishermen, it the SAE seems reasonably not related to galcanezumab.

Infections and Infestations SAEs Dr. Villalba notes in the placebo controlled trials 1 patient on galcanezumab had an SAE of infection (influenza) vs 2 on placebo (appendicitis and pyelonephritis with urosepsis). In Set E, SAEs of infections were 1 case each of osteomyelitis, cellulitis, diverticulitis, influenza, pneumonia, upper respiratory tract infection, urinary tract infection, endocarditis/infective aneurysm, and 3 cases of appendicitis. For all except the case of endocarditis (after which the patient was withdrawn from study drug), no action was taken regarding galcanezumab and the patients were recovered or recovering. CGAJ- (b) (6) was a 33 y.o. female who presented intracranial mycotic aneurysm secondary to aortic valve endocarditis with subarachnoid hemorrhage that occurred 122 days after the 12th dose of galcanezumab. The patient had undetected aortic insufficiency but otherwise no known risk factors for endocarditis. I agree that the event of endocarditis appears unrelated to galcanezumab and that individually the other SAEs in this SOC are not obviously related to galcanezumab.

Metabolism and nutritional disorders SAEs

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

One SAE in this SOC occurred in the placebo controlled trials: Subject CGAI-(b) (6) on galcanezumab 240 mg , a 41 y.o. male with a history of hypertension treated with hydrochlorothiazide (started 2 months prior to study entry), fluticasone, triamterene, and pantoprazole. The patient had an influenza like illness for 10 days beginning approximately 2 weeks after starting the study. The dose of HCTZ was increased 5.5 weeks into the study (that Dr. Villalba suggests could reflect worsening hypertension). Approximately 2 months into the study the patient had a SAE of hypokalemia and had kidney stone, treated with hydration and analgesics. The hypokalemia was thought to be related to HCTZ. It is possible that nephrolithiasis was related to dehydration after the influenza illness. I agree that neither event appears related to galcanezumab.

In the open label period subject CGAI- (b) (6) , a 24 y.o. female on galcanezumab 240 mg, with a history of type 1 diabetes for 10 years with episodes of hypoglycemia and diabetic ketoacidosis, had diabetic ketoacidosis 5 days after the 4th open label dose. I agree this is not likely related to galcanezumab.

Malignancy SAEs Dr. Villalba notes 7 malignancy SAEs in the controlled trials, all on galcanezumab 120 mg, including 5 malignant neoplasms ( tubular breast carcinoma, adenocarcinoma of the cervix, malignant nipple neoplasm, colon cancer, tonsil cancer) and 2 uterine leiomyomas, and 4 neoplasms in the open label studies (3 on 120 mg, 1 on 240 mg that were lung, tongue, squamous cell carcinoma, and malignant melanoma), All occurred less than 1 year into treatment (3 occurring less than 1 month into treatment). I agree with Dr. Villalba that the lack of cases at the highest dose and the early onset support that they are not likely drug related.

Nervous system disorders SAEs Dr. Villalba identified 3 SAEs of seizure (one in the double blind studies and 2 in the open label period) with galcanezumab and 2 non-SAE of seizures: Subject CGAH (b) (6) with tonic-clonic seizure SAE after vasovagal syncope on the day of first dose of galcanezumab 240 mg. Subject continued in the trial without further seizures. I agree that there is insufficient information to confirm that she had a seizure vs seizure-like activity related to vasovagal syncope, although she continued without further seizure suggesting this is unlikely to be related to galcanezumab. Subject CAGI- (b) (6) in subject with pre-existing history of seizures (pseudoseizures and generalized tonic-clonic seizures up to 1.5 years prior to the event) who had local reactions and episodes suggesting hypersensitivity 2-3 days after most injections, had a SAE of seizure 150 days after starting the open label phase, approximately 8 hours after the 9th dose of galcanezumab 240 mg. The patient had flu-like symptoms, cough, fever, nausea, bad taste in mouth and migraine 1 hour after that dose and those symptoms disappeared after the seizure. I agree with Dr. Villalba that a role for galcanezumab cannot be ruled out but I agree that in isolation, it is difficult to attribute this seizure to study drug. Topiramate was started the following day. Two weeks later, the patient had chest pain, dizziness, dyspnea (resolved after 2 months), nausea, decreased appetite, and cognitive impairment (resolved after 5 days). I note that these are all adverse events listed in the topiramate prescribing information. Whether the constellation of symptoms is related to a hypersensitivity event as Dr. Villalba proposes and whether these events are related to galcanezumab, related to each other, or related to topiramate is difficult to determine. Subject CGAI- (b) (6) in a subject with history of non-epileptic psychogenic seizures for 12 years and post-traumatic stress disorder, with concomitant meds including diphenhydramine for

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Reference ID: 4327108

Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

and 3 weeks of moderate exertional dyspnea and seasonal allergies had dyspnea during exercise 11 days after the 4th dose in the open label study, that did not resolve. I agree this does not appear related to galcanezumab. Subject CGAI- (b) (6) had hemoptysis in association with tongue malignant neoplasm 22 days after the 2nd galcanezumab dose that I agree does not appear related to galcanezumab.

Skin and subcutaneous tissues disorders SAEs Dr. Villalba notes no SAE in this SOC in placebo-controlled trials. She identified 2 SAE of urticaria in the open label study: CGAI- (b) (6) with urticaria (requiring hospitalization and prednisolone treatment) beginning 54 days after the 5th dose of galcanezumab, 9 days after treatment with ciprofloxacin and 3 days after beginning treatment with norfloxacin that I agree this is confounded by recent use of antibiotics, and CGAI- (b) (6) (treated with and corticosteroids and epinephrine) beginning 6 days after the 5th galcanezumab dose and lasting 24 days, with mild eye swelling that began 20 days later, in a patient with history of asthma, allergic rhinitis, drug hypersensitivity, for which Dr. Villalba believes there is a possible association and I agree that a role for galcanezumab cannot be ruled out.

Dr. Villalba notes there were no SAEs of aplastic anemia, pancytopenia, rhabdomyolysis, Stevens Johnson Syndrome, Toxic Epidermal Necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), liver failure, renal failure, or reported cases of anaphylaxis in the database.

Discontinuations In Set A+C (controlled trials), Dr. Villalba shows in table 14 that 56 patients discontinued or were withdrawn from studies because of an adverse event; 17 (2.4%) on galcanezumab 120 mg, 14 (1.9%) on galcanezumab 240 mg, and 25 (1.7%) on placebo. As Dr. Villalba notes, there was no obvious dose response. Most AEs resulting in discontinuation occurred only in 1 patient. The most common AEs leading to discontinuation among galcanezumab patients were injection site reactions/erythema/swelling (0.4% for galcanezumab, 0.2% for galcanezumab 120 mg, 0.4% for galcanezumab 240 mg and galcanezumab overall vs 0 for placebo), and hepatic enzyme increased (0.1% for galcanezumab overall, 0.3% for galcanezumab 240 mg, and 0 for galcanezumab 120 mg or for placebo). Dr. Villalba notes the SAEs leading to discontinuation (TIA, pyrexia/disorientation, acute pancreatitis, breast nipple cancer, adenocarcinoma of cervix and tubular breast carcinoma on galcanezumab; MI, suicide attempt, cholelithiasis, vertebral osteophyte and deep vein thrombosis on placebo).

Dr. Villalba notes that AEs leading to withdrawal in Set E, the most common being injection site reactions (0.4% for galcanezumab overall, in addition to injection site erythema [0.1%], pain, pruritus, swelling, and urticaria [<0.1% each]) followed by urticaria (0.3% overall) and rash (0.2% overall). There was no evidence of dose response between the 2 doses. She notes 3 cases of dyspnea leading to drug discontinuation. In addition, Dr. Villalba notes that right eye spots (n=1) and elbow fracture (n=1) resulted in withdrawal in the galcanezumab < 120 mg group and rash (n=1) led to discontinuation on the galcanezumab 300 mg dose, none an SAE.

Selected AEs resulting in discontinuation (but that are not SAEs) are discussed below.

Cardiac and vascular disorders

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

Hypertension in subject CGAH- (b) (6) , a 53 y.o. female with a history of hypertension treated with HCTZ with baseline blood pressure of 144/90 mm Hg. At the treatment completion visit (visit 12) her weight was >7% increased from baseline (from 75 kg to 82 kg). 3 months later her blood pressure was 161/97 and lisinopril was added (after 6 months of galcanezumab). Dr. Villalba believes a relationship to galcanezumab with worsening hypertension and weight gain is possible. A 15 pound weight gain could have led to worsening hypertension. It is not possible to rule out a role for galcanezumab in weight gain and difficult to know the reason for worsening hypertension. Subject CGAH- (b) (6) was a 37 y.o. female with a history of obesity, GERD, drug hypersensitivity with erythromycin and penicillin, and hypertension treated with HCTZ, ibuprofen, sumatriptan, omeprazole, and prednisone (for urticaria before study treatment) who had a non-SAE of chest tightness 6 days after the 4th dose that was ongoing at the time of discontinuation, with no post-treatment follow-up and with no cardiac workup. Dr. Villalba believes the chest tightness/discomfort could be cardiac in origin. There does not appear to be sufficient information to determine a role for galcanezumab in this case, or to determine the origin of the chest tightness.

Ear and Labyrinth disorders leading to discontinuation Subject CAGJ- (b) (6) discontinued due to vertigo because of vertigo that occurred the day after the 5th dose of galcanezumab in an open label study and who also had vertigo 18 days after the first dose, the day of the 4th dose (when blood pressure was normal according to Dr. Villalba) and 3 days after the 5th dose. Dr. Villalba notes that vital sign values at the time of the third episode are not available. Dr. Villalba shows in her review that the risk of vertigo and vestibular dysfunction was 1.4%, 1.6%, and 0.6% on galcanezumab 120, galcanezumab 240, and placebo, respectively and that the preferred term vertigo occurred in 9 patients (0.6%) on galcanezumab and 4 (0.3%) on placebo. I agree that vertigo in this patient may have been drug related.

Ophthalmologic AEs leading to discontinuation Eye pruritus, ocular hyperemia (redness) associated with rash and hypersensitivity occurred in Subject CGAJ-(b) (6) (uncontrolled study) 16 days after the 4th dose of galcanezumab. It is difficult to determine a role for galcanezumab but could be related to hypersensitivity.

Gastrointestinal disorders leading to discontinuation Dr. Villalba identified 10 patients with GI symptoms leading to discontinuation, 4 during the placebo-controlled trials and 6 during open label treatment. The events were 1 each of pancreatitis (SAE previously discussed), dyspepsia, diarrhea, and Crohn’s disease, and abdominal pain/tenderness/distension (n=4), and nausea (n=3). (She also noted a discontinuation because of tongue discomfort with hypertrophy of tongue papillae in an open label study that resolved without specific treatment). Onset of GI symptoms ranged from Day 3 to Day 318 and most resolved after 1-111 days. Dr. Villalba states that GI symptoms could be associated with CGRP inhibition. However, she notes that there was no imbalance in the rate of GI adverse events leading to discontinuation in placebo controlled trials. She notes in her discussion of TEAEs that there was an imbalance in gastrointestinal and hypomotility disorders in controlled trials (1.8% in galcanezumab overall and 0.9% for placebo) but those

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

events included primarily constipation. It is difficult to determine how these discontinuations might be related to galcanezumab.

General disorders AEs leading to discontinuation Dr. Villalba shows that patients discontinued drug because of injection site reactions more frequently in the galcanezumab group overall (0.4% overall) than placebo (0) in Set A+C. In the galcanezumab treated group this included 14 patients (6 in controlled trials and 8 from open label studies); none was an SAE. Most occurred on the day of or day after the 2nd or 3rd dose and none after the first dose. She notes that all resolved with no or minimal intervention. Other single events include influenza-like illness, fatigue, pyrexia, peripheral swelling, chest discomfort, pain, malaise, and chest pain (unspecific). Dr. Villalba also shows an imbalance for galcanezumab vs placebo in TEAEs of injection site reactions and these were among the most frequent TEAEs.

Immune disorders leading to discontinuation Dr. Villalba notes 1 case of hypersensitivity (CGAG- (b) (6) who had a history of seasonal allergy, PTSD, and allergy to promethazine, developed severe rash and pruritus 2 days after starting treatment (treated with diphenhydramine and cetirizine) along with agitation, fatigue and confusional state, and 2 cases of dyspnea consistent with hypersensitivity (CGAG- (b) (6) who had pre-existing ongoing conditions including anxiety, urticaria, and allergic rhinitis, unspecified immune system disorder 5 years prior, and allergy to aspirin and ibuprofen who had dyspnea [resolved the same day] and rash on face and upper trunk [treated with chlorpheniramine and resolved after 3 days] after 4th dose; and CGAG- (b) (6) with a history of asthma and seasonal allergy who had injection site reaction associated with itching and rash 62 days after starting treatment that resolved on the same day, and injection site reaction on Day 92 after the 4th dose associated with shortness of breath that improved on the same day after diphenhydramine) and CGAJ- (b) (6) with preexisting conditions of asthma, drug hypersensitivity (penicillin), latex allergy, and seasonal allergy who had an injection site reaction, GI symptoms, and lethargy [3rd episode in this patient, led to discontinuation] 1 days after the 6th dose) that Dr. Villalba considers may be anaphylaxis although it was not acute, and did not result in generalized skin reaction and there is no blood pressure information available; and a case of “Type IV hypersensitivity” (CGGAI- (b) (6) with limited information available) not requiring steroid treatment that led to withdrawal in the open label period of CGAI. The role of galcanezumab in these events cannot be ruled out.

Infections and Infestations leading to discontinuation Dr. Villalba identified 2 patients who discontinued because of non-SAE of infections, one was a common cold and one was a fall and a leg wound that became infected and does not appear related to galcanezumab.

Investigations leading to discontinuation Dr. Villalba notes that adverse events leading to discontinuation in the Investigations SOC were related to liver enzyme elevation (n=4), weight increased (n=2). There was also 1 discontinuation CT thorax abnormal in a patient with a history of tobacco use and seasonal allergies and with chest congestion and bronchitis for 4 months who went to the ER with

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acute dyspnea on Day 140 and was found to have a pulmonary mass assessed as likely to be scar tissue from bronchitis.

The liver enzyme elevations included CGAI- (b) (6) who with ALT and AST 3X ULN and CK > 10X ULN [mildly elevated at baseline] with a negative hepatic workup and suggestive of rhabdomyolysis related to high intensity sports; CGAI- (b) (6) with slight elevation of ALT and AST at baseline and increased to 6X ULN and 3X ULN, respectively, without increase in bilirubin or alkaline phosphatase, with negative liver workup; CGAI- (b) (6) who had ALT and AST elevation 3X ULN and creatine kinase of 40X ULN in the setting of amino acid dietary supplement with testosterone; and CGAH- (b) (6) who had hepatic enzyme elevations with ALT up to 5X ULN on day of 4th dose in the setting of concomitant ketorolac that has a precaution regarding hepatic effects. These events do not appear likely to be caused by galcanezumab.

Weight gain leading to drug discontinuation occurred in 2 patients (3.5 kg and 23 kg over 2 months). Dr. Villalba notes that CGRP is involved in the regulation of insulin section. I agree that a role for galcanezumab cannot be ruled out.

Nervous system disorders leading to discontinuation Dr. Villalba identified AEs leading to discontinuation of dizziness (CGAI-(b) (6) from day 1 to day 232 that was not reported by patient until after 8 monthly injections with no orthostatic measurements taken; CAGI- (b) (6) with dizziness from day 251-314 who also had cognitive impairment on Day 251-256 and SAE of seizure on Day 238); right sided hemiparesis in subject CGAI- (b) (6) starting 21 days after 8th dose in subject who had history of right sided numbness, with no imaging to rule out a stroke. It is difficult to determine a role for galcanezumab in these events. Hypoesthesia (bilateral upper extremity pain and numbness) was reported in CGAI- (b) (6) on Days 294-365 that resolved after administration of prednisone for 5 days and a visit to a chiropractor. The event does not appear related to galcanezumab. Lethargy (associated with hypersensitivity/immunologic reaction) resulted in discontinuation in CGAJ- (b) (6) .

Skin and subcutaneous tissue disorders leading to discontinuation Dr. Villalba identified 15 galcanezumab treated patient with AEs in this SOC (rash/pruritus or urticaria) leading to discontinuation, including 6 in the placebo controlled studies (vs 1 case of alopecia and 1 of eczema on placebo) in addition to the SAE of skin ulcer (CGAH-(b) (6) that was previously described). Time to event was Day 1 to 184 and duration was 1 day to 3 months. Two occurred after the first dose, most occurred after the subsequent doses. Most were treated with topical treatment and antihistamines; 3 had systemic corticosteroids. It is not possible to rule out a role for galcanezumab and given the imbalance between drug and placebo in the discontinuations (and slight imbalance in TEAES in this SOC and with TEAEs of pruritus) I agree that galcanezumab may have played a role.

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Other discontinuations (b) (6) CGAH- with a history of alveolitis allergic and seasonal allergy discontinued because of bronchiectasis (that occurs after chronic injury to airways) 9 days after starting treatment and 9 days after the 4th dose. I agree this does not appear related to galcanezumab.

CGAI- (b) (6) with low potassium levels (3.2 mmol/L) during placebo treatment had hypokalemia (2.5 mmol/L) after starting galcanezumab. The role for galcanezumab is unknown considering the previously low potassium levels. CGAG-(b) (6) with a history of psoriasis was diagnosed with an episode of psoriatic arthritis after the 3rd dose of galcanezumab. I agree the isolated AE is unlikely related to galcanezumab.

Significant Adverse Events Dr. Villalba notes that the percentage of patients with severe AEs was similar in placebo and each galcanezumab treatment group in Set A+C (approximately 7.4% in each group). The largest differences were related to injection site pain (2.1% for placebo, 4.3% for galcanezumab 120 mg, and 2.3% for galcanezumab 240 mg) In Set E severe injection site pain occurred in approximately 1% on galcanezumab.

Dr. Villalba reviews the cases of chest pain in Sets A and E. In placebo controlled trials she reports that the incidence of non-cardiac chest pain was approximately 5x that of placebo (1.1% vs 0.2%) and occurred in approximately 1.5% in Set E. I agree with Dr. Villalba’s assessment that the cases, not associated with a single common etiology, most likely were not cardiac (although Dr. Villalba notes that most did not have a cardiac workup), some being consistent with hypersensitivity or with anxiety (although some patients had cardiac risk factors and 3 were confounded or had insufficient information to confirm that origin).

One severe case of worsening Raynaud’s phenomenon occurred (ART01-(b) (6) ).

Dr. Villalba identified 2 cases of neutropenia, both on galcanezumab 240 mg, both in patients with below normal neutrophil counts at baseline and without absolute neutropenia or fever, 1 returned to baseline at end of treatment and the other increased to normal levels 2 weeks into treatment. I agree these do not appear related to galcanezumab.

Dr. Villalba identified 7 seizures in the database, with no imbalance in the phase 2 and 3 placebo controlled trials (1 on galcanezumab, 1 on placebo). As previously discussed there were 3 SAEs of seizures (one in a patient with fever and previous history of febrile convulsions who continued without further seizures and 1 in a patient with a potential hypersensitivity reaction). I agree there does not appear to be a signal for an increased risk of seizures.

Treatment Emergent Adverse Events and Adverse Reactions The most commonly reported TEAEs in Set A+C (at least 5%) were infections (all), injection site reactions, and upper respiratory infection/cold/rhinitis as determined by Dr. Villalba using a customized query provided by Dr. Ellis Unger. Similarly, Dr. Villalba’s evaluation using MedDRA HLT groups was consistent with the customized analysis and found the most

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

commonly reported adverse reactions (at least 5%) to be injection site reactions and upper respiratory tract infections that were greater than placebo and with suggestion of dose- response. In controlled trials in migraine, injection site reactions occurred in 16-21% for galcanezumab across dose groups vs 12% for placebo using the customized query and 18-23% for galcanezumab vs 13% for placebo using Dr. Villalba’s analysis of MedDRA HLT. Upper respiratory infections occurred in approximately 19-20% for galcanezumab vs 17% for placebo using the customized query and approximately 11% in galcanezumab groups vs 9% for placebo in Dr. Villalba’s analysis of MedDRA HLT.

The most common AEs with an incidence at least 1% greater than placebo, using the customized FDA query are shown below, extracted from Dr. Villalba’s review (with % rounded to even).

Placebo GMB120 GMB240 N=1451 N=705 N=730 n (%) n (%) n (%) Patients with at least 1 AE 882 (61) 456 (65) 490 (67) Infections (all) 403 (28) 202 (29) 215 (30) Injection site reactions 170 (12) 116 (16) 156 (21) Upper respiratory infection, cold, rhinitis, upper respiratory tract infection 251 (17) 144 (20) 138 (19) Dysfunctional uterine bleeding, menometrorrhagia 7 (0.5) 12 (2) 13 (2) Vertigo, vestibular dysfunction 9 (0.6) 10 (1) 12 (2) Pruritus 4 (0.3) 7 (1) 11 (2) Constipation 9 (0.6) 7 (1) 12 (2) Chest pain (non-cardiac, unknown) 6 (0.4) 8 (1) 10 (1)

I note that although there was a slight imbalance in TEAEs of infections overall and for upper respiratory infections, there were no SAEs of infections for galcanezumab 120 mg in the controlled trials and no dose-response in Set E. Infections did not lead to discontinuations for galcanezumab 120 mg. For these reasons, I do not believe that infections are likely related to galcanezumab.

Dr. Villalba notes that the dysfunctional uterine bleeding category was driven by menorrhagia7 (9 patients on galcanezumab 120 + 240 [0.6%] vs 1 on placebo [<0.1%]) and metorrhagia8 (0.2% vs < 0.1%). In Set A, menorrhagia occurred in 0 placebo patients and 3/599 (0.5%) women taking galcanezumab 120 mg. Dr. Villalba notes that few AEs in the category of dysfunctional uterine bleeding led to withdrawal, and that the mean time to onset was

7 Abnormally heavy menstrual bleeding 8 Irregular uterine bleeding

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

approximately 78 days. I also note that the rate of menorrhagia is less than the background rate as cited in the literature9 of 5% in women 30 to 49 y.o. who consult their general practitioner about menorrhagia, and that states that 12% of all gynecology referrals are for this complaint. I agree with Dr. Villalba that the number of events in this database is small and does not allow for drawing conclusions.

Dr. Villalba found that common AEs in Set E were consistent with those observed in Set A+C.

Laboratory Findings Dr. Villalba does not find significant findings comparing galcanezumab and placebo in controlled trials or between the 120 and 240 mg doses of galcanezumab in the open label studies in changes from baseline and shift analyses in laboratory parameters (chemistry, hematology, and urinalyses) in the clinical development program.

In placebo-controlled trials Dr. Villalba notes that the risk of ALT and AST > 3X ULN was approximately 1%, for all treatment groups. The relative risk of ALT or AST elevation is 2-3 fold in the galcanezumab treated patients compared to placebo, although there were few events and the absolute difference was less than 0.5%. There were no Hy’s law cases. In Set E, 8% and 5% of patients had abnormal high ALT or AST with no evidence of dose response. I agree that galcanezumab does not appear to be associated with liver toxicity.

In Set E, Dr. Villalba finds that 10% had abnormal high creatine kinase, 2% had abnormal high creatinine, with no evidence of dose response; she notes that percentages were higher in the studies with 1 year treatment. In urinalyses in pool E, 35% had abnormal levels of protein in urine and 17% were leukocyte esterase positive (suggesting a urinary tract infection).

She finds that very few patients had potentially clinically significant laboratory values, and finds that in Set E only creatine kinase was a potentially clinically significant abnormality (PCSA) in more than 1% of patients. She notes that there were no SAEs or dropouts related to those labs. Dr. Villalba notes that 4 patients had abnormally low potassium (< 3.2 mmol/L, all receiving galcanezumab 120 mg: 1 had an AE of mild hypokalemia, one was taking a diuretic, and 1 had low potassium before study entry. It is difficult to attribute this finding to galcanezumab.

Dr. Villalba evaluated findings related to glucose, C peptide, and insulin and I agree there does not appear to be a clinically significant impact on these evaluations. . She notes that except for a SAE of diabetic ketoacidosis, no patients with abnormal lab values related to glucose metabolism had SAE or AE leading to study withdrawal.

I agree with Dr. Villalba that galcanezumab does not appear to have a clinically significant impact on laboratory values.

9 Kadir RA et al. Lancet. 1998; 351: P485-489

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

Vital Signs Please refer to Dr. Villalba’s review for details regarding vital signs findings. The findings are summarized below.

Dr. Villalba notes that there were no significant changes from baseline for pulse, blood pressure, temperature or weight for galcanezumab compared to placebo in Set A+C or in Set E) but notes that there were no measurements of orthostatic blood pressure. She notes no difference vs placebo in the shift analysis of blood pressure in Set A+C, and no difference between drug and placebo or outlier analyses of blood pressure in Set A+C controlled trials. She does show a dose response in blood pressure outlier analysis for 240 mg vs 120 mg (systolic > 140 [16 vs 12%]or diastolic > 90 mm Hg [21% vs 18%]) ) in Set E in the treatment period (more than in the treatment plus post-treatment period combined). I agree that interpretation of these changes is difficult.

Dr. Villalba notes that shift analysis of weight showed slightly higher percentage of patients with weight increase of at least 7% for galcanezumab (10%) vs placebo (9%), and no difference for between drug and placebo for at least 7% weight decrease. Whether the small difference between drug and placebo for weight increase is meaningful remains to be determined.

Galcanezumab did not appear to be associated with notable differential effects on vital signs compared to placebo in the placebo controlled trials

Electrocardiograms (ECGs) A thorough QT study was not conducted. Dr. Villalba notes no meaningful changes compared to placebo in ECG parameters or qualitative ECG findings. She notes that some patients had small changes in set E, but that definitive conclusions cannot be drawn in absence of a control group and that there is no obvious signal for ECG abnormalities. I agree with Dr. Villalba that there do not appear to be clinically significant ECG findings in the database.

Immunogenicity At baseline 7-11% of patients were anti-drug antibody (ADA) positive and 4-6% were neutralizing antibody (NA) positive in Set A+C. Treatment emergent ADA+ was observed in 14-15% of patients (approximately 300 patients) on galcanezumab and 2% on placebo. Dr. Villalba notes that NA were present in almost 99% of galcanezumab patients who became ADA+ and 2/3 of placebo patients who became ADA+. Dr. Villalba notes that the percentages of AE were higher among ADA+ patients vs the overall safety population, but notes that available data is not adequate to support a conclusion regarding the impact of ADA positivity on safety. Dr. Villalba and the Sponsor both note that no patient has been re-exposed to galcanezumab treatment after discontinuation following initial exposure. The impact of re-exposure on immune-mediated adverse events is not known.

Submission Specific Safety Issues

Dr. Villalba considers the following, identified during the development program, in her discussion of submission specific safety issues:

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

 Cardiovascular Safety  Hepatic Safety ((based on clinical data from small molecule CGRP) inhibitors)  Injection Site Reactions  Hypersensitivity  Upper Respiratory Tract Infections  Suicidality and Self-Injurious Behaviors

Cardiovascular Safety

Multiple published reports state that CGRP is a potent vasodilator. A theoretical concern has been raised in the literature that inhibition of CGRP could impair adaptive/protective vasodilation in patients with hemodynamically significant coronary artery disease, cerebrovascular disease, and peripheral vascular disease. These concerns have been addressed in a memo from Dr. Freed (see Error! Reference source not found., above). Dr. Villalba’s review did not find a clear cardiovascular risk to patients taking galcanezumab.

I summarize the findings in Dr. Villalba’s review and my memo to consider cardiovascular risk from the combined available findings.

Dr. Villalba found no difference in the percentage of cardiovascular SAE or dropouts in placebo controlled studies for galcanezumab vs placebo. As discussed above and as summarized by Dr. Villalba in Section 8.5.1 of her review, in the placebo controlled trials there were 3 cardiovascular SAEs on placebo (0.2%: 1 myocardial infarction, 1 pulmonary embolism, and 1 deep vein thrombosis), none on galcanezumab 120 mg, and 4 (0.5%) on galcanezumab 240 mg:  Myocardial infarction (CGAH(b) (6) ) 1.5 weeks after the 3rd dose in a 55 y.o. female with a family history of cardiac disease  Dilated cardiomyopathy/congestive heart failure/inverted T wave on ECG (CGAG- (b) (6) ) during the follow-up period in the 3 month controlled trial in a 51 y.o. female with a history of obesity and drinking 1-2 drinks/day  TIA (CGAH-(b) (6) ) on Day 59 (2 days after the 3rd dose) in a 54 y.o. obese female with baseline elevated diastolic blood pressure (120/92) who had a non-SAE of hypertension and began treatment with amlodipine 4 days before the event  Bilateral pulmonary embolism (CGAI-(b) (6) ) in a 24 y.o. female using an intravaginal estrogen ring for 2 years with a history of air travel 3 weeks prior to the event. In the open label studies Dr. Villalba identified the following cardiovascular events:  Myocardial infarction and unstable angina (CGAI-(b) (6) ) 10 days after the 5th dose of galcanezumab 240 mg in a 55 yo. male with no significant medical history but with baseline ECG showing nonspecific T-wave abnormality, and concomitant medications of aspirin and sertraline and started treatment for hyperlipidemia on the first day of the open label study.  Orthostatic intolerance on Day 249, 3 days after beginning amiloride/HCTZ for diastolic hypertension (CGAI-(b) (6) in a 44 y.o. female who had diastolic hypertension after the 6th dose of galcanezumab 240 mg (Day 246) and also taking

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

naproxyn, rizatriptan, caffeine-containing medication and almotriptan on several days within the week before the event.  Congestive heart failure (CGAI-(b) (6) ) with symptoms beginning on Day 70 of galcanezumab 240 mg in a 38 y.o female with a history of obesity and family history of heart disease with an blood pressure at screening of 125/99  Coronary artery stenosis (CGAI-(b) (6) 81 days after the last of 12 doses in a 62 y.o. male with obesity and high blood pressure at baseline and a non-SAE of hypertension (202/134 mm Hg) on the day of the 5th dose resulting in treatment with lisinopril, HCTZ, and candesartan. I agree with Dr. Villalba that none of the cases individually appear to be unequivocally related to galcanezumab. Most of these patients had pre-existing risk factors for their cardiovascular events. It is not clear how galcanezumab may have contributed to the event.

With respect to hypertension, Dr. Villalba notes that there were no SAEs of hypertension in the controlled period of galcanezumab trials. As previously discussed there was 1 SAE of orthostatic intolerance after treatment for diastolic hypertension on galcanezumab 120 mg (CGAI- (b) (6) , and 3 (non-hypertension) SAEs in patients on galcanezumab 240 mg who had high blood pressure at the time of or prior to those events (1 myocardial infarction in subject CGAH- (b) (6) with a family history of heart disease with “high blood pressure” noted at the ER visit but values not documented, 1 TIA in an obese patient (CGAG- (b) (6) ) with baseline elevated diastolic blood pressure and elevated systolic and diastolic blood pressure at the time of the event after having started amlodipine for hypertension, and 1 coronary artery stenosis 81 days after the last of 12 doses of galcanezumab 240 mg in an obese patient (CGAI- (b) (6) ) with baseline blood pressure of 159/109, an AE of hypertension with blood pressure of 202/134 on Day 116 treated with lisinopril, HCZ, and candesartan. The contribution of galcanezumab to hypertension in those patients is not clear. Dr. Villalba notes that 1 placebo patient discontinued because of hypertension; no galcanezumab patient discontinued because of hypertension. Analysis of all AEs showed no increased risk for HLTs of hypertensive disorders (1.1% for galcanezumab vs 1.5% for placebo) or hypotensive disorders (0.5% for both) in controlled trials. In controlled trials there was no difference in outliers in blood pressure measurements for galcanezumab vs placebo and no dose-response; a slight dose response for high systolic and diastolic blood pressure in Set E is difficult to interpret.

Dr. Villalba did not find a risk for galcanezumab vs placebo for cardiovascular events in her analysis of all AEs by HLT and SMQs except for peripheral vascular disorders NEC that included flushing and hot flashes (0.9%, 0.7%, and 0.3% for galcanezumab 120 mg, 240mg, and placebo, respectively). Dr. Villalba noted that these occurred at any time during treatment and were mostly in women above 40 years old. I agree it is not clear if these are drug related.

Dr. Villalba finds no clinically meaningful impact of galcanezumab on vital signs (heart rate, systolic and diastolic blood pressure), or in ECG changes in controlled trials. Orthostatic blood pressure was not systematically measured. In Set E, Dr. Villalba found outliers in systolic blood pressure (>140 mm Hg) and diastolic blood pressure (>90 mm Hg) with

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

suggestion of a dose response, but it is difficult to interpret these findings in the absence of a control group.

Dr. Villalba reported no significant changes in use of cardiovascular medications (antihypertensive, antiarrhythmic, antianginal, antithrombotic) medications in galcanezumab placebo controlled trials. She found that a small percentage increased use of such medications in set E. I agree that no definitive conclusions can be drawn in absence of a control group.

As Dr. Villalba notes there were few patients with underlying cardiovascular risk in the database and I agree that the database would not be sufficient to evaluate a theoretical cardiac risk of CGRP antagonism. However, I agree with Dr. Villalba that the current database does not show an increase in cardiovascular risk with galcanezumab.

Hepatic Safety Dr. Villalba notes that hepatotoxicity has been raised as a potential concern based on small molecule CGRP inhibitors. As previously discussed in my memo, I agree with Dr. Villalba that there is no evidence of increased risk of liver injury with galcanezumab.

Injection Site Reactions As previously noted in my memo, injection site reactions were among the most common adverse reactions, more common in galcanezumab treated patients than in placebo, with evidence of a dose response. Dr. Villalba notes that the most frequently reported AEs for these reactions included injection site pain, injection site erythema, and injection site pruritus. Most events were mild to moderate and resolved within 2 weeks. Dr, Villalba found that injection site reactions could occur at any time during treatment. She notes there were no SAEs of injection site reactions, and the rate of discontinuations due to injection site reactions was less than 0.5%. Dr. Villalba notes that the findings in set E are consistent with Set A.

Hypersensitivity The Sponsor, in the ISS, acknowledges the potential risk of hypersensitivity associated with monoclonal antibodies. As previously noted, Dr. Villalba has identified several cases consistent with hypersensitivity reactions including hypersensitivity, pruritus, and rash that occurred more frequently in galcanezumab-treated patients (3.3%) than with placebo (2.3%). She notes in the controlled trials, none was an SAE; 4 on galcanezumab and none on placebo led to discontinuation. She notes that The Sponsor’s search using the Hypersensitivity (narrow) SMQ found 4.6% on galcanezumab vs 2.8% on placebo, and as shown in Dr. Villalba’s review these included injection site rash and injection site hypersensitivity. Hypersensitivity AEs occurred in approximately 6% in Set E without evidence of dose- response. Dr. Villalba identified approximately 0.7% in Set E with potential hypersensitivity AEs that led to discontinuation, but most were transient and mild or moderate in severity, and that there were no reported cases of angioedema or anaphylaxis in the database. Dr. Villalba notes 1 case of face swelling in the follow-up period to the placebo controlled phase (approximately 17 days after the last dose) that was not serious, did not lead to discontinuation, and lasted only 1 day). Using a broad search for potential hypersensitivity terms in Set A, the sponsor has determined that approximately 22% occurred on the day of drug administration and approximately 78% occurred beyond the day of drug administration.

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

Based on 2 cases of SAEs of urticaria in Set E (which I previously noted in 1 case was confounded by recent use of ciprofloxacin/norfloxacin), the sponsor proposes included hypersensitivity as a warning in the prescribing information and a contraindication in patients with known hypersensitivity to galcanezumab or its excipients. Dr. Villalba also recommends a warning for hypersensitivity. Given the imbalance (although small number of cases) in hypersensitivity reactions for drug vs placebo, I agree that hypersensitivity should be noted in the labeling.

Upper Respiratory Tract Infections The Sponsor suggests that upper respiratory tract infections are a potential risk associated with monoclonal antibodies and has included these as a safety topic of interest. Dr. Villalba shows that upper respiratory tract infections (HLT) were slightly more frequent on galcanezumab (11% [29.4 per 100 PYRs] in pooled galcanezumab doses vs 9.2% [25.1 per 100 PYRs] for placebo in Set A+C), with no evidence of dose-response. The imbalance was also observed (20% for galcanezumab overall vs 17% for placebo) using an FDA customized query (upper respiratory infection, cold, rhinitis, upper respiratory tract infection). Dr. Villalba notes that none in Set A+C were SAE or led to discontinuation. She found the mean time to onset similar for galcanezumab and placebo (mean approximately 112-116 days).The most common preferred terms were upper respiratory tract infection followed by sinusitis. The findings were similar in Set E where the rate was 27.9 per 100 PYRs and where there was 1 SAE and 1 event that led to discontinuation. The lack of dose response makes it difficult to conclude a causal association. Suicidality The Sponsor included suicidal ideation and behavior as a safety topic of interest based on standard drug registration topics. Dr. Villalba notes that there was no difference between galcanezumab and placebo in AE of suicidal ideation or behavior in the placebo controlled trials of galcanezumab. She notes 1 SAE of attempted suicide on placebo and that 1 patient discontinued galcanezumab because of suicidal ideation and 1 had an AE of suicidal thoughts at the last visit of the treatment phase that resolved by post-treatment follow-up. There was no increase in treatment emergent suicidal ideation in Set E (1.3%) compared to set A+C (0.8% for galcanezumab and for placebo). I agree with Dr. Villalba that there is no signal for an increased risk of suicidality with galcanezumab.

Analysis by Demographic Subgroup As previously noted, the majority of patients were women and were white. Dr. Villalba notes no unique safety signals with analysis by gender. I agree there were too few non-white patients to analyze by race and too few to analyze by age > 65 y.o.

Additional Safety Explorations Human Carcinogenicity or Tumor Development Dr. Villalba notes that carcinogenicity has not been raised as a concern with CGRP inhibition. She notes that there were 7 neoplasms (including 5 malignancies) on galcanezumab vs none on placebo in the placebo controlled trials and 4 additional malignancies in the open label periods, all occurring within 1 year of treatment, and all but 1 at the 120 mg dose. As previously noted, I agree with her lack of cases at the high dose and relatively short time to onset does not

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab)

appear to suggest a drug related effect. I agree with Dr. Villalba that the size and duration of the database do not allow for adequate evaluation of tumor development.

Human Reproduction and Pregnancy Please refer to Dr. Villalba’s review for details. I agree with Dr. Villalba that the information is limited (in 16 pregnancies with exposure via the mother and 2 with exposure via the father) to assess the effects of galcanezumab on pregnancy. Given that galcanezumab will be used in women of childbearing potential, I recommend a pregnancy registry and a pregnancy outcomes study as postmarketing requirements.

Pediatrics and Assessment of Effects on Growth Galcanezumab was not evaluated in the pediatric population in this development program.

Overdose, Drug Abuse Potential, Withdrawal, and Rebound No studies were done to specifically evaluate the potential for drug abuse. Dr. Villalba notes that there were no events from the MedDRA Drug abuse and dependence SMQ. She notes that a similar percentage of patients for drug and placebo reported other terms such as somnolence, dizziness, memory impairment, disturbance in attention, mood altered in Set A. She notes that analysis of potential for abuse in Set E showed similar findings as in Set A.. I agree with Dr. Villalba that galcanezumab does not seem to be associated with an increase risk of abuse.

Concerns identified through U.S. or foreign postmarket experience Galcanezumab is not yet marketed in the rest of the world.

Potential safety issues that could cause concern when considering how the drug may be used in the postmarket setting As Dr. Villalba notes, additional adverse reactions will likely be identified after a larger group of patients is exposed to galcanezumab, particularly those with comorbidities who were not allowed to participate in the trials.

8. Advisory Committee Meeting An advisory committee meeting is not planned.

9. Pediatrics This application did not evaluate use in pediatrics.

10. Other Relevant Regulatory Issues Please refer to the clinical efficacy review.

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Reference ID: 4327108 Safety Team Leader Review BLA 761063 Emgality (Galcanezumab) 11. Labeling Prescribing Information If galcanezumab is approved, consideration should be made as to whether to include hypersensitivity as a WARNING and PRECAUTION.

Other Labeling I do not believe that a Medication Guide is necessary to ensure the benefits of the drug outweigh the risks. A Patient Package Insert, proposed by the Sponsor, may be helpful in educating patients and caregivers about adverse events observed with galcanezumab.

12. Postmarketing Recommendations Risk Evaluation and Management Strategies (REMS) A REMS is not required for safe use of galcanezumab. Labeling can adequately provide information regarding the potential risks.

Postmarketing Requirements (PMRs) and Commitments (PMCs) I suggest a pregnancy registry and a pregnancy outcomes study as PMRs as follows:

Conduct prospective pregnancy exposure registry cohort analyses in the United States that compare the maternal, fetal, and infant outcomes of women with migraine exposed to Emgality during pregnancy with two unexposed control populations: one consisting of women with migraine who have not been exposed to Emgality before or during pregnancy and the other consisting of women without migraine. The registry will identify and record pregnancy complications, major and minor congenital malformations, spontaneous abortions, stillbirths, elective terminations, preterm births, small-for-gestational-age births, and any other adverse outcomes, including postnatal growth and development. Outcomes will be assessed throughout pregnancy. Infant outcomes, including effects on postnatal growth and development, will be assessed through at least the first year of life.

Conduct a pregnancy outcomes study using a different study design than provided for in PMR [refers to prospective pregnancy exposure registry PMR] (for example, a retrospective cohort study using claims or electronic medical record data or a case control study) to assess major congenital malformations, spontaneous abortions, stillbirths, and small-for-gestational-age births in women exposed to Emgality during pregnancy compared to an unexposed control population.

Pharmacovigilance I recommend that the Sponsor be requested to perform postmarketing surveillance for liver toxicity, myocardial infarction, and stroke after exposure to Emgality, and that they include comprehensive summaries and analyses of these events quarterly as part of their required postmarketing safety reports [e.g., periodic safety update reports (PSURs)].

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Reference ID: 4327108 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

SALLY U YASUDA 09/27/2018

Reference ID: 4327108

Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

placebo arm. Furthermore, the MSQ v2.1 Role Function-Restrictive domain endpoint was not tested in the CM pivotal trial (CGAI) for the 120 mg. dose (another pre-specified secondary endpoint higher in the endpoint testing hierarchy was not statistically significant). B. BACKGROUND See Appendix A for migraine and headache endpoint terminology definitions.

Galcanezumab (LY2951742) is being reviewed by the Agency as a potential migraine prevention agent (via monthly subcutaneous administration) in migraineurs suffering from episodic or chronic migraine.

Materials reviewed: • Three previous COA reviews from this reviewer during the IND 111295 phase of this BLA: o C2017189 (Kovacs, finalized in DARRTS on January 8, 2018 [Reference ID: 4204675]) o AT 2016-142 (Kovacs, finalized in DARRTS on January 15, 2017 [Reference ID: 4031896]) o AT 2015-112 (Kovacs; finalized in DARRTS on October 14, 2015 [Reference ID: 3832643]) • Previous COA reviews on migraine under different INDs: o AT 2013-013 (Miskala; finalized in DARRTS on March 25, 2013) o AT 2014-041 (Kovacs; finalized in DARRTS on June 13, 2014) o AT 2015-005(Kovacs; finalized in DARRTS on April 16, 2015) • Applicant’s BLA 761063 package, including PRO evidence dossier and annotated labeling. • Applicant’s responses to Agency information requests • Minutes from meetings during the IND phase C. CLINICAL OUTCOME ASSESSMENT REVIEW The review concludes that the evidence submitted by the applicant demonstrates that the MSQ v2.1 Role Function-Restrictive domain’s content validity and psychometric properties and performance (i.e., internal consistency reliability, test-retest reliability, convergent validity, known-groups validity, and ability to detect change over time) are acceptable.

1 CONTEXT OF USE 1.1 Clinical Trial Population Adult patients with episodic migraine (4 to 14 migraine days per month) or chronic migraine (≥15 headache days per month with ≥8 migraine days per month), with a history of migraine

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

with or without aura, or chronic migraine according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria.

1.1.1 Episodic migraine studies (Studies CGAG and CGAH) • Adult patients (18-65 years of age [inclusive]) at time of screening with a diagnosis of migraine as defined by International Headache Society (IHS) International Classification of Headache Disorders (ICHD)-3 beta guidelines (1.1 or 1.2) (ICHD-3 2013), with a history of migraine headaches of at least 1 year prior to Visit 1, and migraine onset prior to age 50. • Prior to Visit 1, have a history of 4 to 14 migraine headache days and at least 2 migraine attacks per month on average within the past 3 months. • From Visit 2 to Visit 3 (prospective baseline period), have a frequency of 4 to 14 migraine headache days and at least 2 migraine attacks. To avoid biased reporting, patients must not be told the number of migraine headache days on which study qualification is based. • From Visit 2 to Visit 3 (prospective baseline period), must achieve sufficient compliance with ePRO daily headache entries as demonstrated by completion of at least 80% of daily diary entries.

1.1.2 Chronic migraine study (Study CGAI) • Adult patients (18-65 years of age [inclusive]) at the time of screening with a diagnosis of chronic migraine as defined by the IHS ICHD-3 beta guidelines (1.3) (ICHD-3 2013), that is, a headache occurring on 15 or more days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month. • Migraine onset prior to age 50 • Prior to Visit 1, a history of at least 1 headache-free day per month for the past 3 months. • From Visit 2 to Visit 3 (prospective baseline period), have a frequency of at least 15 headache days, of which at least 8 must have the features of migraine headache. To avoid biased reporting, patients must not be told the number of migraine headache days on which study qualification is based. • From Visit 2 to Visit 3 (prospective baseline period), have at least one headache-free day. • From Visit 2 to Visit 3 (prospective baseline period), must achieve sufficient compliance with ePRO daily headache entries as demonstrated by completion of at least 80% of daily diary entries.

1.2 Clinical Trial Design The applicant conducted three randomized, double-blind, placebo-controlled studies: two studies in patients with episodic migraine (4 to 14 migraine days per month [Studies 1 and 2]) and one study in patients with chronic migraine (≥15 headache days per month with ≥8 migraine days per month [Study 3]). The studies enrolled a total of 2886 adult patients with a history of migraine

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

with or without aura, or chronic migraine according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria. In all 3 studies, patients were randomized in a 2:1:1 ratio to receive placebo, galcanezumab-gnlm 120 mg, or galcanezumab-gnlm 240 mg once monthly by subcutaneous injection. Patients in the 120-mg group received a 240-mg loading dose.

1.2.1 Episodic migraine studies (Studies CGAG and CGAH) • Two phase 3, multi-site (CGAG: United States and Canada; CGAH: in 11 countries [United States, United Kingdom, Netherlands, Spain, Czech Republic, Germany, Argentina, Israel, Korea, Taiwan, and Mexico]), randomized, 6-month double-blind, placebo-controlled studies of LY2951742 in patients with episodic migraine, with 4 study periods (each) in patients who meet the International Classification of Headache Disorders (ICHD) criteria for a diagnosis of migraine as confirmed during a prospective baseline period that demonstrates episodic frequency (4 to 14 migraine headache days per month) • Three treatment arms per phase 3 study: LY2951742 (120 mg/month with a 240 mg loading dose at the first injection [Visit 3]), LY2951742 (240 mg/month), and placebo. Following a prospective baseline (30-40 days) period, eligible patients were randomized in a 2:1:1 ratio to receive placebo, 120 mg/month of LY2951742, or 240 mg/month of LY2951742, respectively, and included a 6-month treatment phase. This phase was followed by a 4-month, post-treatment washout phase during which patients no longer received any study medication. • For the primary efficacy assessments, patients were asked to use an ePRO device (starting at Visit 2) to complete an ePRO diary and record headache symptoms, duration, and severity. The device also was used to collect the name and dose of concomitant medications used for the acute treatment of migraine, and the use of other pain medications. • Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., , derivatives), NSAIDs, and acetaminophen. Patients were not allowed any treatments for the prevention of migraine. Both studies excluded patients with medication overuse headache as well as patients with acute cardiovascular events and/or with serious cardiovascular risk.

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

CGAG study design diagram (copied from applicant’s protocol):

CGAH study design diagram (copied from applicant’s protocol):

1.2.2 Chronic migraine study (Study CGAI) • A phase 3, randomized, multi-site (in 12 countries: Argentina, Canada, Czech Republic, Germany, Israel, Italy, Mexico, Netherlands, Spain, Taiwan, UK, and US), 3-month

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

double-blind, placebo-controlled study of LY2951742 in patients with chronic migraine, with 5 study periods in patients who meet the International Classification of Headache Disorders (ICHD) criteria for a diagnosis of chronic migraine as confirmed during a prospective baseline period • Three treatment arms: LY2951742 (120 mg/month with a 240 mg loading dose), LY2951742 (240 mg/month), and placebo. Following a prospective baseline period (30 to 40 days), eligible patients were randomized in a 2:1:1 ratio to receive placebo, 120 mg/month of LY2951742, or 240 mg/month of LY2951742, respectively, and began a 3- month double-blind treatment phase. Patients who completed the double-blind period could enter a 9-month open-label extension phase for treatment with flexibly dosed LY2951742 (120 mg or 240 mg/month). All patients were followed for a 4-month, post- treatment washout phase during which patients will no longer receive any study medication. • Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives), NSAIDs, and acetaminophen. Up to one-third of patients were allowed to continue stable doses of topiramate or propranolol for prevention of migraine. Patients with medication overuse headache were not excluded. Patients with acute cardiovascular events and/or with serious cardiovascular risk were excluded.

CGAI study design diagram (copied from applicant’s protocol):

Reviewer’s comments: During the IND phase, this reviewer asked the applicant to clarify whether the MSQ v2.1 and PGI-S will be completed at Visit 2 during the run-in period as the baseline assessment. This reviewer also recommended to the applicant that they administer the PGI-S, not only at baseline, but also at monthly post-baseline visits during the treatment phase.

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Reference ID: 4300420

Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Reviewer’s comments: In collaboration with DNP, this reviewer recommended the revised language below (in bolded font) regarding MSQ Role Function-Restrictive domain endpoint results from the EM Studies 1 and 2 for inclusion in the labeling. It is important to note that testing of the MSQ Role Function-Restrictive domain endpoint in the CM pivotal trial (Study 3) for the 120 mg dose was stopped due to a pre-specified secondary endpoint higher in the endpoint testing hierarchy resulting in non-statistically significant results. Therefore, this reviewer does not agree that the MSQ Role Function-Restrictive domain results from CM Study 3 should be included in labeling given that it would be misleading to report nominal statistically significant results of endpoints that are not alpha-controlled. However, this reviewer defers to DNP and the Office of Biostatistics regarding their expertise related to inclusion of untested endpoints in the labeling.

• Key secondary endpoints included impact of migraine on daily activities as assessed by the mean change from baseline compared to the average across months 4 to 6 in the Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive domain using an electronic device administered monthly at clinic site visits. Role Function-Restrictive domain scores are scaled from 0 to 100, with higher scores indicating less impact of migraine on daily activities.

• Compared to placebo, patients treated with EMGALITY 120 mg once monthly showed greater improvement from baseline in mean Role Function-Restrictive domain score averaged across months 4 to 6 [difference from placebo: 7.7 for EMGALITY 120 mg and 8.8 for EMGALITY 120 mg for Studies 1 and 2, respectively; p-value < 0.001 for both].

2 CONCEPT(S) OF INTEREST AND CONCEPTUAL FRAMEWORK The MSQ v2.1 Role Function-Restrictive domain measures impact of migraine on daily activities. The diagram below depicting the conceptual framework of this domain was copied from the applicant’s PRO evidence dossier (dated September 16, 2017).

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

(b) (6)

Reviewer’s comments: During the IND phase, the applicant cited Jhingran et al., 19981 in their briefing document in support of a conceptual framework for the MSQ v2.1. This reviewer could not locate the article and submitted an information request (on September 2, 2015) for the applicant to submit copies of all of the content validity articles and qualitative and quantitative study reports for the MSQ v2.1. Including, but not limited to, both Jhingran et al., 1998 papers that were cited.

1 Jhingran P, Davis SM, LaVange LM, Miller DW, Helms RW. MSQ: Migraine-Specific Quality of Life Questionnaire. Further investigation of the factor structure. Pharmacoeconomics. 1998;13(6):707-717. 13

Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

3 CLINICAL OUTCOME ASSESSMENTS In Studies CGAG, CGAH, and CGAI, patients were asked to use an electronic device to record headache information daily to support the primary endpoint, such as clinical features of headaches, duration, and severity. The device was also used to collect the name and dose of concomitant medications used for the acute treatment of migraine and whether any pain medication was taken for other conditions. See Appendix A for migraine and headache terminology.

The MSQ v2.1 was completed by patients using an electronic device at the clinical site visits and the electronic device was retained by the clinical sites. In Studies CGAG and CGAG (episodic migraine), the MSQ v2.1 was administered to patients at baseline (Visit 3 at the clinical site), at monthly clinical site visits from months 1 to 6 (the double-blind treatment period), and at Month 10 (last visit of the post-treatment period) or ET (early termination visit). In Study CGAI (chronic migraine). The MSQ v2.1 was administered to patients at baseline (Visit 3 at the clinical site), at monthly clinical site visits from months 1 to 3 (the double-blind treatment period), during the open label and post-treatment phases, including Month 16 (last visit of the post- treatment period) or ET.

The MSQ v2.1 is a self-administered instrument developed to measure the impact of migraine on patients’ daily lives. The instrument consists of 14 items that address 3 independent domains: (1) Role Function-Restrictive; (2) Role Function-Preventive; and, (3) Emotional Function. The Role Function-Restrictive domain, used as secondary endpoint in the three phase 3 clinical trials, consists of 7 items (see conceptual framework in Section 2 above) which measure impact of migraine on daily activities. Scoring on each of the three domains ranges from 0 to 100, with higher scores indicating less impact of migraine on patients’ daily lives. The instrument was designed with a 4-week recall period.

See Appendix B for a copy of the MSQ v2.1 Role Function-Restrictive domain items (the first 7 items of the MSQ v2.1), which was included by the applicant as a pre-specified alpha-controlled secondary endpoint in their phase 3 trials.

During the IND phase, the applicant submitted a user manual, which included the scoring information for the MSQ v2.1 and instructions for the site investigators regarding what to tell patients when they complete the MSQ v2.1. at clinic visits. Patients were not trained on completion of the MSQ v2.1; however, site investigators were provided with a site user manual and training materials (submitted by the applicant in their PRO evidence dossier).

The MSQ v2.1 was originally developed as a paper-based questionnaire; however, the sponsor reformatted it for electronic administration and for patients’ self-administration using an electronic device. There were previous paper-based versions of the MSQ (v.1.0 and v.2.0).

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Patients also completed a patient global impression of severity (PGI-S) scale (see Appendix C for a copy) and a patient global impression of improvement (PGI-I) scale (see Appendix D for a copy) as anchor scales. Note that the PGI-I also assessed patient-reported worsening (not just improvement) from before starting the treatment.

Reviewer’s comments: This reviewer agrees with the applicant’s decision to ask patients regarding their symptoms (e.g., nausea, vomiting, sensitivity to light and sound, etc.) regardless of whether or not the patients reported experiencing a headache/migraine that day. During the IND phase, this reviewer asked the applicant to provide the ePRO screen shots for the headache/migraine symptom questions (e.g., nausea, vomiting, sensitivity to light and sound, etc.). 4 SCORING ALGORITHM The 14-item MSQ v2.1 total and domain (RR, RP, EF) scores are scored independently, with higher scores indicating less impact of migraine on patients’ daily lives. Response options range from 1 (None of the time) to 6 (All of the time), and are reverse-scored before the domain scores are calculated. The MSQ v2.1 ePRO required a response to each item; therefore, item-level missing data could not occur.

Once a final item value has been assigned to each item, a raw score can be computed for each MSQ v2.1 domain. The raw score for each domain is simply the sum of the final item value for all items in that domain after reverse-scoring. After the raw score for each MSQ v2.1 domain is computed, each domain score is linearly transformed to a 0 to 100 scale, where a higher score indicates less impact of migraine on patients’ daily lives. The transformation formulas for each MSQ v2.1 domain and total score are below.

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Reference ID: 4300420

Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

The sponsor stated that 25 one-on-one patient interviews were conducted o support the content, comprehensiveness, comprehension, and appropriateness of the items and response options of the MSQ v1.0. instrument. The sponsor stated that 30 one-on-one patient interviews were conducted with individuals with migraine to evaluate the patients’ responses to the MSQ v1.0 items. In this same study, the authors stated that the MSQ v2.0 was developed and that 20 patients with migraine were administered this revised version and were interviewed after completing the instrument. The authors stated that patients reported that the changes made were appropriate. The sponsor stated that the revisions made included “minor rewording of 5 items, minor formatting changes, and standardization of the response scale.”

The sponsor also cited other journal articles that reported both qualitative and quantitative research conducted with migraine patients regarding. One cited study of interest conducted a patient interview study in the United States with 21 patients with episodic migraine and 11 patients with chronic migraine and focused on functional impacts of the patients’ migraine symptoms.3 However, the citation included only an abstract and not a full article. The authors concluded that physical function appeared to be the most immediate impact due to migraine symptoms. The applicant also reviewed and cited other articles and concluded that the “literature clearly demonstrates that restrictions on roles and functioning related to important areas of daily life are important, meaningful and relevant to patients who suffer from either episodic or chronic migraine” (page 43 of the applicant’s PRO evidence dossier).

With regard to the 4-week recall period of the MSQ v2.1, the sponsor cited a number of references asserting that a 4-week recall period is appropriate for assessment of impacts of migraine, capturing a more representative picture of the patients’ migraine experience. Some authors compared the reliability of a daily diary versus a 4-week recall instrument and stated that the scores were highly correlated for headache severity, frequency, and duration.

The applicant conducted hybrid open-ended concept elicitation, cognitive interview, and usability testing research with one-on-one interviews with 11 patients. The applicant stated that patient inclusion criteria were similar to those used in the phase 3 CGAG, CGAH, and CGAI clinical trials.

Below is a table with the demographic and clinical characteristics of the interviewed patients (copied from the applicant’s response to the Agency’s information request dated March 8, 2018):

3 Hareendran A, Mannix S, Skalicky A, Widnell K, Corey-Lisle P, Sapra S. A qualitative study of the functional impact of symptoms on migraine patients. J Headache Pain. 2014;15(suppl 1):D53. [abstract EHMTI-0236] 17

Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Interviews were conducted at physician offices in the United States (New Hampshire, Oklahoma, and California), and lasted up to two hours. All interviews were conducted by 1 of 2 researchers trained in qualitative research and interview techniques using semi-structured interview guides. Institutional Review Board (IRB) approval was obtained for all study procedures, and all participants provided written informed consent prior to participating in an interview. All interviews were audio-recorded (with participants’ permission) and subsequently transcribed. A content analysis approach was used to analyze the qualitative data from the interview transcripts using qualitative data analysis software ATLAS.ti version 7.5.17.

Reviewer’s comments: This reviewer believes that a recall period of four weeks may be appropriate for episodic migraine sufferers; however, a shorter recall period may be more meaningful (e.g., past 24 hours) for chronic migraine sufferers. This reviewer requested, during the IND phase, that the applicant provide support for the four-week recall period from the qualitative work with both episodic and chronic patients and the applicant provided support in their PRO evidence dossier (see below).

A major limitation in the applicant’s qualitative interview study with 11 patients is the generalizability of the study. The patients included were mostly White ((90.9%), educated, employed women (n=9 of 11) with a mean age of 34.8 years (SD=7.7, ranging from 24-53 years). However, the applicant provided further support for content validity of the MSQ v2.1 Role Function-Restrictive domain from published literature on previous versions of the MSQ.

During the IND phase, this reviewer conveyed the following comments and recommendations to the applicant:

• Provide the demographic and clinical characteristics of the 75 patients interviewed for the qualitative studies, as well as the interview scripts, patient transcripts, and a detailed results report with item tracking matrices tailored to focus on the Role Function – Restrictive items, response options, and recall period. Provide the full results of Hareendran and colleagues (2014) study, including the detailed information listed above.

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

The full results of the qualitative research done thus far should clear up concerns with some of the Role Function – Restrictive domain items, such as: a. Did patients find the wording of item #7 (“how often have migraines limited the number of days you have felt energetic”) clear and understandable, or did they suggest alternative, simpler wording? . [Upon review of the applicant’s PRO evidence dossier, this reviewer found support for this item as clear and understandable to the patients cognitively interviewed.] b. Did most patients agree that item #1 (“how often have migraines interfered with how well you dealt with family, friends and others who are close to you”) is meaningful and important to assess as an impact of migraine symptoms? Did patients find the wording clear and understandable, or did they suggest alternative, simpler wording? This item may be less sensitive to treatment effects, given that it may be affected by factors other than migraine severity (e.g., psychosocial influences). . [Upon review of the applicant’s PRO evidence dossier, this reviewer found support for this item as meaningful, clear and understandable to all of the patients cognitively interviewed.] c. There is concern with “double-barreled” items (i.e., two or more concepts are included in one item, e.g., “reading or exercising,” “work or daily activities,” “at work or at home”). The risk with these types of items is that if a patient improves in one aspect, but not the other, the item will not show improvement with treatment effects. Using item #2 as an example, if a patient’s migraine symptoms do not allow the patient to be able to read for leisure (i.e., mental exertion), the patient may report at baseline that migraines have interfered “all of the time” with their “leisure time activities, such as reading or exercising.” However, if after treatment the patient can now read for leisure, but the now less severe migraine symptoms do not allow the patient to be able to exercise for leisure (i.e., physical exertion), the patient may not change his/her answer to item #2 at the end of treatment, despite being able to now read for leisure. The same can be said with regard to the patients improving in the ability to complete activities in the home, but not necessarily with activities at work. If feasible, consider modifying the item(s) by either a) asking about daily activities without specifying the types (e.g., reading, exercising) and where they take place (e.g., at home, at work), or b) splitting the “double-barreled” items into two or more items. . [Upon review of the applicant’s PRO evidence dossier, this reviewer found support for this item as clear and understandable to the patients cognitively interviewed.] d. Did patients report what a meaningful change or improvement in functioning would look like?

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

. [Upon review of the applicant’s PRO evidence dossier, this reviewer found that the patients interviewed spoke about experiencing less pain or severity during their migraine so they could function (n=7 of 11).] e. Did patients interviewed report that they could accurately average their migraine impact experience across a 4-week period of time without recall error. Note that a 4-week recall period can be obtained by combining data across four consecutive one-week recall diaries. . [Upon review of the applicant’s PRO evidence dossier, this reviewer found that the patients interviewed reported that they were thinking of specific events or instances over the past 4 weeks when they were responding to each question. Multiple participants reported using significant dates or occasions (for example, holidays, end of the school year) as reference points. The applicant stated that “all participants confirmed that they could recall the 4-week period. However, 2 participants did state that it could be difficult to recall accurately because their migraines happen so frequently: I get quite a few of them, so it’s a little difficult; it happened so frequently that I did my best to remember. As to an alternative to the 4-week recall period, 2 participants suggested using a 2-week recall period. However, these suggestions were specific to 2 items only, with each participant making the suggestion for just 1 item— 1 participant for item #5 (“limit your ability to concentrate on work or daily activities”), and 1 participant for item #6 (“…left you too tired to do work or daily activities”). Hence, across the 11 participants and 7 RR domain items, the 4-week recall period was endorsed 97% (75/77) of the time (page 59 in the applicant’s PRO evidence dossier).] f. Did patients differentiate between, and consistently define differently, all of the response options (e.g., between “a little bit of the time” and “some of the time”; between “a good bit of the time” and “most of the time”). . [Upon review of the applicant’s PRO evidence dossier, this reviewer found that 10 patients reported that they clearly understood the response options, and demonstrated that they were able to differentiate between the six response options. The applicant stated that one patient reported that there was no perceived difference between “some of the time” and “a good bit of the time.] • The Role Function – Restrictive items focus mostly on functioning in everyday activities. Given that the submission included the Hareendran and colleagues (2014) finding that physical function appears to be the most meaningful and important impact of migraine symptoms, we recommend considering inclusion of a measure of physical function in the planned phase 3 trials. One option that may be considered is use of the PROMIS® physical function item bank as an exploratory endpoint, and exploring selection of some items that are most relevant and important to the patient population so the items would

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

likely be sensitive to treatment effects. To find more information about PROMIS instruments, see: http://www.nihpromis.org/measures/availableinstruments.

Reviewer’s comments: During the BLA review phase, this reviewer requested the following additional information from the applicant (dated March 8, 2018):

“We acknowledge that you do not have the source data from the qualitative research conducted in the 1990s; however, in our email to you during the IND 111295 phase (dated November 15, 2016) we requested that you provide the demographic and clinical characteristics for the qualitative studies, as well as the interview scripts, patient transcripts, and a detailed results report with item tracking matrices tailored to focus on the Role Function – Restrictive items, response options, and recall period. We requested that you provide the full results of Hareendran and colleagues (2014) study, including all of the detailed information listed above.

Please provide these data as soon as possible for Agency review of the Role Function- Restrictive domain and items by resubmitting all available qualitative research results (including those data that you submitted with the BLA and the Hareendran and colleagues [2014] data) split into episodic migraine (EM) and chronic migraine (CM) patient subgroups to ensure that the Role Function–Restrictive items are relevant and important to both patient populations. For example, resubmit Tables 9.3 and 9.4 split by EM and CM patient subgroups.”

The applicant replied on March 15, 2018 with the patient demographic and clinical characteristics of the patients separated by episodic versus chronic migraine, the interview script for the qualitative work specific to the MSQ v2.1 Role Function-Restrictive domain, patient transcripts from the interviews (conducted from June 6-19, 2017). The applicant stated that the Hareendran and colleagues (2014) study was not research specific to the MSQ and the requested information is not publicly available. They provided a citation to a published manuscript for the study results of the aforementioned study:

Mannix S, Shalicky A, Buse DC, Desai P, Sapra S, Ortmeier B, Widnell K, Hareendran A. Measuring the impact of migraine for evaluating outcomes of preventive treatments for migraine headaches. Health Qual Life Outcomes. 2016;14(1):143.

Upon review of all of the applicant’s submitted materials during both the IND and BLA phases, this reviewer agrees with the applicant that there is adequate support based on patient input for the meaningfulness and importance of the concepts included in the MSQ v2.1 Role Function- Restrictive domain for both episodic and chronic migraine sufferers and that the recall period, instructions, items, and response options appear acceptable within this patient population. In conclusion, this reviewer believes that the content validity of the MSQ v2.1 Role Function- Restrictive domain appears to acceptable for the applicant’s targeted context of use.

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Reference ID: 4300420

Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Reliability • Internal consistency reliability o The Cronbach’s alpha coefficients for the MSQ v2.1 Role Function-Restrictive domain in each clinical trial (0.93 for CGAG, 0.92 for CGAH, and 0.92 for CGAI) indicated good internal consistency, based on the applicant’s pre-specified criterion of a coefficient of 0.70 to 0.90. Cronbach’s alpha coefficients did not go up with deletion of any item correlation with the domain. The applicant did not delete any items from the domain.

• Test-retest reliability o Stable patients were evaluated for test-retest reliability analysis of the MSQ v2.1 Role Function-Restrictive domain using the last two time points of the treatment phase for each of the three clinical trials (rather than at month 1 as was pre-specified, due to an early placebo response in all three clinical trials). The applicant compared the stable patients’ scores at months 5 and 6 for Studies CGAG and CGAH, and months 2 and 3 for Study CGAI) using paired t-tests and intra-class correlations coefficients (ICCs). The ICCs for the MSQ v2.1 Role Function-Restrictive domain were 0.82, 0.84, and 0.85 for Studies CGAG, CGAH, and CGAI, respectively (all statistically non- significant). These ICCs exceeded the applicant’s pre-specified threshold of 0.61 to 0.80 indicating substantial test-retest reliability.

Reviewer’s comments: The MSQ v2.1 Role Function-Restrictive domain’s internal consistency and test-retest reliability results are acceptable and comparable across all three clinical trials.

Construct Validity • Convergent validity o The relationship between the MSQ v2.1 Role Function-Restrictive domain with other pre-specified relevant PRO instruments and clinical measures (number of migraine headache days) was examined for all three clinical trials using Pearson’s product- moment and Spearman’s rank correlation coefficients at baseline. The associations the applicant found between the MSQ v2.1 Role Function-Restrictive domain and the other pre-specified relevant PRO instruments were as the applicant expected (Spearman’s correlations ranging from -0.46 to -0.57 across all three clinical trials, p<0.0001), but the association with number of migraine headache days was smaller than anticipated by the applicant (Spearman’s correlations ranging from -0.22 to -0.27 across all three clinical trials, p<0.0001). The applicant remarked that this small association may be due to the MSQ v2.1 Role Function-Restrictive domain may be reflecting features of migraine experience not captured by migraine headache days. Therefore, the applicant conducted the same analysis following treatment (average of months 4-6 for Studies CGAG and CGAH and month 3 for Study CGAI) and found

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

higher associations with number of migraine headache days (Spearman’s correlations ranging from -0.44 to -0.59, p<0.0001).

Reviewer’s comments: The MSQ v2.1 Role Function-Restrictive domain’s convergent validity results are acceptable.

• Known-groups validity o In Studies CGAG, CGAH, and CGAI, statistical tests were performed to explore the MSQ v2.1 Role Function-Restrictive domain’s ability to discriminate between subgroups of patients with different disease severity levels as measured by the PGI-S and number of migraine headache days per month at baseline. PGI-S response categories were collapsed from seven levels into five PGI-S groups (combining ‘Normal’ with Borderline Ill,’ and ‘Severely Ill’ with ‘Extremely Ill’ groups). The groups based on number of migraine headache days were defined as <8 versus ≥8 migraine headache days per month for episodic migraine (Studies CGAG and CGAH), and < 20 versus ≥20 migraine days per month for chronic migraine (Study CGAI). The applicant used these groupings based on the inclusion/exclusion criteria (at Visit 2) of the CGAG, CGAH, and CGAI protocols. It was hypothesized that those patients with worse severity levels of illness as assessed by the PGI-S would have lower mean MSQ v2.1 Role Function-Restrictive domain scores. And that patients with fewer migraine headache days per month would have higher mean MSQ v2.1 Role Function- Restrictive domain scores. The analysis of covariance (ANCOVA) model included the MSQ v2.1 Role Function-Restrictive domain as the dependent variable and the known-group criterion variable as the independent variable, while age and sex were included as covariates.

The applicant found statistically significant differences in mean MSQ v2.1 Role Function-Restrictive domain scores at baseline between participants in nearly all of the PGI-S levels (both 7-level, and 5-level comparisons); however across all three clinical trials there were no statistically significant differences between patients with PGI-S levels of “Normal” and “Borderline,” between “Normal” and “Mildly Ill,” or between “Borderline” and “Mildly Ill.” The applicant also observed statistically significant findings showing that the groups with fewer migraine headache days per month had higher mean MSQ v2.1 ePRO RR domain scores for all three clinical trials (p<0.001), as was expected by the applicant.

Reviewer’s comments: The MSQ v2.1 Role Function-Restrictive domain’s known-groups validity results are acceptable and comparable across all three clinical trials.

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Ability to Detect Change Over Time • Mean change in MSQ v2.1 Role Function-Restrictive domain scores compared to change in anchor scales (PGI-S scores, PGI-I scores, and percent change in migraine headache days) from baseline to the end of the treatment period (months 4-6 average for Studies CGAG and CGAH, and month 3 for Study CGAI) was analyzed by the applicant using ANCOVA (adjusted for baseline MSQ v2.1 Role Function-Restrictive domain scores). The applicant hypothesized that those patients with improved scores in the anchor scales would have statistically significantly higher (improved) MSQ v2.1 Role Function- Restrictive domain change scores than those in the group that stayed the same or worsened. Pearson and Spearman correlations between the change in MSQ v2.1 Role Function-Restrictive domain scores and the change in anchor scales were also calculated.

The correlations between the MSQ v2.1 Role Function-Restrictive domain score and the anchor scales were adequate across the three clinical trials (Pearson correlations ranged from -0.40 to -0.65; Spearman correlations ranged from -0.40 to -0.66). ANCOVA tests showed that mean MSQ v2.1 Role Function-Restrictive domain change scores were statistically significantly different (p<0.0001) between patients who improved versus stayed the same or worsened in the anchor scales (≥1 unit improvement in PGI-S vs. no improvement; ≥1 unit improvement in PGI-I vs. no improvement; and ≥50% improvement in number of migraine headache days vs. <50% improvement).

Reviewer’s comments: The applicant’s results provide support for the MSQ v2.1 Role Function- Restrictive domain’s ability to detect change and appear to be acceptable.

During the IND phase, this reviewer reviewed the applicant’s cited journal article reporting results from psychometric evaluation of the MSQ v2.1.4 and found that the measurement properties assessed by the authors appeared acceptable; however, the version of the MSQ that was used included 14 items from the 16-item MSQ v.2.0 that corresponded with the final 14-item MSQ v2.1, that included some modifications to item wording and response options. Therefore, this reviewer cannot have full confidence in the previously conducted psychometric results when considering acceptability of v2.1 of the MSQ instrument and relied solely on the psychometric evaluation conducted by the applicant using data from their three phase 3 clinical trials (CGAC, CGAH, and CGAI) described in this section above.

Additionally, during the IND phase, this reviewer conveyed to the applicant that they will be taking a risk if they choose to proceed with phase 3 without confirmation that the Role Function – Restrictive domain of the MSQ v2.1 is a well-defined and reliable instrument, if this domain is intended for labeling claims. Typically, we recommend evaluation of the instruments’ longitudinal measurement properties and performance (i.e., item descriptive analyses, reliability,

4 Martin BC, Pathak DS, Sharfman MI, Adelman JU, Taylor F, Kwong WJ, Jhingran P. Validity and reliability of the Migraine-Specific Quality of Life Questionnaire (MSQ version 2.1). Headache. 2000;40(3):204-215. 26

Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

validity, and ability to detect change) prior to initiation of phase 3 pivotal trials (e.g., in a standalone phase 2, or a separate non-pivotal phase 3 study) rather than using the phase 3 data. However, if it is not feasible to conduct such a study before phase 3, we recommend that sponsors develop a detailed psychometric analysis plan to evaluate the final version of the instrument and submit it for Agency review and concurrence before initiating the psychometric evaluation study. 7 INTERPRETATION OF SCORES During the IND phase, the applicant cited a journal article reporting results from a minimal important difference (MID) evaluation of the MSQ v2.1.5 However, the applicant was informed by the Agency that from a regulatory standpoint, the Agency is more interested in what constitutes a clinically meaningful within-patient change in scores (i.e., improvement threshold), from the patient perspective, rather than an MID across all patients.

In the empirical cumulative distribution function (eCDF) figures below (Figures 1-6), the change in the MSQ v2.1 Role Function-Restrictive domain scores from baseline to end of treatment for each of the phase 3 clinical trials (months 4-6 average for CGAG and CGAH, and month 3 for CGAI) for all patients (pooled across treatment arms) are plotted on the x-axis. The y-axis represents the cumulative percentage of the patients having up to a particular change in the MSQ v2.1 Role Function-Restrictive domain score (from the x-axis). When exploring a meaningful change score, we typically look at the intersection between the median line on the y-axis (representing one-half of the patients) and each curve, then trace those intersection points down to the x-axis to see the corresponding change in the MSQ v2.1 Role Function-Restrictive domain score. (Note: It is unclear whether blinded or unblinded clinical trial data were used for these analyses.)

The curves shown in Figures 1-3 represent each PGI-S change category (Improved [≥1 point decrease from baseline]; Stayed the same [>-1 to <1 point change from baseline]; Worsened [≥1 point increase from baseline]) across all three phase 3 clinical trials (episodic [CGAG and CGAH] and chronic [CGAI]). Looking at the median line in Figures 1-3, 50% of patients who “improved” on the PGI-S achieved a 32.4-point (CGAG), 30.5-point (CGAH), or 28.6-point (CGAI) or greater improvement in the MSQ v2.1 Role Function-Restrictive domain score.

5 Cole JC, Lin P, Rupnow MF. Minimal important differences in the Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1. Cephalalgia. 2009;29(11):1180-1187. 27

Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Figure 1. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Months 4-6 Average by Change in PGI-S in the CGAG (Episodic Migraine) Clinical Trial

Figure 2. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Months 4-6 Average by Change in PGI-S in the CGAH (Episodic Migraine) Clinical Trial

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Figure 3. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Month 3 by Change in PGI-S in the CGAI (Chronic Migraine) Clinical Trial

The curves shown in Figures 4-6 represent each PGI-I change category (Improved [≥1 level of improvement from baseline]; Stayed the same [no level change from baseline]; Worsened [≥1 level of worsening from baseline]) across all three phase 3 clinical trials (episodic [CGAG and CGAH] and chronic [CGAI]). Looking at the median line in Figures 1-3, 50% of patients who “improved” on the PGI-S achieved a 30.5-point (CGAG), 28.6-point (CGAH), or 28.6-point (CGAI) or greater improvement in the MSQ v2.1 Role Function-Restrictive domain score.

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Figure 4. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Months 4-6 Average by Change in PGI-I in the CGAG (Episodic Migraine) Clinical Trial

Figure 5. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Months 4-6 Average by Change in PGI-I in the CGAH (Episodic Migraine) Clinical Trial

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Figure 6. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Month 3 by Change in PGI-I in the CGAI (Chronic Migraine) Clinical Trial

Figures 7-9 represent the eCDFs of MSQ v2.1 Role Function-Restrictive domain change scores by treatment group for all three phase 3 clinical trials (episodic [CGAG and CGAH] and chronic [CGAI]).

Figure 7. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Months 4-6 Average by Treatment Group in the CGAG (Episodic Migraine) Clinical Trial

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Figure 8. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Months 4-6 Average by Treatment Group in the CGAH (Episodic Migraine) Clinical Trial

Figure 9. Change in MSQ v2.1 Role Function-Restrictive Domain Score from Baseline to Month 3by Treatment Group in the CGAI (Chronic Migraine) Clinical Trial

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

See reviewer’s comments below for evaluation of the applicant’s anchor-based eCDF analyses conducted in determining an improvement threshold in MSQ v2.1 Role Function-Restrictive domain scores.

Reviewer’s comments: During the IND phase, this reviewer reviewed the article cited by the applicant and found that the MID analyses conducted by Cole and colleagues (2009) on the MSQ v2.1 used an alternate scoring algorithm that they referred to as “a truncated 5-point MSQ ordinal scale” that was “non-standard 5-point scale.” Therefore, this reviewer cannot have confidence in their results.

Additionally, this reviewer suggested that the applicant consider also including the PGI-I and any other relevant measures as anchors, in addition to the PGI-S. No single anchor measure is preferable on its own, but including a number of anchor measures may provide an accumulation of evidence to help interpret a clinically meaningful change in the MSQ v2.1 scores.

In addition, this reviewer conveyed to the applicant that they should consider establishing a threshold for meaningful within-patient change in scores in one of their phase 3 episodic migraine trials (choosing the trial that will be completed first and has an adequate sample size for evaluation), and then pre-specifying the responder definition obtained from this study in their other two phase 3 clinical trials (episodic migraine and chronic migraine), which would be used for efficacy analysis and labeling. This reviewer also stated that they should plan to use anchor- based methods to evaluate the Role Function – Restrictive domain’s ability to detect change over time and empirical cumulative distribution function (eCDF) curves to determine what constitutes a meaningful change in this domain, using the PGI-S and PGI-I items as anchor scales.

During the BLA review phase, this reviewer requested the following information from the applicant (dated March 8, 2018):

“In the same email to you during the IND 111295 phase (dated November 15, 2016), we requested that as part of the psychometric evaluation results you “should plan to use anchor- based methods to evaluate the Role Function – Restrictive domain’s ability to detect change over time and cumulative distribution function (CDF) curves to determine what constitutes a meaningful change in this domain, using the PGI-S and PGI-I items as anchor scales.” In the BLA submission, you included empirical CDF (eCDF) curves for the treatment arms; however, we have not yet received the two anchor-based eCDF curve figures.

Please submit the anchor-based eCDFs of change in Role Function – Restrictive domain score by change in both the PGI-S and PGI-I items as anchor scales (in two separate eCDF figures; one for each anchor scale) and the provide the sample size and median score for each curve in each figure’s legend.

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

Please submit anchor-based probability density function (PDF; many times estimated using kernel density estimation) curves of change in Role Function–Restrictive domain score by change in both the PGI-S and PGI-I items as anchor scales (in two separate PDF figures; one for each anchor scale) and provide the sample size for each curve in each figure’s legend (see example of a PDF figure below).”

The applicant replied on March 15, 2018 submitting everything that was requested from the Agency.

The Office of Biostatistics reviewers looked at other submissions from the applicant in response to Agency information requests for individual item scores (dated March 29, 2018) and raw baseline item-level scores (dated April 12, 2018) for the MSQ v2.1 Role Function-Restrictive domain. The statistical reviewers found the item-level mean baseline scores and the mean changes from baseline to be similar across items and the changes are consistent, and found no issues to report. It does not appear that any particular item is driving the domain score above and beyond the contribution from the other items to the domain score.

Based on the empirical cumulative distribution function (eCDFs) submitted by the applicant (dated March 15, 2018) in response to the Agency’s information request dated March 8, 2018 the clinically meaningful within-patient improvement thresholds for the MSQ v2.1 Role Function-Restrictive domain appear to be the following in each of the three phase 3 clinical trials:

CGAG: Median for Improved (PGI-S change) category is 32.4 Median for Improved (PGI-I at Month 6) category is 30.5 CGAH: Median for improved (PGI-S change) category is 30.5 Median for improved (PGI-I at Month 6) category is 28.6 CGAI: Median for improved (PGI-S change) category is 28.6 Median for improved (PGI-I at Month 3) category is 28.6

To this reviewer, the anchor-based eCDFs for the CGAG and CGAH episodic migraine trials suggested that the clinically meaningful within-patient improvement threshold is between 28.6 and 32.4. And the anchor-based eCDFs for the CGAI chronic migraine study suggested that the clinically meaningful within-patient improvement threshold is 28.6. These thresholds are higher than those proposed by the applicant.

In conclusion, this reviewer found that the eCDF curves showed clear and consistent separation between the 120 mg/240 mg treatment arm curves compared to the placebo arm curve in both episodic migraine clinical trials (CGAG and CGAH), and this held true for MSQ v2.1 Role Function-Restrictive domain score changes that fall within the aforementioned range of clinically meaningful within-patient improvement thresholds. However, in the chronic migraine clinical trial (CGAI) there was less of a separation (and less consistent) between the 120 mg

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

treatment arm compared to the placebo arm, but a clearer and more consistent separation observed between the 240 mg treatment arm versus the placebo arm. 8 LANGUAGE TRANSLATION AND CULTURAL ADAPTATION The applicant conducted the phase 3 trials multi-nationally (Studies CGAH and CGAI) and stated that they have certificates for 21 translations of the MSQ v2.1 in different languages and countries. The applicant provided certification of forward and back translations of the instrument by independent reviewers and clinicians as well as cognitive debriefing interviews with patients in the United States for translation of the instrument from English to Spanish, as an example.

9 REFORMATTING FOR NEW METHOD OR MODE OF ADMINISTRATION In preparation for the three phase 3 migraine clinical trials (CGAG, CGAH, and CGAI), the applicant stated that the paper and pencil MSQ v2.1 was migrated to the MSQ v2.1 ePRO on the TrialSlate electronic device. The TrialSlate was programmed to allow only one response to be selected for each item; therefore, the instruction stating patients should “select only one response” was eliminated. Text was modified by eliminating underlining and bolding, and the overall instructions to “please think about all migraine attacks you may have had in the past 4 weeks” were eliminated because each item included the prefix “in the past 4 weeks.”

The applicant conducted a usability testing cognitive interview study with 11 episodic/migraine patients (same patients that participated in the rest of the qualitative interviews) and found that no one experienced any difficulty using the electronic TrialSlate device (the same version that was used in the phase 3 clinical trials), and all patients reported that it was easy to use overall, and that using their finger to select their responses was sufficient. The applicant stated that all reported that it was easy or simple to move back and forth between screens and experienced no difficulty in viewing the questions and responses on each screen. All patients were asked whether they changed response options for any of the items, and if they were able to do so without difficulty; two patients reported that they had changed their response to one or more items and were able to do so without any difficulty.

Reviewer’s comments: The applicant’s usability testing study results appear reasonable.

During the IND phase, this reviewer conveyed the following to the applicant:

There are some differences between the paper version of the MSQ v2.1 that was submitted previously and the screen shots of the electronic version: 1. The paper version includes the following instructions for the patient: “While answering the following questions, please think about all migraine attacks you may have had in the past 4 weeks.”

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

These patient instructions are not included in the electronic version, but should be added to ensure consistency between the two versions. 2. The paper version includes the following parenthetical instruction in each item stem: (Select only one response.). This parenthetical instruction is not included in the electronic version’s item stems, but should be added, including the underlining of the word “one” to ensure consistency between the two versions. 3. The paper version has the following words underlined in the 7 items, when applicable: “past 4 weeks,” “interfered,” “difficulty,” “keep you,” “limit,” “left you too tired,” “limited,” and “one”; the electronic version has no underlining of any words, but the underlining should be added to ensure consistency between the two versions.

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

APPENDIX A – MIGRAINE AND HEADACHE ENDPOINT TERMINOLOGY DEFINITIONS

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

APPENDIX B - MIGRAINE-SPECIFIC QUALITY OF LIFE QUESTIONNAIRE VERSION 2.1(MSQ V2.1) ROLE FUNCTION- RESTRICTIVE DOMAIN

(b) (4)

6 Pages has been Withheld in Full as b4 (CCI/TS) immediately following this page

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

APPENDIX C – PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) (b) (4)

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Reference ID: 4300420 Clinical Outcome Assessment Review Sarrit M. Kovacs, PhD BLA 761063 Galcanezumab; LY2951742/Emgality Migraine-Specific Quality of Life Questionnaire version 2.1(MSQ v2.1) Role Function- Restrictive Domain

APPENDIX D – PATIENT GLOBAL IMPRESSION OF IMPROVEMENT (PGI-I)

(b) (4)

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Reference ID: 4300420 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

SARRIT M KOVACS 08/01/2018

WEN-HUNG CHEN 08/01/2018 Serving as acting AD and signing on Dr. Elektra Papadopoulos' behalf

Reference ID: 4300420 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

STATISTICAL AND CLINICAL EFFICACY REVIEW Application Type BLA; 351 (a) Application Number(s) 761063 Priority or Standard Standard Submit Date(s) September 27, 2017 Received Date(s) September 27, 2017 PDUFA Goal Date September 27, 2018 Division/Office Division of Biometrics 1/Office of Biostatistics Division of Neurology Products/Office of New Drugs Reviewer Name(s) Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Review Completion Date March 5, 2018 Established/Proper Name Galcanezumab (LY2951742) (Proposed) Trade Name Emgality Applicant Eli Lilly and Company (Lilly) Dosage Form(s)  Single-dose prefilled pen (auto-injector) and  Single-dose prefilled syringe for Subcutaneous Injection 120 mg/mL in each single-dose syringe Applicant Proposed Dosing 120 mg injected subcutaneously once monthly, with a 240 mg Regimen(s) loading dose as the initial dose Applicant Proposed Prophylaxis of migraine headache in adults Indication(s)/Population(s) Recommendation on Approval Regulatory Action

CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

Table of Contents

Glossary ...... 7

1. Executive Summary...... 9 1.1. Product Introduction...... 9 1.2. Conclusions on the Substantial Evidence of Effectiveness...... 9 1.3. Benefit-Risk Assessment ...... 10 1.4. Patient Experience Data...... 14

2. Therapeutic Context...... 14 2.1. Analysis of Condition...... 14 2.2. Analysis of Current Treatment Options ...... 18

3. Regulatory Background ...... 20 3.1. U.S. Regulatory Actions and Marketing History...... 20 3.2. Summary of Presubmission/Submission Regulatory Activity ...... 20 3.3. Foreign Regulatory Actions and Marketing History ...... 24

4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ...... 24 4.1. Office of Scientific Investigations (OSI) ...... 24 4.2. Product Quality ...... 24 4.3. Clinical Microbiology...... 24 4.4. Nonclinical Pharmacology/Toxicology ...... 24 4.5. Clinical Pharmacology ...... 24 4.6. Devices and Companion Diagnostic Issues ...... 25 4.7. Consumer Study Reviews...... 25

5. Sources of Clinical Data and Review Strategy ...... 25 5.1. Table of Clinical Studies ...... 26 5.2. Review Strategy ...... 30

6. Review of Relevant Individual Trials Used to Support Efficacy ...... 30 6.1. Protocol CGAG Phase 3 Episodic Migraine (EVOLVE-1) ...... 30 6.1.1. Study Design ...... 30 CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

6.1.2. Study Results ...... 42 6.2. Protocol CGAH Phase 3 Episodic Migraine (EVOLVE-2) ...... 59 6.2.1. Study Design ...... 59 6.2.2. Study Results ...... 59 6.3. Protocol CGAI Phase 3 Chronic Migraine (REGAIN) ...... 72 6.3.1. Study Design ...... 72 6.3.2. Study Results ...... 80

7. Integrated Review of Effectiveness...... 94 7.1. Assessment of Efficacy Across Trials...... 94 7.1.1. Primary Endpoints ...... 94 7.1.2. Secondary and Other Endpoints...... 96 7.1.3. Subpopulations...... 96 7.1.4. Dose and Dose-Response ...... 102 7.1.5. Onset, Duration, and Durability of Efficacy Effects...... 102 7.2. Additional Efficacy Considerations...... 102 7.3. Integrated Assessment of Effectiveness ...... 103

8. Review of Safety...... 104

9. Advisory Committee Meeting and Other External Consultations ...... 104

10. Labeling Recommendations ...... 104 10.1. Prescription Drug Labeling ...... 104

11. Risk Evaluation and Mitigation Strategies (REMS) ...... 104

12. Postmarketing Requirements and Commitments...... 104

13. Appendices...... 104 13.1. References...... 104 13.2. Financial Disclosure ...... 105

CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

Table of Tables

Table 1: Patient Experience Data Relevant to BLA 761063 ...... 14 Table 2: ICHD-3 (Beta) Diagnostic Criteria for Chronic Migraine...... 16 Table 3: Drugs for Prophylaxis of Migraine Headaches...... 18 Table 4: Indirect Comparison of Efficacy Data of Migraine Prophylaxis Medications ...... 19 Table 5: BLA 761063 Galcanezumab Summary of Presubmission Regulatory Activity...... 20 Table 6: BLA 761063 Tabular Listing of Clinical Studies for Galcanezumab Migraine Prophylaxis ...... 26 Table 7: BLA 761063 EM Study CGAG and CGAH Planned Sample Size...... 32 Table 8: EM Study CGAG and CGAH Schedule 6 months Double-Blind Treatment...... 34 Table 9: Migraine Day and Headache Day Endpoint Definitions (Studies CGAG, CGAH, and CGAI) ...... 36 Table 10: Secondary Endpoints and Analysis Methods Studies CGAG, CGAH, and CGAI ...... 41 Table 11: Study CGAG Summary...... 42 Table 12: Phase 2 Dose-Ranging Study I5Q-MC-CGAB – Topline Efficacy, Change from Baseline in Migraine Days Hierarchical Logistic Dose Response Model ...... 43 Table 13: Phase 2 Dose-Ranging Study I5Q-MC-CGAB – Topline Efficacy, Change from Baseline in Migraine Days Repeated Measures Analysis...... 44 Table 14: Study CGAG Patient Disposition ...... 46 Table 15: Study CGAG Episodic Migraine Demographic Characteristics ...... 48 Table 16: Study CGAG Episodic Migraine Baseline disease Characteristics...... 49 Table 17: Study CGAG Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM ...... 50 Table 18: Study CGAG Key Secondary Efficacy Analyses ...... 54 Table 19: Study CGAG Additional Secondary Efficacy Analyses ...... 55 Table 20: Study CGAG Mean Change from Baseline in Monthly Migraine Headache Days ...... 58 Table 21: Study CGAG Mean Change from Baseline in Monthly Headache Days, Sensitivity Analysis...... 58 Table 22: Study CGAH Summary...... 59 Table 23: Study CGAH Patient Disposition...... 60 Table 24: Study CGAH Episodic Migraine Demographic Characteristics ...... 61 Table 25: Study CGAH Episodic Migraine Baseline Disease Characteristics ...... 62 Table 26: Study CGAH Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM ...... 64 Table 27: Study CGAH Key Secondary Efficacy Analyses ...... 68 Table 28: Study CGAH Additional Secondary Efficacy Analyses ...... 69 Table 29: Study CGAH Mean Change from Baseline in Monthly Migraine Headache Days ...... 71 Table 30: Study CGAH Mean Change from Baseline in Monthly Headache Days, Sensitivity Analysis...... 71

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Table 31: BLA 761063 Overview of Study Design EM Study CGAG and CGAH, and CM Study CGAI ...... 73 Table 32: BLA 761063 Chronic Migraine Study CGAI Planned Sample Size...... 75 Table 33: CM Study CGAI Schedule of Assessments Double-Blind Treatment Phase (3 months) 76 Table 34: Study CGAI Summary ...... 80 Table 35: Chronic Migraine Study CGAI Patient Disposition ...... 81 Table 36: Study CGAI Chronic Migraine Demographic Characteristics...... 83 Table 37: Study CGAI Chronic Migraine Baseline Disease Characteristics...... 84 Table 38: Study CGAI Chronic Migraine Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM...... 86 Table 39: Study CGAI Key Secondary Efficacy Analyses...... 90 Table 40: Study CGAI Additional Secondary Efficacy Analyses...... 92 Table 41: Study CGAI Mean Change from Baseline in Monthly Migraine Headache Days...... 94 Table 42: BLA 760103 Primary and Key Secondary Efficacy Analyses Studies CGAG,CGAH,CGAI95 Table 43: Study CGAG and CGAH Subgroup Analysis - Age (Pooled ITT; MMRM)...... 97 Table 44: Study CGAI Subgroup Analysis - Age (ITT; MMRM) ...... 97 Table 45: Study CGAG and CGAH Subgroup Analysis - Race (Pooled ITT; MMRM) ...... 98 Table 46: Study CGAI Subgroup Analysis - Race (ITT; MMRM)...... 98 Table 47: Study CGAG and CGAH Subgroup Analysis - Gender (Pooled ITT; MMRM)...... 99 Table 48: Study CGAI Subgroup Analysis - Gender (ITT; MMRM)...... 100 Table 49: Study CGAG and CGAH Subgroup Analysis - BMI (Pooled ITT; MMRM) ...... 100 Table 50: Study CGAI Subgroup Analysis - BMI (ITT; MMRM) ...... 101

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Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

Table of Figures

Figure 1: CGRP and Pathophysiology of Migraine ...... 17 Figure 2: BLA 761063 Phase 3 Clinical Studies for Galcanezumab Migraine Prophylaxis...... 29 Figure 3: BLA 761063 Study Design EM studies CGAG and CGAH for Galcanezumab Migraine Prophylaxis ...... 31 Figure 4: Phase 2 Design Dose-Ranging Study I5Q-MC-CGAB ...... 33 Figure 5: BLA 761063 Phase 2 PD model Galcanezumab Concentrations for Phase 3 Dose Selection ...... 45 Figure 6: Study CGAG Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM ...... 52 Figure 7: Study CGAG Histogram Mean Change from Baseline in Migraine Headache Days ...... 53 Figure 8: Study CGAG Histogram Percent Change from Baseline in Migraine Headache Days....57 Figure 9: Study CGAH Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM ...... 66 Figure 10: Study CGAH Histogram Mean Change from Baseline in Migraine Headache Days .....67 Figure 11: Study CGAH Histogram Percent Change from Baseline in Migraine Headache Days..70 Figure 12: BLA 761063 CM Study Design for Galcanezumab Migraine Prophylaxis...... 72 Figure 13: Study CGAI Chronic Migraine Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 3 month Treatment Period - MMRM...... 88 Figure 14: Study CGAI Histogram Mean Change from Baseline in Migraine Headache Days...... 89 Figure 15: Study CGAI Histogram Percent Change from Baseline in Migraine Headache Days ...93

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Glossary

AC advisory committee AE adverse event AR adverse reaction BLA biologics license application BPCA Best Pharmaceuticals for Children Act BRF Benefit Risk Framework CBER Center for Biologics Evaluation and Research CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CDTL Cross-Discipline Team Leader CFR Code of Federal Regulations CMC chemistry, manufacturing, and controls COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms CRF case report form CRO contract research organization CRT clinical review template CSR clinical study report CSS Controlled Substance Staff DMC data monitoring committee ECG electrocardiogram eCTD electronic common technical document ETASU elements to assure safe use FDA Food and Drug Administration FDAAA Food and Drug Administration Amendments Act of 2007 FDASIA Food and Drug Administration Safety and Innovation Act GCP good clinical practice GMB galcanezumab (LY2951742) GRMP good review management practice ICH International Council for Harmonization IND Investigational New Drug Application ISE integrated summary of effectiveness ISS integrated summary of safety ITT intent to treat MedDRA Medical Dictionary for Regulatory Activities mITT modified intent to treat NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event

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NDA new drug application NME new molecular entity OCS Office of Computational Science OPQ Office of Pharmaceutical Quality OSE Office of Surveillance and Epidemiology OSI Office of Scientific Investigation PBRER Periodic Benefit-Risk Evaluation Report PD pharmacodynamics PI prescribing information or package insert PK pharmacokinetics PMC postmarketing commitment PMR postmarketing requirement PP per protocol PPI patient package insert PREA Pediatric Research Equity Act PRO patient reported outcome PSUR Periodic Safety Update report REMS risk evaluation and mitigation strategy SAE serious adverse event SAP statistical analysis plan SGE special government employee SOC standard of care TEAE treatment emergent adverse event

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1. Executive Summary

1.1. Product Introduction

Eli Lilly (Lilly) submitted the original 351(a) application for BLA 761063 to evaluate galcanezumab as a potential migraine prophylaxis therapy in migraineurs suffering from episodic or chronic migraine via monthly subcutaneous administration.

Galcanezumab (LY2951742) is a humanized IgG4 monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) and prevents its biological activity without blocking the CGRP receptor. Calcitonin gene-related peptide is a potent vasodilator (see section 2.1). According to the sponsor, galcanezumab inhibits CGRP activity as a sensory neuropeptide in the trigeminal system involved in the pathophysiology of migraine. Elevated blood concentrations of CGRP have been associated with migraine and other painful conditions. In addition, CGRP infusions can induce migraine-like attacks in some individuals with a history of migraine.

During the galcanezumab development program, several names were used in its description. Please note that LY2951742, galcanezumab (GMB), and LA468 are one and the same. Emgality is the proposed proprietary trade name.

Lilly proposed the following indication statement for labeling: Galcanezumab is indicated for the prophylaxis of migraine in adults.

Lilly’s proposed dosing regimen for galcanezumab: The recommended dose is 120 mg injected subcutaneously once monthly, with a 240 mg loading dose as the initial dose. (b) (4)

The proposed commercial presentation of galcanezumab will be a 1 mL prefilled syringe or a pen device (autoinjector) for subcutaneous injection containing 120 mg/mL in each single-dose syringe. The prefilled syringe was used in all phase 3 studies. The autoinjector was used in the phase 3, open-label safety study (CGAJ) and a phase 1 study (CGAQ). The same primary container closure system, (b) (4) is used for both the prefilled syringe and the autoinjector and both devices were designed to deliver the entire dose in a single injection (Module 2.5).

1.2. Conclusions on the Substantial Evidence of Effectiveness

Based on the available information reviewed for the determination of efficacy in BLA 761063,

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Lilly’s application provides substantial evidence supporting galcanezumab for migraine prophylaxis indication based on clinically significant endpoints.

1.3. Benefit-Risk Assessment

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Benefit-Risk Integrated Assessment

Please refer to the information for this section in Heather Fitter, MD Cross-Discipline Team Leader review for BLA 761063.

Benefit-Risk Dimensions Dimension Evidence and Uncertainties Conclusions and Reasons

 Migraine headache is a very common, chronic neurological disease,  Migraine is a serious and disabling condition characterized as moderate to severe headache with associated that can impact the quality of patients’ lives. hypersensitivity to environmental stimuli such as light and sound, as  The World Health Organization estimates well as nausea. Headaches typically last from 4 to 72 hours if left based on the Global Burden of Disease, untreated, are generally unilateral in nature, and frequently include migraine to be the sixth-highest cause throbbing or pulsating pain. Patients with severe and/or frequent worldwide of time lost due to disability, with migraines requiring chronic intermittent therapy with prophylaxis effects that can interfere significantly with therapy with the goal of reduction in migraine frequency. everyday functioning.  The clinician identifies the headache based upon the frequency and Analysis of duration of the attacks. Episodic migraines (EM) occur on fewer than 15 Condition days per month, with usually between 4-14 days of migraine headache days. Chronic migraines (CM) is characterized by headaches on 15 or more days per month with features of migraine on at least 8 days per month or respond to treatment specifically for migraine. Chronic migraine and episodic migraine are part of the spectrum of migraine disorders, although distinct clinical entities.  Migraine affects an estimated 36 million Americans, with a gender difference in prevalence. 18% women experience episodic migraine compared with 6% of men. Estimates of chronic Migraine prevalence range from 1% to 3% (1.3% women compared with 0.5% of men).

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Dimension Evidence and Uncertainties Conclusions and Reasons

 Five drugs are FDA approved for migraine prophylaxis, as well as many The treatment armamentarium would benefit from other drugs that are used off-label. The FDA approved therapies include therapeutic options that reduce the frequency of the beta-adrenergic blocking agents propranolol (tablets and liquid) and monthly migraine headaches, and that are better timolol (tablets) and the anticonvulsants divalproex sodium or sodium tolerated offering the convenience of infrequent valproate (tablets) and topiramate (tablets) and injectable botulinum interval dosing with the expectation to improve neurotoxin type A, or onabotulinumtoxinA (approved for chronic compliance. migraine only).  Migraine prophylaxis products are expected to be administered at least daily, and up to three times daily for propranolol, with the exception of onabotulinumtoxinA that is the only approved product for chronic migraine prophylaxis which requires 31 injections in the head and neck every three months, and needs to be administered every three months. Current The currently available FDA-approved products for migraine prophylaxis Treatment are shown to reduce the frequency of monthly migraine headaches or Options the headache days of at least moderate severity between three to six days, and although there is some amelioration in their condition most patients continue to experience migraines even on therapeutic doses of effective medications.  Although widely used, the approved preventive medications are associated with adverse events as informed in individual product labeling, such as anorexia, fatigue, memory problems, paresthesia, dizziness, vertigo, nausea, and tremor, hepatotoxicity, with some products often requiring dose titration, special laboratory monitoring, and carry special precautions, warnings, or contraindications. Several of the available prophylactic medications have some intolerable side effects making it difficult for patients to justify continuing to take a daily medication that does not completely prevent migraines.

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Dimension Evidence and Uncertainties Conclusions and Reasons

Phase 3 studies CGAG and CGAH in episodic migraineurs and study CGAI in The evidence submitted by the applicant to chronic migraine patients provide a reasonable assessment of benefit support the approval of galcanezumab has met the supporting effectiveness for the proposed indication, prophylaxis of migraine. statutory evidentiary standard for providing substantial evidence of effectiveness under the There were statistically significant and clinically meaningful changes on the proposed conditions of use. The studies were primary efficacy endpoint demonstrated in all three studies with an overall adequate and well-controlled. The endpoints were reduction in 2 monthly migraine days compared to placebo. The appropriate, clinically relevant, and similar to galcanezumab 120 mg administered subcutaneous monthly (with initial 240 endpoints used for previously approved products mg loading dose), and monthly galcanezumab 240 mg dose groups showed 4- for migraine prophylaxis. The treatment effect 5 days reduction from baseline as compared to reduction of 2-3 days in the observed with galcanezumab is consistent with placebo group, although there did not appear to be any meaningful previously therapies for migraine prophylaxis and Benefit therapeutic benefit of administering the higher monthly galcanezumab 240 the duration of the effect was adequately studied. mg dose. In addition, there were statistically significant and clinically meaningful reductions in the acute migraine medications used and the hours of headache experienced overall.

The data provided in the pivotal efficacy studies, CGAG and CGAH supportive in the episodic migraine population and study CGAI (chronic migraine), provide for substantial evidence of effectiveness and the results are persuasive and clinically meaningful. The design of the studies was in alignment with FDA advice during development.

Please refer to the information for this section in Heather Fitter, MD Cross- Risk and Risk Discipline Team Leader review for BLA 761063. Management

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1.4. Patient Experience Data

Listed below is the patient experience data and related information relevant to BLA 761063 submitted and reviewed as part of the application. The relevant discussions for these outcome assessments are referenced to the applicable sections or other FDA review.

Table 1: Patient Experience Data Relevant to BLA 761063

 The patient experience data that was submitted as part of the application Section where discussed, if include: applicable  Clinical outcome assessment (COA) data  Patient reported outcome (PRO) Please refer to Sections 6.1 Daily Headache Diary and 6.2 discussion Migraine Specific Quality of Life Questionnaire (MSQ v2.1) regarding study endpoints Migraine Disability Assessment test (MIDAS) and to Sarrit Kovacs, Ph.D. Patient Global Impression-Improvement (PGI-I) Clinical Outcome Patient Global Impression-Severity (PGI-S) Assessments review □ Observer reported outcome (ObsRO) □ Clinician reported outcome (ClinRO) □ Performance outcome (PerfO) □ Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel, etc.) □ Patient-focused drug development or other stakeholder meeting summary reports □ Observational survey studies designed to capture patient experience data □ Natural history studies □ Patient preference studies (e.g., submitted studies or scientific publications) □ Other: (Please specify)

2. Therapeutic Context

2.1. Analysis of Condition

Migraine is a common disabling primary headache disorder that affects an estimated 36 million

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Americans1, with a gender difference in prevalence. 18% women experience episodic migraine compared with 6% of men. Estimates of chronic Migraine prevalence range from 1% to 3% (1.3% women compared with 0.5% of men). The World Health Organization (WHO) estimates based on the Global Burden of Disease (GBD), migraine to be the sixth-highest cause worldwide of time lost due to disability (YLD), with effects that can interfere significantly with everyday functioning.

Migraine headache is understood to be a complex neurovascular disorder resulting in pain and further nerve activation involving the trigeminovascular system and associated release of CGRP from activated trigeminal sensory nerves, a potent vasodilator and modulator of cerebrovascular nociception (See section 4.5). Migraines attacks are characterized as moderate to severe headache with associated hypersensitivity to environmental stimuli such as light and sound, as well as nausea. These headaches typically last from 4 to 72 hours if left untreated, are generally unilateral in nature, and frequently include throbbing or pulsating pain.

Patients experience episodic exacerbations associated with significant pain, disability, and diminished quality of life that typically affects patients during their most productive years. Patients with severe and/or frequent migraines requiring chronic intermittent therapy are offered long-term preventive therapy with the goal of reduction in migraine frequency.

Migraine diagnostic criteria

As summarized in the referenced literature1, if the patient has a primary headache disorder, the clinician identifies the headache based upon the frequency and duration of the attacks. Episodic migraine (EM) by definition includes headaches that occur on fewer than 15 days per month, with usually between 4-14 days of migraine headache days. Chronic migraine (CM) is characterized by headaches on 15 or more days per month for at least 3 months; headaches must have the features of migraine on at least 8 days per month or respond to treatment specifically for migraine. Chronic migraine and episodic migraine are part of the spectrum of migraine disorders, but they are distinct clinical entities as classified by International Classification of Headache Disorders–3rd edition, beta guidelines for primary and secondary headache disorders2.

1 Lipton RB, Silberstein SD. Episodic and chronic migraine headache: breaking down barriers to optimal treatment and prevention. Headache. 2015 Mar;55 Suppl 2:103-22. 2 Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;33(9):629-808. CDER Clinical Review Template 15 Version date: September 6, 2017 for all NDAs and BLAs

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Table 2: ICHD-3 (Beta) Diagnostic Criteria for Chronic Migraine

Chronic migraine patients are more debilitated and more likely to miss work or have decreased productivity. CM patients have more comorbid conditions, including psychiatric and pain disorders. They also use more health resources than EM patients, including emergency department visits, clinic visits, and medications3.

Phenotypically, migraine features may change with the transition from less-frequent episodic migraine to chronic migraine. Patients with chronic migraine more often have bilateral headache, and their associated symptoms are not as pronounced as they are for those with episodic migraine.4

Risk of progression from episodic migraine to chronic migraine

As reported in the referenced literature1, CM develops in individuals with EM at a rate of about 2.5% per year, and some of the risk factors for progression are non-modifiable which include older age, female gender, and Caucasian ethnicity. The potentially modifiable risk factors for CM onset are obese individuals with EM who are two to five times more likely to develop CM than are persons of normal weight.

Migraine and Calcitonin Gene-Related Peptide (CGRP)

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide that is a potent vasodilator and is widely distributed throughout the central and peripheral nervous systems. As illustrated in the referenced Figure 1, CGRP is released from trigeminal afferent nerve fibers during a migraine and causes vasodilatation and neurogenic inflammation. Raised levels of CGRP are observed both peripherally and centrally in migraine patients. CGRP antibodies and antagonists are thought to reduce migraine by reducing these CGRP levels or through blocking the actions of CGRP. CGRP antibodies are peripherally restricted, whereas CGRP antagonists

3 Sanderson JC et al. Headache-related health resource utilisation in chronic and episodic migraine across six countries. J Neurol Neurosurg Psychiatry. 2013 Dec;84(12):1309-17. 4 Diener HC et al. Integrated care for chronic migraine patients: epidemiology, burden, diagnosis, and treatment options. Clinical Medicine 2015 Vol 15, No 4: 344–50. CDER Clinical Review Template 16 Version date: September 6, 2017 for all NDAs and BLAs

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may have central actions5. The referenced citation additionally provides background into the development of CGRP products, as CGRP small molecule antagonists and CGRP monoclonal antibodies (against the free peptide and others targeting the CGRP receptor) for acute and preventative migraine management.

During spontaneous migraine attacks, there is elevated CGRP concentrations measured from the external jugular vein and CGRP serum levels decrease after administration of triptans in parallel with symptomatic relief therefore suggesting CGRP is involvement in the pathophysiology of migraine6.

Figure 1: CGRP and Pathophysiology of Migraine

The CGRP, a potent vasodilator, is a well-validated target in the pathophysiology of migraine. The “gepants” ( (IV), /MK0974 (oral)) were the first class of drugs to target the CGRP pathway in the treatment of migraine. CGRP receptor antagonists have shown

5 Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin Gene-Related Peptide: Physiology And Pathophysiology. Physiol Rev. 2014 Oct;94(4):1099-142 6 Tso AR, Goadsby PJ. Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention? Curr Treat Options Neurol 2017 19: 27 CDER Clinical Review Template 17 Version date: September 6, 2017 for all NDAs and BLAs

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efficacy in the treatment of EM while the CV effects that are associated with medications were not observed (references: Hewitt et al 2011, Ho et al 2008, Olesen et al 2004). However, despite these reported therapeutic effects with other CGRP products, evidence of liver toxicity was observed with at least two of these compounds (telcagepant/MK0974 and MK3207), resulting in subsequent discontinuation of development of the gepants.

2.2. Analysis of Current Treatment Options

Five drugs are FDA approved for migraine prophylaxis (Table 3). These include the beta- adrenergic blocking agents propranolol (tablets and liquid) and timolol (tablets) and the anticonvulsants divalproex sodium or sodium valproate (tablets) and topiramate (tablets). Injectable botulinum neurotoxin type A, or onabotulinumtoxinA (155 units in 31 standardized injections), is currently the only product approved for chronic migraine prophylaxis, in adults aged 18 years or older who have ≥15 days per month with headache lasting ≥4 hours per day.

Table 3: Drugs for Prophylaxis of Migraine Headaches

DRUG CLASS DRUG BRAND NAME DRUG GENERIC NAME Inderal propranolol hydrochloride β-adrenergic antagonists Blocadren timolol maleate Topamax topiramate Anti-Epileptics Depakote ER divalproex sodium Botulinum Toxin BOTOX onabotulinumtoxinA

Although widely used, these medications for prophylaxis are associated with AEs as informed in labeling, such as anorexia, fatigue, memory problems, paresthesia, dizziness, vertigo, nausea, and tremor, hepatotoxicity, and often require dose titration, special laboratory monitoring, and carry special precautions, warnings, or contraindications.

Efficacy in approved migraine prophylaxis products

The reviewer is not aware of the sponsor having conducted head to head clinical studies comparing the efficacy of galcanezumab to other migraine prophylaxis products. The summary Table 4 provides efficacy information from the clinical studies for the labeled migraine prophylaxis products conducted to demonstrate safety and efficacy that are FDA approved, and is not intended for cross study comparisons. Table 4 shows the treatment effect compared to the placebo arms for the products and the endpoints used that were supportive to establish efficacy and clinical meaningfulness. It is to be noted that the information shown in Table 4 is only for on overview of the efficacy, and that the primary efficacy endpoints maybe different for the clinical studies, including the definitions for the endpoint variables and the method for evaluating the treatment effect over the controlled study period. CDER Clinical Review Template 18 Version date: September 6, 2017 for all NDAs and BLAs

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Table 4: Indirect Comparison of Efficacy Data of Migraine Prophylaxis Medications

Headache/Migraine Migraine Headache Total cumulative Days Episodes hours of headache on headache days Duration Dose Change Treatment Change Treatment Change Treatment (mg) from difference from difference from difference Baseline, (drug- Baseline, (drug- baseline (drug- mean placebo) mean placebo) placebo) Episodic Migraine Topiramate 26-week (8- 100 mg -2.7 -1.6 -2.1 -1.3 -- -- (study 1)7 week 200 mg -2.7 -1.6 -2.2 -1.4 titration Placebo -1.1 -0.8 Topiramate period and 100 mg -2.6 -1.3 -2.1 -1.0 -- -- (study 2)8 18-week 200 mg -2.9 -1.6 -2.4 -1.3 maintenance Placebo -1.3 -1.1 period) Divalproex 500 to -3.0 -2.0 -2.5 -2.2 -- -- (study 1)9 12-week (4- 2,500 -1.0 (Depakote) week mg a -0.3 titration day1 (Placebo) period and Placebo Divalproex 8-week 500 mg -- -- -1.7 -1.2 -- -- (study 2)10 maintenance 1000 (Depakote) period) mg -0.5 Placebo (Placebo) Chronic Migraine OnabotulinumtoxinA 24-week 155 U -7.8 -1.4 -5.4 -0.4 -107 -37 (study 1) study, 2 Placebo -6.4 -5.0 -70 OnabotulinumtoxinA injection 155 U -9.2 -2.3 -5.6 -1.0 -134 -39 (study 2) cycles Placebo -6.9 -4.6 -95 Topiramate11 16-week (4- 100 mg -6.4 -1.7 ------week Placebo -4.7 titration period and 12-week maintenance period) Source: Please see referenced citations, and section 14 of labeled information for the products. 1 Depakote doses ranged from 500 to 2,500 mg a day guided by trough total serum valproate levels. Mean dose of Depakote was 1,087 mg/day.  The shaded information notes the primary efficacy endpoints pre-specified in the clinical study

As described above, the products displayed in Table 3 are products that were studied for

7 Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001 Study Group. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004 Apr;61(4):490-5. 8 Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, Neto W, Schwabe S, Jacobs D; MIGR-002 Study Group. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004 Feb 25;291(8):965-73. 9 Mathew NT. Migraine prophylaxis with divalproex. Arch Neurol. 1995 Mar;52(3):281-6. 10 Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia. 1997 Apr;17(2):103-8. 11 Topiramate Chronic Migraine Study Group. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double- blind, placebo-controlled trial. Headache. 2007 Feb;47(2):170-80 CDER Clinical Review Template 19 Version date: September 6, 2017 for all NDAs and BLAs

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prophylaxis of migraine and that are used for prophylaxis of episodic and chronic migraine. Only OnabotulinumtoxinA (BOTOX) was studied in trials that specifically enrolled patients with chronic migraine because the other products in Table 3 were studied prior to the development of the nomenclature classification of chronic migraine. Therefore, BOTOX is the only product approved specifically for chronic migraine prophylaxis. Yet the standard of care is to use all products approved for migraine prophylaxis in patients with chronic migraine.

3. Regulatory Background

3.1. U.S. Regulatory Actions and Marketing History

Lilly submitted the original 351(a) application for BLA 761063 to evaluate galcanezumab as a potential migraine prophylaxis agent in migraineurs suffering from episodic or chronic migraine via monthly subcutaneous administration. Galcanezumab is currently not marketed in the U.S.

3.2. Summary of Presubmission/Submission Regulatory Activity

The presubmission regulatory summary chronologically listed in Table 5 below includes only key clinical discussions in developing galcanezumab regarding study design and efficacy that are applicable to this clinical efficacy review.

Table 5: BLA 761063 Galcanezumab Summary of Presubmission Regulatory Activity

Administrative and Procedural Discussions March 4, 2011 Initial IND 111,295 Galcanezumab (LY2951742) for Migraine Prophylaxis submitted December 8, 2011 Change in sponsor – Lilly to Arteaus Therapeutics December 17, 2013 Change in sponsor – Arteaus Therapeutics to Lilly Galcanezumab (LY2951742) migraine prophylaxis – Study Design and Efficacy Discussions April 11, 2014 (Type C Meeting)  Definition of the patient population for episodic migraine patients (4 to 14 migraine headache days per month) is acceptable. Trials of shorter duration would be acceptable for migraine prophylaxis, but recommended treatment duration of 6 months for phase 3 trials.  The primary endpoint based on the number of migraine headache days was appropriate.  Recommended conducting separate phase 3 clinical studies for episodic and chronic migraine to support a prophylaxis claim and to allow for meaningful conclusions to be made about the efficacy of galcanezumab in each of the respective populations rather than combining the two populations in a single study. In that circumstance, the Division agreed CDER Clinical Review Template 20 Version date: September 6, 2017 for all NDAs and BLAs

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that the trial results from single adequate and well-controlled studies in each population (episodic and chronic migraine) would be adequate for approval provided each study is adequately powered and the data is supportive. September 10, 2015 (Type B - End of Phase 2 Meeting to discuss development plans for Phase3) Dose Justification  The two dose regimens (120 mg/month with a 240-mg loading dose and 240 mg/month) selected for the phase 3 studies based on the results of the dose-ranging study I5Q-MC- CGAB and PK/PD analyses appeared reasonable Clinical Plan  Migraine Headache Day definition including migraine and probable migraine headache was acceptable  A ≥30 minutes duration as a defining criterion for migraine headache for study inclusion and for primary objective analysis was acceptable  The proposed 30 day dosing period to enable monthly administration in the label was acceptable  The Agency recommended that administration of abortive migraine treatments (triptans and ergots) on a given day maybe counted as a migraine headache day  Continued use of stable doses of topiramate or propranolol as concomitant medications that was to not exceed one-third of the study population in the chronic migraine study (CGAI) was acceptable  The proposed 6-month double-blind treatment duration for the episodic migraine studies (study I5Q-MC-CGAG [CGAG] and study I5Q-MC-CGAH [CGAH]) or the 3 month double-blind treatment duration for the chronic migraine study (study CGAI) was acceptable. While a 3 month treatment duration is the minimum study duration that is acceptable for migraine prevention, a 6 month treatment duration is preferable, as it allows for better evaluation on sustained effect of treatment Statistical Analysis Plan and Study Endpoints  There was agreement that the primary endpoint analysis is based on the average over the entire treatment period, and based on these discussions the sponsor will propose a new primary analysis method instead of the previously planned MMRM analysis  FDA agreed with Lilly on the proposed statistical approach (submitted for the meeting) to control for multiplicity for the key secondary endpoints.  Issues for including information in labeling without control for multiplicity because of difficulty interpreting and to reliably determine the onset of treatment effect/durability were discussed April 13, 2017 FDA communication (email) In general, the proposed statistical method appeared adequate for the almost completed Studies CGAG, CGAH, and CGAI with the following comments:  As for the normality assumption check of the MMRM model, the proposed sensitivity analysis using negative binomial distribution on the raw monthly headache days with SAS

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PROC GLIMMIX, with the addition of checking residuals and outlier appears to be acceptable. If you ever consider switching the primary analysis based on violation of the normality assumption, you need to decide on a detailed set of numerical rules to check normality and to detect outliers, and propose an alternative primary analysis plan.  The multiple imputation method for missing data appears adequate. You need to consider the different scenarios of missing, which could be imputed, and which could not be imputed. For those that could be imputed, what variables, and assumptions the imputation will be based on.  We discourage using imputation methods for assessing treatment effects. In addition, the dropouts should be handled as “treatment failures” in the statistical analysis. Patient Reported Outcomes  There was agreement that the Role Function-Restrictive domain of the Migraine Specific Quality of Life Questionnaire (MSQ v.2.1), (b) (4) is acceptable as a key secondary endpoint in both the episodic and chronic migraine trials to assess patient functioning and support labeling.  The Agency reiterated the acceptability of physical functioning as a key secondary endpoint but emphasized the importance of keeping the measure focused on what is most relevant and meaningful to the patient.  Recommendations were made to use the patient global rating scales to indicate not only improvement, but also no change and worsening. The proposed PGI-I (Patient Global Impression of Improvement) and PGI-S (Patient Global Impression of Severity) scales may be used as anchors for defining a responder for the MSQ v.2.1 endpoint, and to help interpret a clinically meaningful change in the MSQ v.2.1 dimension score. No single anchor measure is preferable on its own, but including a number of anchor measures may provide an accumulation of evidence. The PGI-S, should be assessed at baseline and at monthly post- baseline visits during the treatment phase.  The Agency agreed that the full MSQ v.2.1 scale should be administered despite the decision to use only the Role Function-Restrictive domain for the key secondary endpoint. November 15, 2016 FDA communication (e-mail):  FDA provided detailed comments for developing their psychometric analysis plan to evaluate the domains measurement properties and performance and to establish a responder definition in addition to addressing concerns before moving forward with phase 3 studies assessing the Role Function – Restrictive domain of the MSQ v.2.1 as a pre- specified secondary endpoint. Typically, the concerns for evaluation of the instruments’ longitudinal measurement properties and performance (i.e., item descriptive analyses, reliability, validity, and ability to detect change) would have been conducted prior to initiation of phase 3 pivotal trials (e.g., in a standalone phase 2, or a separate non-pivotal phase 3 study).  The adequacy of the proposed domain to support labeling claims would be a review issue at the time of BLA submission, based on the FDA’s thorough review of all qualitative and quantitative evidence supporting the content validity, psychometric properties and CDER Clinical Review Template 22 Version date: September 6, 2017 for all NDAs and BLAs

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performance, and interpretation of meaningful change in the Role Function – Restrictive domain scores. Pediatric Study Plan Interactions  September 10, 2015: Agreed iPSP letter

General Study Design Elements And Endpoints To Establish Efficacy For Migraine Prophylaxis

For regulatory purposes, in general, a single adequate and well controlled trial in the prevention of episodic migraine and a single adequate and well controlled trial in the prevention of chronic migraine may be sufficient to support a BLA/NDA for a global prophylaxis claim. Alternatively, two adequate and well-controlled studies for the prophylaxis of episodic (or chronic) migraine in adults may be acceptable to support the indication for the migraine population studied although any product specific guidance should be sought by sponsors regarding their development program.

Primary endpoints currently accepted by the Division for migraine prophylaxis trials and that are consistent with the published guidelines from the International Headache Society for controlled trials of migraine in adults12 13are headache days with moderate or severe intensity; migraine days; or frequency of migraine episodes. Variable durations for migraine days and headache days for prophylaxis studies have been considered, for example duration of at least 30 minutes for migraine days or a headache day with headache pain that lasts ≥4 h with a peak severity of moderate or severe intensity, or of any severity or duration if the subject takes and responds to a triptan or ergot have been considered acceptable for regulatory purposes, although the planned primary and any key secondary efficacy endpoints should be discussed with the Division early during development. The longer headache duration increases the chance of a separation of drug from placebo in the primary analysis, and provides predictive enrichment for the study population. While there is a high placebo response rate in the migraine population (as high as 40%), and categorizing a continuous outcome measure may causes loss of information, the 75% responder rate definition has been considered acceptable primary endpoint.

A primary efficacy endpoint measurement at week 12 is usually acceptable although studies of up to 6 month treatment duration may allow for a better evaluation of the sustained effect of treatment without necessarily providing specific claims.

Acceptable secondary endpoints are intensity of headache; duration of headache episode in hours; responder rates; use of acute treatments; and conversion to episodic migraine. Validated disease-specific health-related quality of life and disability instruments are acceptable

12 Tfelt-Hansen P et al. Guidelines for controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia. 2012 Jan;32(1):6-38. 13 Silberstein S et al. Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. Cephalalgia. 2008 May;28(5):484- 95. CDER Clinical Review Template 23 Version date: September 6, 2017 for all NDAs and BLAs

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as secondary endpoints as well. Selection of endpoints, however, must be done a priori. Considering that the treatment is for migraine prophylaxis, the efficacy endpoints intended to assess the durability and persistence of the treatment effect following repeat dosing will be evaluated.

3.3. Foreign Regulatory Actions and Marketing History

Galcanezumab has not received marketing approval in any country.

4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety

4.1. Office of Scientific Investigations (OSI)

Please refer to Cara Alfaro PharmD BCPP, Office of Scientific Investigations review. Clinical site inspection was requested for the study sites 601 (Praha, Czech Republic), 602 (Praha, Czech Republic), 235 (Charleston, SC), and 238 (Ocoee, FL) all of which enrolled patients in more than one of the pivotal efficacy phase 3 studies I5Q-MC-CGAG, I5Q-MC-CGAH and I5Q-MC-CGAI. These study sites were considered for OSI inspections after considering the primary efficacy results and the high treatment responders from these sites, study enrollment, and data anomalies identified in the diary entry for further verification.

4.2. Product Quality

Please refer to Yan Wang, PhD Office of Product Quality (OPQ) multidisciplinary review.

4.3. Clinical Microbiology

Please refer to the Office of Product Quality (OPQ) multidisciplinary review.

4.4. Nonclinical Pharmacology/Toxicology

Please refer to Edmund Nesti, PhD nonclinical review.

4.5. Clinical Pharmacology

Please refer to Bilal AbuAsal, PhD Clinical Pharmacology review and Gopichand Gottipati, PhD Pharmacometrics review for BLA 761063.

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4.6. Devices and Companion Diagnostic Issues

Galcanezumab injection is supplied as a 120 mg/mL solution and is a clear to opalescent, colorless to slightly yellow to slightly brown, (b) (4) , sterile, (b) (4) parenteral solution for subcutaneous administration. Galcanezumab drug product is contained in a 1 mL long, (b) (4) glass (b) (4) (b) (4)

The human factor and comprehension for instructions for use reviews are pending at the time of this review, and based on preliminary discussions no further information is available that impacts clinical efficacy of fremanezumab.

4.7. Consumer Study Reviews

Not applicable.

5. Sources of Clinical Data and Review Strategy

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5.1. Table of Clinical Studies

Table 6: BLA 761063 Tabular Listing of Clinical Studies for Galcanezumab Migraine Prophylaxis

Trial Identity/ Trial Design/ Regimen/ schedule/ route Study Endpoints No. of Study Population/ No. of Sites and NCT no. Double-Blind patients Key Inclusion Countries Duration enrolled Criteria Controlled Studies to Support Efficacy and Safety I5Q-MC-CGAG Phase 3, multicenter Monthly SC injection: mean change from Total (N) = Patients with episodic United (Episodic randomized, double-  GMB 120 mg (with GMB baseline in the 858 migraine States, Canada migraine) blind, placebo- 240 mg loading dose) OR average (number GMB 120 controlled, parallel  GMB 240 mg OR of) monthly mg (n) =  ICHD-3 diagnosis of Sites = 90 NCT02614183 group trial with 4-  Placebo migraine headache 213 migraine with or study periods: days (≥30 minutes GMB 240 without aura  SP I- Screening and duration) during the mg (n) =  History of 4 to 14 washout (3-45 double-blind 212 MHDs prior to Visit days) treatment period placebo (n) 1 and at least 2  SP II- Prospective = 433 migraine attacks Baseline (30-40 per month on days) average within the  SP III- Double-Blind past 3 months Treatment (6-  4 to 14 MHDs and months) at least 2 migraine  SP IV- Follow-up attacks per month (galcanezumab during the washout phase; 4 prospective months) baseline period Concomitant migraine prophylaxis medications not permitted I5Q-MC-CGAH Phase 3, multicenter Monthly SC injection: mean change from Total (N) = Patients with episodic United States, (Episodic randomized, double-  GMB 120 mg (with GMB baseline in the 915 migraine Argentina, Czech migraine) blind, placebo- 240 mg loading dose) OR average (number GMB 120 Republic, Germany, CDER Clinical Review Template 26 Version date: September 6, 2017 for all NDAs and BLAs

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controlled, parallel  GMB 240 mg OR of) monthly mg (n) =  ICHD-3 diagnosis of Israel, S. Korea, NCT02614196 group trial with 4-  Placebo migraine headache 231 migraine with or Mexico, study periods: days (≥30 minutes GMB 240 without aura Netherlands, Spain,  SP I- Screening and duration) during the mg (n) =  History of 4 to 14 Taiwan, United washout (3-45 double-blind 223 MHDs prior to Visit Kingdom days) treatment period placebo (n) 1 and at least 2  SP II- Prospective = 461 migraine attacks Sites = 112 Baseline (30-40 per month on days) average within the  SP III- Double-Blind past 3 months Treatment (6-  4 to 14 MHDs and months) at least 2 migraine  SP IV- Follow-up attacks per month (galcanezumab during the washout phase; 4 prospective months) baseline period Concomitant migraine prophylaxis medications not permitted I5Q-MC-CGAI Phase 3, multicenter Monthly SC injection: mean change from 3-month Patients with chronic United States, (Chronic randomized, double- 3-month Double-Blind baseline in the Double-Blind migraine Argentina, Canada, migraine) blind, placebo- monthly dosing average (number monthly Czech Republic, controlled, parallel  GMB 120 mg (with GMB of) monthly dosing  ICHD-3 diagnosis of Germany, Israel, NCT02614261 group trial with 5- 240 mg loading dose) OR migraine headache Total (N) = chronic migraine Italy, Mexico, study periods:  GMB 240 mg OR days (≥30 minutes 1113  For at least 3 Netherlands, Spain,  SP I- Screening and  Placebo duration) during the GMB 120 months, history of Taiwan, United washout (3-45 9-month Open-Label double-blind mg (n) = 15 or more Kingdom days) monthly dosing treatment period 278 headaches per  SP II- Prospective 1st OL dose: GMB 240 mg GMB 240 month, of which at Baseline (30-40 2nd OL dose: GMB 120 mg mg (n) = least 8 have days) Thereafter monthly: 277 features of Sites = 116  SP III- Double-Blind GMB 120 mg OR placebo (n) migraine, and at Treatment (3- GMB 240 mg per clinical = 558 least 1 headache- CDER Clinical Review Template 27 Version date: September 6, 2017 for all NDAs and BLAs

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months) Judgment free day per month  SP IV- Open-Label Following open-label  15 to 29 headache Extension (9 treatment phase, 4 month days per 30 day months) post-treatment (washout) period in the  SP V- Follow-up phase prospective (galcanezumab baseline period, of washout phase; 4 which at least 8 are months) MHDs Concomitant migraine prophylaxis medications permitted in up to 1/3rd study subjects Studies to Support Safety I5Q-MC-CGAJ Phase 3, multicenter, Monthly SC injection: Refer to criteria Refer to Patients with episodic United States, (open-label randomized open-  GMB 120 mg (with GMB above Maria Villalba or chronic migraine Belgium, Canada, safety study) label, 1 year long- 240 mg loading dose) OR Lourdes, MD France, Hungary term safety study  GMB 240 mg clinical safety NCT02614287 For second monthly dose review for administration and all dose further administrations thereafter, details patients were allowed to self-inject GMB using pre- filled syringe and then auto- injector, when it became available to patients. Following open-label treatment phase, 4 month post-treatment (washout) phase Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.2 Galcanezumab = GMB; ICHD-3 = International Classification of Headache Disorders – 3rd edition, beta; SP = Study Period

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The following schematic shows the clinical studies supporting the BLA.

Figure 2: BLA 761063 Phase 3 Clinical Studies for Galcanezumab Migraine Prophylaxis

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5.2. Review Strategy

Lilly submitted materials for review via eCTD submission for BLA 761063 via \\CDSESUB1\evsprod\BLA761063\761063.enx>. I reviewed the efficacy information together with Junshan Qiu, PhD for the two episodic migraine studies (study I5Q-MC-CGAG, and study I5Q-MC-CGAH) and one study in patients with chronic migraine (study I5Q-MC-CGAI) included in Table 6 for the clinical development of galcanezumab for prophylaxis of migraine headache.

Junshan Qiu, PhD reviewed the sponsor’s statistical data and presented the efficacy analyses, although any additional information referenced in the data tables are included to reference the sponsor’s submission. Maria Lourdes Villalba, MD reviewed the safety of galcanezumab for the indication.

The two episodic migraine studies (study I5Q-MC-CGAG, and study I5Q-MC-CGAH) will be referred to as CGAG and CGAH in the review, and single study in patients with chronic migraine (study I5Q-MC-CGAI) will be hereafter referred to as CGAI in the review.

6. Review of Relevant Individual Trials Used to Support Efficacy

6.1. Protocol CGAG Phase 3 Episodic Migraine (EVOLVE-1)

6.1.1. Study Design

Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 in Patients with Episodic Migraine.

The EVOLVE-1 (study I5Q-MC-CGAG) and the EVOLVE-2 (study I5Q-MC-CGAH) studies were of identical design in patients with episodic migraine, and are therefore discussed together in the review.

Trial Design for EM studies CGAG and CGAH for Galcanezumab Migraine Prophylaxis

Studies CGAG and CGAH were phase 3, multicenter, randomized, stratified, double-blind, placebo-controlled, parallel-group studies in subjects with episodic migraine, and these 2-studies used the same inclusion criteria (Figure 3).

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Figure 3: BLA 761063 Study Design EM studies CGAG and CGAH for Galcanezumab Migraine Prophylaxis

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0008. Module 5.3.5.3 Figure ISE 5.2. *Eligibility period determined between a minimum of 30 days and a maximum of 40 days. Investigators may have up to 5 additional days (beyond the 40 days) if needed to schedule patients’ Visit 3 appointment. aPatients randomized to the 120 mg dose will receive a loading dose of 240 mg at the first injection only (Visit 3) . Abbreviations: LY2951742 = galcanezumab; OLE = open-label extension; SP = Study Period.

18 to 65 year old patients were enrolled with a diagnosis of migraine as defined by International Headache Society (IHS) International Classification of Headache Disorders – 3rd edition, beta (1.1 or 1.2) (ICHD-3 2013), a history of migraine headaches of at least 1 year prior to Visit 1 (screening), and migraine onset prior to age 50. Prior to Visit 1, patients had to have a history of 4 to 14 MHDs per month occurring during at least 2 migraine attacks per month on average over the past 3 months.

Study Period I Visit 1 screening period (Table 8). Study Period II (Visit 2 to 3 prospective baseline period): Beginning at Visit 2, patients logged in daily to the electronic patient-reported outcomes (ePRO) diary to answer questions to confirm eligibility for study inclusion (Table 6). In addition, the patient selection included the following criteria.  Patients were allowed to use acute medications to treat migraines as needed, with the exception of medications containing opioids and , which could not be used more than 3 times per month (CSR Table CGAG 14.1).

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 Patients with history of chronic migraine, persistent daily headache, cluster headache or migraine subtypes including hemiplegic (sporadic or familial) migraine, ophthalmoplegic migraine, and migraine with brainstem aura (basilar-type migraine), Medication Overuse Headache were excluded as defined by ICHD-3 beta. Patients with tension-type headache were permitted.  Patients with ECGs showing abnormalities compatible with acute cardiovascular events and/or serious cardiovascular risk, including but not limited to a corrected QT (QTcB [Bazett's]) interval > 470 msec for women and >450 for men, or have had myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, stroke, or deep vein thrombosis/pulmonary embolism within 6 months of screening, or have planned cardiovascular surgery or percutaneous coronary angioplasty were excluded.  From Visit 2 to Visit 3 (prospective baseline period), patients must have achieved sufficient compliance with ePRO daily headache entries as demonstrated by completion of at least 80% of daily diary entries Study Period III (6 month double-blind treatment phase studies CGAG and CGAH)

Table 7: BLA 761063 EM Study CGAG and CGAH Planned Sample Size

Eligible for Randomization (n=825) Placebo 413 Screen (n=1557) 120 mg monthly 206 240 mg monthly 206

Doses - Phase 3 Episodic Migraine Study CGAG and CGAH, and for Chronic Migraine Study CGAI

The following dosing schedule was followed.  Patients randomized to galcanezumab 120 mg dose received an initial loading dose of 240 mg (2 injections of 120 mg each at Visit 3 only)  All patients received 2 injections at each subsequent dosing visit to maintain the blind with either o 2 injections of placebo, OR o 1 injection of placebo and 1 injection of galcanezumab 120 mg, OR o 2 injections of galcanezumab 120 mg. Patients were administered subcutaneous injections of investigational product (using prefilled syringes) once monthly (defined as 30 days +/- 2 days) at the dosing visits during site/office visits (Figure 3) to these possible injection sites including the abdomen, thigh, and upper arm. Buttocks were used, if needed. Study blinding was maintained by supplying galcanezumab and matching placebo (containing excipients only) as an injectable solution in 1 mL, single-dose, prefilled, disposable manual syringes with study specific labels. Each syringe of galcanezumab

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delivered 120 mg. The syringes (and contents) containing either galcanezumab or placebo were visibly indistinguishable from each other.

Justification for Phase 3 Dose Selection Doses of either galcanezumab 120 and galcanezumab 240 mg administered once monthly were selected primarily on the basis of clinical efficacy and pharmacokinetic/pharmacodynamic data from study CGAB phase 2 dose-ranging 12 week double-blind study, which assessed galcanezumab (5, 50, 120, or 300 mg administered every 4 weeks) for the prevention of migraine in patients with episodic migraine (Figure 4). Please see dose selection explanation based on the results from the phase 2 study CGAB shown in section 6.1.2 of this review.

Figure 4: Phase 2 Design Dose-Ranging Study I5Q-MC-CGAB

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. CSR Figure CGAB 9.1 a For patients who did not require a wash-out of migraine prevention or other medication, the screening period could have been completed in as few as 5 days. b Electronic patient-reported outcomes interactive voice response system reporting was completed daily during SPII, SPIII, and SPIV. c Between office visits, sites were required to have a telephone visit at Visit 4, Visit 6, Visit 10, and Visit 12 to assess spontaneously reported AEs. d Visit 8 was to obtain PK and CGRP blood samples and assess safety.

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Table 8: EM Study CGAG and CGAH Schedule 6 months Double-Blind Treatment

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Abbreviations: AE = adverse event; CGRP = Calcitonin-gene related peptide; C-SSRS = Columbia-Suicide Severity Rating Scale; ePRO = electronic patient reported outcomes; ET = early termination; FSH = follicle stimulating hormone; HDL = High-density lipoprotein; MIDAS = Migraine Disability Assessment test; MSQ (v2.1) = Migraine Specific Quality of Life Questionnaire; PGI-I = Patient Global Impression of Improvement; PGI-S = Patient Global Impression of Severity; PK = pharmacokinetics; RNA = ribonucleic acid; SHSF = Self-harm supplement form; SHFU = Self-harm follow-up form. Note: Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may be required in follow-up with patients in consultation with the Lilly, or its designee, clinical research physician. See Appendix 4 for more details regarding specific hepatic monitoring tests. If the patient has discontinued the trial and returns for hepatic follow-up, the site should use the recommended visit designation. a The eligibility period of the prospective baseline assessment will last from 30 to 40 days. Investigators and patients may have up to an additional 5 days to schedule their Visit 3 appointment (beyond the 40 days); however, eligibility will be based on the 30-40 day period. b Visit is to include a review of any spontaneously reported adverse events and collection of blood samples for immunogenicity, PK, and CGRP plasma. c Visit 9 and Visit 11 are laboratory visits (for PK and CGRP plasma) only. Adverse events are not intended to be collected at these visits because patients may be going to a different location for laboratory assessments. However, any spontaneously reported AEs at these lab visits should be reported on the AE page. d Physical examinations at screening must include a neurological exam. e Electrocardiograms (ECGs) will be performed at Visit 1, Visit 3, Visit 12, and Visit 14 or early termination. Note: The Visit 3 ECG should be collected prior to blood draws and dosing. Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection. f Vital signs will include body temperature, blood pressure, and pulse. Blood pressure and pulse will be measured in triplicate in the sitting position and should be measured prior to blood draws. Blood pressure will be assessed by utilizing a calibrated machine. g Chemistry samples collected at Visit 3, Visit 7, Visit 12, and Visit 14 or early termination must be fasting. Fasting is defined as no food or drink, except water, for at least 8 hours prior to testing. h In the event of a positive urine leukocyte esterase result, a repeat urine sample will be collected and shipped to the central laboratory. i A positive urine test must be followed by a serum pregnancy test for confirmation. j Immunogenicity, CGRP plasma sample, and PK sampling to be performed at the indicated visits and prior to dose administration if the visit is a dosing visit. Samples will be taken in the event of early termination. Immunogenicity samples also may be collected in the event of a systemic allergic/hypersensitivity reaction (see Section 8.4.3). The timing of samples will be recorded. k Patients will receive injections of placebo or LY2951742 after all other visit procedures are completed. Following the first dose at Visit 3, patients will be observed for at least 30 minutes in the office. l Questionnaire administered by clinician to assess other chronic pain conditions. m The C-SSRS and SHSF (and SHFU when applicable) will be completed at scheduled and unscheduled office visits.

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Efficacy Endpoints

Table 9: Migraine Day and Headache Day Endpoint Definitions (Studies CGAG, CGAH, and CGAI)

Diagnosis Definition/Criteria Migraine Headache A headache, with or without aura, of ≥30 minutes duration*** with both of the following required features (Criteria A and B): A. At least 2 of the following headache characteristics: Unilateral location Pulsatile quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity AND B. During headache at least one of the following: Nausea and/or vomiting Photophobia and phonophobia

OR, for chronic migraine study CGAI only, Criteria C based on the diagnostic criteria for chronic migraine in ICHD-3: C. The headache is believed by the patients to be migraine at onset and is relieved by a triptan or ergot derivative (Definition adapted from the Standard International Headache Society [IHS] International Classification of Headache Disorders (ICHD)-3rd edition beta) Probable migraine A headache missing 1 of the migraine features in the ICHD-3 beta definition such that one feature in criteria A is missing or one feature in criteria B is missing; that is, the headache meets at least 2 A criteria and none of the B criteria or meets 1 A criterion and 1 B criterion. For study CGAI, the headache also could not meet criteria C. Migraine headache day A calendar day on which a migraine headache or probable migraine headache (primary objective) (MHD) occurred ICHD Migraine Headache A calendar day on which a migraine headache occurred (excludes probable migraine Day headache) Migraine headache Beginning on any day a migraine headache or probable migraine headache is attack/Migraine Episode recorded and ends when a migraine-free day occurs Non-migraine headache All headaches of at least 30 minutes duration not fulfilling the definition of migraine or probable migraine are classified as non-migraine headaches. Headache day A calendar day on which any type of headache occurs (including migraine headache, probable migraine headache, and non-migraine headache, e.g., tension type headache). Migraine-Specific Quality The instrument consists of 14 items that address 3 independent domains: of Life Questionnaire 1. Role Function-Restrictive (MSQ-RR, Role Function- 2. Role Function-Preventive Restrictive) 3. Emotional Function The Role Function-Restrictive domain consists of 7 items which measure impact of Applicable to study CGAG, migraine on work or daily activities, relationships with family and friends, leisure CGAH and CGAI time, productivity, concentration, energy, and tiredness. This domain was considered the most relevant during regulatory meetings with the Division to measure treatment CDER Clinical Review Template 36 Version date: September 6, 2017 for all NDAs and BLAs

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benefit related to the degree that performance of daily activities is limited by migraine. Scoring on each domain ranges from 0 to 100, with higher scores indicating better functioning. The instrument was designed with a 4-week recall period Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0008. Module 5.3.5.3 Table ISE 5.3. Galcanezumab = GMB; ICHD-3 = International Classification of Headache Disorders – 3rd edition, beta; SP = Study Period ***As per the ISE, the criteria for migraine headache were adapted from the Standard (IHS) ICHD-3. The only modification from the original criteria is a reduction in required minimum duration from “4 hours untreated” to “30 minutes.” This reduction was made so that patients would not feel compelled to delay taking acute medications to relieve the oncoming migraine headache. Reviewer Comment: The primary endpoints definitions for migraine headaches of 30 minutes duration was considered acceptable based on discussions during the EOP2 meeting (see Table 5 and section 3.2).

Migraine Specific Quality of Life (MSQ Total and domain scores) There was agreement based on prior discussions with the Division during product development that the Role Function-Restrictive domain of the Migraine Specific Quality of Life Questionnaire (MSQ v.2.1), (b) (4) , was acceptable as a key secondary endpoint in both the episodic and chronic migraine trials to assess patient functioning and support labeling based on the FDA’s thorough review of all qualitative and quantitative evidence supporting the content validity, psychometric properties and performance, and interpretation of meaningful change. Please see summary Presubmission discussions in Table 5, and refer to Sarrit Kovacs, PhD review of the submitted Galcanezumab Patient-Reported Outcomes Evidence Dossier.

The mean change from baseline to each postbaseline visit for MSQ total and domain scores averaged across months 4 to 6 (inclusive of month 6) was evaluated using an MMRM model. The MSQ Role Function-Restrictive domain responders were planned to be analyzed using GLIMMIX. However following database lock, for the MSQ Role Function-Restrictive responder analysis, the model was changed to logistic regression to analyze responder at one time point/interval only (change from baseline to average of months 4 to 6) in order to ensure that the same data were used for determining the thresholds for responder, and for the analyses of responder.

Study CGAG CSR section 9.7.1.7 (study CGAI CSR section 9.7.1.7) stated that the initially determined threshold of “change from baseline in MSQ v2.1 Role Function-Restrictive domain ≥10.9” was changed in SAP Version 4 based on their analysis of phase 3 data from Studies CGAG and CGAH using an anchor-based approach that differentiated MSQ v2.1 responders and non- responders in order to compare galcanezumab with placebo with respect to categorical changes in quality of life, with respect to health outcomes measures, namely the MIDAS, PGI-I, PGI-S, and MHDs.  The final analysis for the episodic migraine studies (CGAG and CGAH) was conducted assessing the percentage of patients with change from baseline in MSQ v2.1 Role Function-Restrictive domain (threshold) ≥25. i.e., response was defined as change from baseline to average of months 4 to 6 ≥25. The value of ≥25 corresponds to a change of 9 points on the raw scale.  The final analysis for the chronic migraine study (CGAI) was conducted assessing the

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percentage of patients with change from baseline in MSQ v2.1 Role Function-Restrictive domain (threshold) ≥17.14. i.e., response was defined as change from baseline to 3 month average ≥17.4 points on the transformed 100-point scale. The value of 17.14 corresponds to a change of 6 points on the raw scale. Full description of the independent analyses and results to determine the threshold for clinically meaningful response on the MSQ Role Function-Restrictive domain for the CGAG and CGAH episodic migraine population, and for the CGAI chronic migraine population were referenced in the Galcanezumab Patient-Reported Outcomes Evidence Dossier.

Primary Efficacy Endpoint (Episodic Migraine Studies CGAG, CGAH)

 mean change from the baseline period in the number of monthly migraine headache days during the 6 month double-blind treatment phase

The primary endpoint treatment main effect is estimated from the primary MMRM model. The treatment main effect is, by definition, the treatment effect averaged across the multiple post- baseline assessment times (months).

Key Secondary Endpoints (Episodic Migraine Studies CGAG, CGAH)

The following key secondary endpoints were pre-specified and adjusted for multiplicity  The proportion of patients with reduction from baseline ≥50%, (≥75% and 100%) in monthly migraine headache days during the 6 month double-blind treatment phase  mean change from baseline in monthly migraine headache days that acute medication was taken  functional impact of migraine on usual activities assessed by the Role Function- Restrictive domain of the Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1 (months 4 to 6)

The overall mean change (applicable to the primary endpoint variable) also applied to the secondary study endpoints, estimated as the main effect of treatment from the MMRM analysis averaged across the multiple post-baseline assessment times during the 6 month double-blind treatment phase.

Statistical Analysis Plan (applicable to Episodic Migraine Studies CGAG and CGAH)

The following information was abstracted from the ISE, and the CSR.

The statistical analysis plan (SAP) finalized for study CGAG was Version 4 (25 April 2017) Version 1 November 23, 2015 (first approved) Version 2 September 13, 2016

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Version 3 January 17, 2017

The reporting database was validated and locked for analysis on April 28, 2017. The database lock date was determined based on the last patient visit date of March 22, 2017 for the double- blind treatment phase. The additional time to the data lock date was needed to resolve and close all queries, process laboratory samples, and complete signoff by investigators. Any data after this cutoff date were excluded from the study data tabulation model/analysis data model (SDTM/ADaM) dataset.

For both studies CGAG and CGAH, randomization was stratified within each region and by baseline migraine frequency (<8 migraine headache days per 30 day period, and ≥8 migraine headache days per 30 day period). To ensure an appropriate balance of low and high frequency patients, the enrollment of low frequency patients would be stopped if the number of low frequency patients exceeded 578. Study CGAG included patients from North America (US and Canada), while study CGAH included patients sites in Europe, Latin America, and Asia in addition to N. America.

General Statistical Issues Applied to Studies CGAG and CGAH

The following general statistical issues were defined or specified in the Statistical Analysis Plan (SAP).

Patient Populations for Analysis Efficacy analyses were conducted on the ITT population, which included data from all randomized patients who received at least 1 dose of IP, with analyses conducted according to the treatment group to which patients were randomized.

Specification of Baseline In calculating the number of migraine headache days for each period (including baseline), if the period was not equal to 30 days, the number of migraine headache days was adjusted by multiplying the number of migraine headache days by (30/x) where ‘x’ is the total number of non-missing diary days in the period.

ePRO diary The ePRO diary was part of an ePRO/Clinical Outcome Assessment (COA) system, and the patient-rated scales/questionnaires were collected directly via an ePRO tablet device at each visit. Data entered into the ePRO/COA system served as the source data. The daily ePRO diary data were aggregated, and the number of MHDs was provided for each of the monthly visit or dose intervals. In calculating the number of MHDs for each monthly interval, the number of MHDs was normalized to a 30 day period by multiplying the number of MHDs by (30/x) where ‘x’ was the total number of nonmissing diary days in the monthly interval. This approach to missing

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ePRO diary data assumed that the rate of migraine headache per day was the same for days with missing and nonmissing ePRO diary days. The same approach was also applied to secondary and exploratory efficacy measures that were derived from ePRO data. If the compliance rate for a monthly interval was ≤50%, then all endpoints to be derived from the ePRO diary data for that 1 month period were considered missing.

Handling of Missing Data For the repeated measures analyses, the model parameters were simultaneously estimated using restricted likelihood estimation incorporating all of the observed data based on the assumption of missing at random (MAR). For analyses using ANCOVA model, change from baseline to the average of observed monthly values during 6 months of treatment phase (for measures with objectives evaluated during the entire 6 months of treatment phase), or change from baseline to LOCF endpoint (for measures with objectives evaluated at month 6) was used to handle missing data.

To assess the robustness of the primary analysis conclusions to deviations from missing at random (MAR) assumption, the assumptions of missing data for the primary analysis were varied in a systematic way. Basically, the method was to predict the missing outcomes via multiple imputation based on observed primary endpoint and baseline values and then add values (Δ120, Δ240, ΔP) to the predictions in the galcanezumab 120 mg/month, galcanezumab 240 mg/month, and placebo treatment groups respectively, regardless of the reason the data are missing.

Primary Efficacy Analyses For Studies CGAG and CGAH, the primary analysis evaluated the efficacy of 2 doses of galcanezumab compared with placebo on the overall mean change from baseline in the number of monthly MHDs during the 6 month double-blind treatment phase. A mixed model repeated measures (MMRM) analysis was applied. The MMRM model included the fixed, categorical effects of treatment, pooled region1, month, and treatment-by-month interaction, as well as the continuous, fixed covariates of baseline value and baseline-by-month interaction. The baseline value and baseline-by-month interaction were included to account for the differential influence over time that the baseline value has on the post-baseline values. The type I error rate for the study was controlled at a 2-sided 0.05 level (equivalently, 1-sided 0.025 level). Table 10 summarizes key and other secondary analyses and analysis methods used in the phase 3 confirmatory studies.

Secondary Efficacy Analyses If secondary endpoints were continuous, repeated measures analyses as described for the primary efficacy analysis were used. For repeated binary endpoints, a categorical, pseudo- likelihood-based repeated measures analysis was implemented using the GLIMMIX procedure in SAS to compare treatments and included the fixed, categorical effects of treatment, month, and treatment-by-month interaction, as well as the continuous, fixed covariate of baseline value.

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For non-repeated binary endpoints, a logistic regression analysis with covariates of treatment, baseline, and pooled region1 was conducted.

Response rate was defined as the mean percentage of patients meeting a defined threshold in the reduction of the number of monthly MHDs across the double-blind treatment period compared to the baseline period.

Table 10: Secondary Endpoints and Analysis Methods Studies CGAG, CGAH, and CGAI

Abbreviations: ANCOVA = analysis of covariance; GLIMMIX = generalized linear mixed model (for binary variables); ICHD = International Classification of Headache Disorders; LOCF = last observation carried forward; MIDAS = Migraine Disability Assessment; MHD = migraine headache day; MMRM = mixed model repeated measures; MSQ = Migraine-Specific Quality of Life Questionnaire Version 2.1; NA = not applicable; PGI-I = Patient Global Impression of Improvement; PGI-S = Patient Global Impression of Severity. a ANCOVA for change from LOCF endpoint for MIDAS total score of Study CGAI only . Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.3 ISE Table 5.4

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Multiplicity Adjustment For episodic migraine studies (CGAG and CGAH) and chronic migraine study CGAI, the primary and key secondary objectives were tested using an overall superchain procedure multiple testing approach (sponsor reference: Kordzakhia and Dmitrienko 2013),14 providing control of the familywise type 1 error rate at a 2-sided 0.05 alpha level with alpha propagation (or alpha recycling) techniques, which was detailed in section 5.5.10.4 in the SAP (v4). There were no adjustments for multiplicity for analyses of other endpoints besides the primary and key secondary endpoints.

Interim Analysis for Safety and Futility An independent Data Monitoring Committee (DMC) comprised of 4 members external to Lilly, including 1 statistician and 3 physicians performed an interim analysis to assess safety and futility. An independent Statistical Analysis Center (SAC) performed the analyses for the DMC. The sponsors study team remained blinded. The reporting database for the interim analysis was locked on September 16, 2016. This was the only DMC data review conducted, and it included review of efficacy data from the phase 3 double-blind galcanezumab studies (CGAH and CGAI) as well as safety data from all of the phase 3 galcanezumab studies (CGAG, CGAH, CGAI, and CGAJ). The date of the DMC meeting was October 27, 2016. Based on their review of the data, the DMC recommended continuing all 4 studies with no modifications.

Sample Size Determination Based on the observation of 2 double-blind, placebo-controlled, phase 2 studies, a 26% discontinuation rate and an effect size of 0.33 in the last month of the 6 month treatment phase were assumed. It needed approximately 825 subjects including at least 611 completers to provide approximately 95% power that at least 1 dose of galcanezumab would separate from placebo at a one-sided 0.025 significance level based on simulations using Dunnett test.

Protocol Amendments

The protocol for study CGAG was approved on September 23, 2015; there were no protocol amendments. There were 2 addenda to the protocol (October 09, 2015 Addendum 1; and March 27, 2017 Addendum 2).

6.1.2. Study Results

Table 11: Study CGAG Summary

CGAG 6 month double-blind treatment phase; 5 month post-treatment phase Episodic Migraine Randomized patients with at least 1 injection: 858 (GMB + PBO); EVOLVE-1 Number of patients who completed double-blind treatment: 703

14 Kordzakhia G, Dmitrienko A. Superchain procedures in clinical trials with multiple objectives. Stat Med. 2013 Feb 10;32(3):486-508. CDER Clinical Review Template 42 Version date: September 6, 2017 for all NDAs and BLAs

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Galcanezumab Doses  single loading dose of 240 mg (two 120 mg subcutaneous injections) followed by 120 mg/month maintenance dose  240 mg/month fixed dose (two 120 mg subcutaneous injections)

Justification for Dose Selection for Phase 3 Studies CGAG, CGAH and CGAI Please see brief explanation of study design for phase 2 study CGAB that evaluated galcanezumab (5, 50, 120, or 300 mg administered every 4 weeks) for the prophylaxis of migraine in patients with episodic migraine in section 6.1.1 under discussions for dose selection. In the phase 2 study CGAB superiority was defined such that at least one galcanezumab dose arm would have a ≥95% posterior probability of greater improvement compared with placebo for a migraine headache day of ≥30 minutes duration.

According to the CSR, based on the results from the primary analysis model (CSR Table CGAB.11.6), the primary objective of the study was met: the posterior probability (99.6%) of greater improvement for galcanezumab 120 mg compared with placebo met the prespecified threshold for the mean change from baseline in the number of migraine headache days (MHD) at month 3 even though there was numerical improvement with galcanezumab 120 mg and 300 mg compared to placebo when administered every 4 weeks for the mean change from baseline in the number of MHD for the 12 week treatment phase. However, the sponsor further explained that a dose-response relationship was not observed at month 3 because posterior mean change for the highest galcanezumab dose arm of 300 mg (-4.28) was smaller than that of lower galcanezumab dose arm of 120 mg (-4.80) at month 3 (Table 12).

Table 12: Phase 2 Dose-Ranging Study I5Q-MC-CGAB – Topline Efficacy, Change from Baseline in Migraine Days Hierarchical Logistic Dose Response Model

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. CSR Table CGAB.11.9. *a, Efficacy Criteria is Prob (LY=0.95 & Prob(LY-POB<-1)>=0.5. Change from Baseline in MHD Bayesian Time Course Hierarchical Longitudinal and Hierarchical Logistic Dose Response Model ITT Population

The supporting analysis of the primary outcome was based on a repeated measures analysis assessing change from baseline in the number of migraine headache days, and the results for galcanezumab 120 mg dose remained consistent. While the monthly dose of galcanezumab 300

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mg did not demonstrate statistically significant separation from placebo at month 3, it did so at both months 1 and 2, and also showed treatment effect across all 3 months (Table 13).

Table 13: Phase 2 Dose-Ranging Study I5Q-MC-CGAB – Topline Efficacy, Change from Baseline in Migraine Days Repeated Measures Analysis

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. CSR Table CGAB.11.9.

The sponsor developed a PD model relating galcanezumab concentrations to reductions in MHDs (Figure 5), and based on their simulation/modeling these results were predictive of clinical efficacy observed in the phase 3 studies. The PD model additionally provided supportive information for the use of 120 mg/month maintenance dose with a 240 mg loading dose, and the 240 mg/monthly dose. However, a dose less than 120 mg/month (for example 50 mg/month) was predicted to not have clinical efficacy, and a dose higher than 240 mg/month (for example 300 mg/month) was predicted to have a clinical effect similar to that of 240 mg/monthly. In addition, the submission stated that the use of the 240 mg dose offered the benefit of requiring only two 1-mL injections whereas a higher dose would require at least 3 injections. Furthermore, PK modeling of phase 3 data for the 240 mg loading dose achieved steady-state galcanezumab concentrations by month 1 for the 120 mg/month dose regimen (Source: Module 5.3.5.3 ISE, Figure ISE 10.3).

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Figure 5: BLA 761063 Phase 2 PD model Galcanezumab Concentrations for Phase 3 Dose Selection

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.3 ISE, Figure ISE 10.2

It appears the sponsor conducted adequate dose exploration for the phase 3 studies prior to selecting galcanezumab 120 mg/month maintenance dose with a 240 mg loading dose, and the 240 mg/monthly dose for the phase 3 studies (CGAG, CGAH and CGAI). The information from phase 2 study CGAB and the PD model explained above appeared to have been predictive of clinical efficacy in the phase 3 studies for the doses studied.

Compliance with Good Clinical Practices

Lilly provided attestation that the study was conducted in accordance with the CFR governing the protection of human subjects (21 CFR part 50), Institutional Review Boards (21 CFR part 56), and the obligations of clinical investigators (21 CFR 312.50 to 312.70) in accordance with good clinical practice (GCP).

Financial Disclosure

Lilly provided certification that there was no financial agreement with the clinical investigators defined in 21 CFR part 54.2. Financial disclosure and certification information was submitted in module 1.3.4 included in Form FDA 3454 with Certification from applicant for those investigators (Box 1 checked) with no disclosable financial interests or arrangements. Lilly appended a list of clinical investigators to Form FDA 3454.

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Patient Disposition

Screen failures A total of 1671 patients entered the study and 858 patients who received at least 1 dose of IP were included in the ITT population were randomized. The most common reason for screen failure was patients not meeting criteria for study enrollment based on migraine headache information collected in the ePRO diary during the prospective baseline phase.

Table 14: Study CGAG Patient Disposition

Patient Disposition Placebo GMB 120 mg GMB 240 mg (N=433) (N=213) (N=212) Completed DB period 351 (81%) 177 (83%) 175 (83%) Discontinued DB period 82 (19%) 36 (17%) 37 (17%) Adverse Event 10 (2%) 9 (4%) 7 (3%) Lack of Efficacy 10 (2%) 1 (0.5%) 2 (1%) Lost to Follow-up 18 (4%) 9 (4%) 5 (2%) Physician Decision 7 (2%) 3 (1%) 2 (1%) Protocol Deviation 2 (0.5%) 2 (1%) 2 (1%) Withdrawal by 33 (7%) 11 (5%) 16 (8%) Patient Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (Table CGAG.10.1, CSR for study CGAG) and Module 5.3.5.3 ISE, Table ISE 8.2. Galcanezumab = GMB

Post-Randomization A total of 858 randomized patients received at least 1 dose of investigational product and were included in the ITT population. 703 patients (81.9%) completed the double-blind treatment phase. Please note that 15 patients (placebo: 8; GMB 120 mg: 3; GMB 240 mg: 4) from study CGAG were excluded from the primary efficacy analysis population due to ePRO compliance <=50%. Several sensitivity analyses on the primary endpoint was conducted removing patients with an eligibility related important protocol deviation, and other protocol deviations identified that affected small numbers of patients relative to the study population, or that had minimal impact on study efficacy and the conclusion remained unchanged.

Baseline Demographic and Disease Characteristics

There were no significant differences between the treatment groups with respect to their baseline demographic characteristics, Table 15. Overall, the study population was representative of the US migraine population based on available epidemiological data with over 80% white females older than 25, of which approximately 40% subjects were >45 years old. Between 3-14% of the subjects included patients of Asian or African American race. The demographic characteristics of sex, age, race, and BMI were generally similar across treatment groups with between 30-40% patients classified as obese based on the BMI.

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The enrolled episodic migraineurs experienced at baseline on average 9 migraine days and 11 headache days. At baseline about 60% patients experienced between 8-14 monthly migraine headache days and monthly headache days (see definitions Table 9). Overall, treatment groups were balanced with respect to baseline disease characteristics and any treatment group differences were not considered meaningful on the study outcomes (Table 16). Use of concomitant migraine preventive medications was not permitted, and there were no differences across the dose arms in the allowed baseline rescue acute medications. Treatment compliance was high in all groups possibly because the treatments were administered by investigative site personnel.

Reviewer Comment

Exclusionary criteria specified that patients with a history of ≥15 headache days (migraine, probable migraine, or any other headache) per month on average during the past 3 months or were suspected of suffering from chronic migraine as defined per ICHD-3 beta, were to be excluded. 10-13% subjects at baseline experienced over 15 monthly headache days (Table 16). Please see sensitivity analysis for the primary endpoint excluding these patients in Table 21.

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Table 15: Study CGAG Episodic Migraine Demographic Characteristics

Placebo Galcanezumab Monthly GMB 120 mg GMB 240 mg Total Demographic Parameters (N=433) (N=213) (N=212) (N=858) n (%) n (%) n (%) n (%) Sex Male 71 (16.40) 32 (15.02) 37 (17.45) 140 (16.32) Female 362 (83.60) 181 (84.98) 175 (82.55) 718 (83.68) Age Mean years (SD) 41.33 (11.40) 40.93 (11.87) 39.07 (11.52) 40.67 (11.57) Median (years) 41 40 38 41 Min, max (years) 18, 64 17, 65 17, 65 17, 65 Age Group < 25 years 26 (6.00) 23 (10.80) 25 (11.79) 74 (8.62) ≥ 25 - < 45 years 234 (54.04) 103 (48.36) 110 (51.89) 447 (52.10) ≥ 45 years 173 (39.95) 87 (40.85) 77 (36.32) 337 (39.28) Race White 356 (82.22) 169 (79.34) 165 (77.83) 690 (80.42) Black or African American 42 (9.70) 29 (13.62) 23 (10.85) 94 (10.96) Asian 13 (3.00) 7 (3.29) 4 (1.89) 24 (2.80) American Indian or Alaska Native 0 (0.00) 0 (0.00) 3 (1.42) 3 (0.35) Native Hawaiian or Other Pacific Islander 1 (0.23) 0 (0.00) 2 (0.94) 3(0.35) Multiple 21 (4.85) 8 (3.76) 15 (7.08) 44 (5.13) Race group Caucasian 356 (82.22) 169 (79.34) 165 (77.83) 690 (80.42) Non-Caucasian 77 (17.78) 44 (20.66) 47 (22.17) 168 (19.58) Ethnicity Not Hispanic or Latino 359 (82.91) 180 (84.51) 171 (80.66) 710 (82.75) Hispanic or Latino 58 (13.39) 27 (12.68) 37 (17.45) 122 (14.22) Unknown or Missing 16 (3.70) 6 (2.82) 4 (1.89) 26 (3.03) BMI Category Underweight (<18.5/Kg/m2) 10 (2.31) 1 (0.47) 3 (1.42) 14 (1.63) normal (≥18.5 and <25/Kg/m2) 112 (25.87) 68 (31.92) 65 (30.66) 245 (28.55) Overweight (≥25 and <30/Kg/m2) 140 (32.33) 76 (35.68) 62 (29.25) 278 (32.40) Obese (≥30 Kg/m2) 171 (39.49) 68 (31.92) 82 (38.68) 321 (37.41) Region United States 389 (89.84) 193 (90.61) 191 (90.09) 773 (90.09) Canada 44 (10.16) 20 (9.39) 21 (9.91) 85 (9.91) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR for study CGAG). Galcanezumab = GMB

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Table 16: Study CGAG Episodic Migraine Baseline disease Characteristics

Placebo Galcanezumab Baseline Disease Monthly GMB 120 mg GMB 240 mg Total Characteristics (N=433) (N=213) (N=212) (N=858) n (%) n (%) n (%) n (%) Number of migraine days Mean (SD) 9.08 (2.97) 9.21 (3.05) 9.14 (2.91) 9.13 (2.97) Median (min, max) 9 (4, 16.67) 9 (4, 14.55) 9 (4, 17.59) 9 (4, 17.6) ≤ 8 days 183 (42.26) 85 (39.91) 89 (41.98) 357 (41.61) 8< and ≤ 14 days 249 (57.51) 127 (59.62) 122 (57.55) 498 (58.04) 14< and ≤ 22 days 1 (0.23) 1 (0.47) 1 (0.47) 3 (0.35) Number of headache days Mean (SD) 10.57 (3.35) 10.59 (3.62) 10.94 (3.88) 10.67 (3.56) Median (min, max) 10.38 10.34 10.34 10.34 (4, 21.6) (4, 23.79) (4, 29) (4, 29) ≤ 8 days 114 (26.33) 63 (29.58) 51 (24.06) 228 (26.57) 8< and ≤ 14 days 272 (62.82) 121 (56.81) 132 (62.26) 525 (61.19) 14< and ≤ 22 days 47 (10.85) 28 (13.15) 26 (12.26) 101 (11.77) >22 days 0 (0.00) 1 (0.47) 3 (1.42) 4 (0.47) Number of headache days of at least moderate severity Mean (SD) 7.54 (3.11) 7.66 (3.24) 7.7 (3.44) 7.62 (3.22) Median (min, max) 7.24 (0, 21.6) 7.5 (1, 16.07) 8 (0, 19) 7.24 (0, 21.6) ≤ 8 days 269 (62.12) 126 (59.15) 117 (55.19) 512 (59.67) 8< and ≤ 14 days 160 (36.95) 84 (39.44) 90 (42.25) 334 (38.93) 14< and ≤ 22 days 4 (0.92) 3 (1.41) 5 (2.36) 12 (1.40) Number of headache hours Mean (SD) 58.75 (39.36) 59.91 (39.99) 64.98 (60.24) 60.58 (45.57) Median (min, max) 48.81 (8.28, 50 (6, 281.54) 48 (5, 191) 49.31 (5, 581) 581) Number of migraine headache days acute headache medications/ Abortive Medication Use Mean (SD) 7.38 (3.48) 7.42 (3.68) 7.34 (3.30) 7.38 (3.48) Median (min, max) 7.24 (0, 14) 7.24 (0, 14) 7.24 (0, 16) 7.24 (0, 16) Number of days of use of Triptan Mean (SD) 3.64 (4.48) 4.26 (4.72) 3.29 (4.32) 3.71 (4.51) Median (min, max) 0 (0, 14) 7 (0, 14) 0 (0, 14) 0 (0, 14) Number of days of use of NSAID/Aspirin use Mean (SD) 6.11 (4.20) 5.80 (4.47) 5.90 (4.09) 5.98 (4.24) Median (min, max) 6 (0, 14) 6 (0, 14) 6 (0, 16.55) 6 (0, 16.55) MSQ Role Function Restrictive score Mean (SD) 52.92 (15.41) 51.39 (16.20) 48.76 (16.82) 51.52 (16.03) Median (min, max) 54.29 (0, 91.43) 51.43 (0, 94.29) 48.57 (0, 94.29) 51.43 (0, 94.29) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table 14.6 and Table 14.7 study CGAG). Galcanezumab = GMB; N/A=No data available **No Concomitant preventive migraine medications permitted in study CGAG and CGAH Episodic migraine population CDER Clinical Review Template 49 Version date: September 6, 2017 for all NDAs and BLAs

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Efficacy Results – Primary Endpoint

Efficacy analysis following the methods specified in the SAP was performed, and the results reported by the sponsor in the analyses of the primary endpoint were confirmed. The primary efficacy endpoint analysis is shaded in gray (Table 17). The treatment effect across the multiple post-baseline assessment times (months) are also included in Table 17.

There was statistically significant mean between-group difference favoring both galcanezumab dose groups compared to placebo in the overall mean reduction in the number of monthly migraine headache days with onset of effect as early as month 1 (Table 17, Figure 6). The overall LS mean reduction from baseline in the number of monthly MHDs during the double-blind treatment phase was 4.7 days for galcanezumab 120 mg and 4.6 days for galcanezumab 240 mg compared with 2.8 days for placebo (LS mean change difference from placebo: -1.9 and -1.8; p<.001 for each dose group versus placebo). Please note that patients in the galcanezumab 120 mg treatment group received a loading dose of galcanezumab 240 mg at the first injection followed by monthly galcanezumab 120 mg injection, which provides information for efficacy at month 1. Therefore, the initial treatment effect observed at month 1 was based on galcanezumab 240 mg dose (Figure 6). The higher maintenance dose of galcanezumab 240 mg did not seem to provide better efficacy than the initial dose of galcanezumab 240 mg followed by lower monthly galcanezumab 120 mg SC injections during the monthly intervals.

Table 17: Study CGAG Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM

Episodic Migraine Study CGAG Statistic Galcanezumab Placebo (N=425) GMB 120 mg (N=210) GMB 240 mg (N=208) Overall LS mean (SE) -2.81 (0.24) -4.73 (0.29) -4.57 (0.29) 95% CI (-3.28, -2.34) (-5.31, -4.16) (-5.15, -3.99) Comparison with Placebo LS mean (SE) -1.92 (0.28) -1.76 (0.28) 95% CI (-2.48, -1.37) (-2.31, -1.20) p-value <.001 <.001 Month 1 LS mean (SE) -1.67 (0.26) -3.72 (0.32) -3.59 (0.32) 95% CI (-2.17, -1.16) (-4.35, -3.09) (-4.22, -2.95) Comparison with Placebo LS mean (SE) -2.05 (0.32) -1.92 (0.33) 95% CI (-2.69, -1.41) (-2.56, -1.28) p-value <.001 <.001

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Month 2 LS mean (SE) -2.54 (0.26) -4.39 (0.33) -4.35 (0.33) 95% CI (-3.05, -2.02) (-5.03, -3.75) (-4.99, -3.70) Comparison with Placebo LS mean (SE) -1.85 (0.33) -1.81 (0.33) 95% CI (-2.51, -1.20) (-2.47, -1.15) p-value <.001 <.001 Month 3 LS mean (SE) -2.99 (0.27) -4.67 (0.34) -4.45 (0.34) 95% CI (-3.52, -2.46) (-5.34, -4.01) (-5.12, -3.78) Comparison with Placebo LS mean (SE) -1.68 (0.35) -1.46 (0.35) 95% CI (-2.37, -1.00) (-2.15, -0.77) p-value <.001 <.001 Month 4 LS mean (SE) -3.19 (0.28) -5.11 (0.35) -4.53 (0.35) 95% CI (-3.73, -2.64) (-5.79, -4.42) (-5.23, -3.84) Comparison with Placebo LS mean (SE) -1.92 (0.37) -1.34 (0.37) 95% CI (-2.64, -1.19) (-2.07, -0.61) p-value <.001 <.001 Month 5 LS mean (SE) -3.11 (0.28) -5.37 (0.35) -5.21 (0.35) 95% CI (-3.65, -2.57) (-6.05, -4.68) (-5.90, -4.52) Comparison with Placebo LS mean (SE) -2.26 (0.37) -2.10 (0.37) 95% CI (-2.98, -1.54) (-2.83, -1.38) p-value <.001 <.001 Month 6 LS mean (SE) -3.38 (0.28) -5.16 (0.35) -5.30 (0.36) 95% CI (-3.93, -2.83) (-5.85, -4.46) (-6.00, -4.60) Comparison with Placebo LS mean (SE) -1.77 (0.37) -1.92 (0.38) 95% CI (-2.50, -1.04) (-2.66, -1.18) p-value <.001 <.001 Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAG 11.3). Galcanezumab = GMB **No Concomitant preventive migraine medications permitted in study CGAG and CGAH Episodic migraine population The primary endpoint was the average change from baseline in the number of MHDs over the entire double-blind treatment period, denoted as overall mean change. This endpoint is the treatment main effect from the primary MMRM model, averaged across the multiple post-baseline assessment times (months).

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Figure 6: Study CGAG Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Figure CGAG 11.1). Galcanezumab = GMB

Post Hoc Empirical Distribution Analysis of Primary Endpoint (Figure 7) Distribution of the average change from baseline in migraine headache days (MHDs) The sponsor’s Figure 7 plotted post hoc as histogram by dose (placebo, 120 and 240 mg) is based on the distribution of the average change from baseline in migraine headache days (MHDs). The x-axis represented the change from baseline in number of monthly migraine days (including all patients with either negative or positive values on this measure). For patients who discontinued early or had missing data at any of the months during the double-blind treatment phase, only the change values from non-missing months were used to calculate the average changes. The y- axis represented the relative frequency (%) of patients with change from baseline in MHDs falling within each specific bar of the histogram. Percentages were calculated based on the total number of patients with non-missing average change in MHD within each treatment arm. The number of patients represented by each histogram bar is displayed on top of each respective bar, and the total number of patients displayed for each treatment arm is provided in the upper right corner of each histogram.

Note to reader: As an instructional example in interpreting the histogram, note that 15.5% (66/425) of placebo patients in study CGAG had an average change from baseline in MHDs of ≥-3 to <-2.

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Both galcanezumab 120 mg and 240 mg dosing regimens consistently had greater reduction in the monthly number of migraine days as indicated by the shift to the left in the active treatment groups as compared to placebo group and in particular in those patients who experienced at least 6 day reduction, which indicates more improvement with the active treatment than with placebo.

Figure 7: Study CGAG Histogram Mean Change from Baseline in Migraine Headache Days

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0013. Module 1.11.3, Figure 2.1. LY = Galcanezumab For calculation of "Average Change from Baseline in Number of Migraine Headache Days over Months 1 to 6", it is the average of non-missing change value among 6 months.

Efficacy Results – Key Secondary endpoints

Efficacy analysis following the methods specified in the SAP was performed, and the results reported by the sponsor in the analyses of the secondary endpoints were confirmed. The key secondary endpoints shown in Table 18 were pre-specified and adjusted for multiplicity, and there was statistically significant difference compare to placebo in both dose groups.

Similar to the observations based on the primary efficacy analysis , for the key secondary efficacy variables the higher maintenance dose of galcanezumab 240 mg did not seem to provide better efficacy than the initial dose of galcanezumab 240 mg followed by lower monthly galcanezumab 120 mg SC injections during the monthly intervals.

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 The mean percentage of patients with ≥50%, ≥75%, and 100% reduction from baseline in monthly MHDs during the 6 month treatment phase was statistically significantly greater in both the galcanezumab 120 mg and 240 mg treatment groups compared with placebo. The response rates in Table 18 and in Figure 8 show that nearly half of the responders in in both galcanezumab treated groups (40%) experienced a 75% reduction in migraine headache days and after considering the placebo response rate there was on average 20% treatment difference. Hence, a 100% responder had no migraines over the study period (galcanezumab 15% compared to placebo response 6%).  Compared to the baseline use of acute medications there was statistically significant and clinically meaningful reduction in both the galcanezumab 120 mg and 240 mg treatment groups compared with placebo (-1.8 days for galcanezumab 120 mg and -1.6 days for galcanezumab 240 mg).  The functional impact of migraine in this study was measured by the Role Function- Restrictive domain of the Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1 over the final 3 months of double-blind treatment (average of months 4 to 6). See reviewer discussions with Table 9. Even though there were statistically significant differences from placebo in favor of galcanezumab, any meaningful inferences cannot be made at this time. The reader is referred to Sarrit Kovacs, COA review for details.

Table 18: Study CGAG Key Secondary Efficacy Analyses

Episodic Migraine Study CGAG (Months 1 to 6) Statistic Galcanezumab Placebo (N=425) GMB 120 mg (N=210) GMB 240 mg (N=208) Reduction of at least 50% in monthly average number of migraine days % responder, SE 38.6 (1.7) 62.3 (2.4) 60.9 (2.5) p-value <.001 <.001 Reduction of at least 75% in monthly average number of migraine days % responder, SE 19.3 (1.4) 38.8 (2.4) 38.5 (2.4) p-value <.001 <.001 100% reduction in monthly average number of migraine days % responder, SE 6.2 (0.8) 15.6 (1.6) 14.6 (1.6) p-value <.001 <.001 mean change from baseline in monthly migraine headache days using acute medication Placebo (N=425) GMB 120 mg (N=210) GMB 240 mg (N=208) LS mean change (SE) -2.15 (0.21) -3.96 (0.25) -3.76 (0.26) Comparison with Placebo LS mean (SE) -1.81 (0.24) -1.61 (0.24) 95% CI (-2.28, -1.33) (-2.09, -1.14) p-value <.001 <.001

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Change from Baseline in MSQ Role Function-Restrictive Domain (months 4 to 6) Placebo (N=377) GMB 120 mg (N=189) GMB 240 mg (N=184) LS mean (SE) 24.69 (1.07) 32.43 (1.31) 32.09 (1.32) Comparison with Placebo LS mean (SE) 7.74 (1.29) 7.40 (1.31) 95% CI (5.20, 10.28) (4.83, 9.97) p-value <.001 <.001 Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAG 11.4, 11.8, ISE Table 8.5). Galcanezumab = GMB *Responders are defined as patients whose change from baseline to average of month 4, 5 and 6 in MSQ role function restrictive >=25 on the transformed 100-point scale. The value of 25 corresponds to a change of 9 points on the raw scale

Efficacy Results –other relevant endpoints

Additional variables were considered that were not pre-specified with a priori statistical methods applied to control for multiplicity. The nominal p-values were <0.001 for these endpoint in Table 19. All results should be interpreted in the context that the results are from post hoc analysis without adjusting for multiplicity.

The mean change from baseline in the monthly average number of headache days of any severity, and for at least moderate severity during the study period showed similar reductions in both dose groups from placebo in favor of galcanezumab, and there appeared to be at least a 50% reduction in the mean numbers of headache hours in the galcanezumab treated population.

Table 19: Study CGAG Additional Secondary Efficacy Analyses

Episodic Migraine Study CGAG Statistic Galcanezumab Placebo (N=425) GMB 120 mg (N=210) GMB 240 mg (N=208) Change from Baseline in Number of Monthly Headache Days LS mean (SE) -3.03 (0.26) -4.69 (0.32) -4.79 (0.32) Comparison with Placebo LS mean (SE) -1.66 (0.30) -1.77 (0.30) Change from Baseline in Number of Monthly Headache Days of at least Moderate Severity LS mean (SE) -2.89 (0.21) -4.24 (0.25) -4.15 (0.25) Comparison with Placebo LS mean (SE) -1.35 (0.23) -1.26 (0.24) Change from Baseline in Number of Monthly Headache Hours LS mean (SE) -15.67 (2.24) -29.65 (2.70) -29.31 (2.70) Comparison with Placebo LS mean (SE) -13.98 (2.55) -13.64 (2.57) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAG 11.5, Table CGAG.14.37). Estimates were obtained using unstructured covariance structure. MMRM model. Galcanezumab = GMB This analysis model includes an additional fixed effect: grouped baseline monthly migraine headache days compared with the primary efficacy analysis model.

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Post-Hoc Analysis of Distribution of specified percentage levels of reduction for the average change from baseline in migraine headache days (MHDs) (Figure 8) The sponsors post-hoc analysis of responder rates for the percent reduction from baseline in the number of migraine days is shown in Figure 8 for the distribution analysis presented as a histogram by dose (placebo, 120 and 240 mg) based on the average change from baseline in migraine headache days (MHDs) displayed as “bins” of either 0 ≤ 25% reduction of migraine days/month from baseline, >25 - ≤ 50%, >50% - ≤ 75% and >75- 100% reduction. The y-axis represents the mean percentages of patients within each category for each treatment arm. Please see earlier discussion regarding responders.

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Figure 8: Study CGAG Histogram Percent Change from Baseline in Migraine Headache Days

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0013. Module 1.11.3, Figure 2.4. LY = Galcanezumab Example, Mean percentages of patients with ≥0% to <25% is equal to values from "≥0% decrease" minus values from "≥25% decrease".

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Additional Analyses Conducted

The overall mean difference from placebo was reduction of about 2 migraine days in both the galcanezumab treated groups from an average of 9 days at baseline (Table 17). At baseline, 60% subjects experienced >8 migraine days. A sub analyses showed that there were nominally greater mean reductions in the patients with between 8-14 migraine days (6 days reduction) in both galcanezumab dose groups over placebo compared to the patients with <8 migraine days monthly (3 days reduction) (Table 20, Figure 7) suggestive that with either dose of galcanezumab treatment efficacy was greater in the episodic migraine patients experiencing more frequent migraines.

Table 20: Study CGAG Mean Change from Baseline in Monthly Migraine Headache Days

Episodic Migraine Study CGAG Galcanezumab Placebo GMB 120 mg GMB 240 mg Statistic ≤8 days >8-14 days ≤8 days >8-14 days ≤8 days >8-14 days (N=183) (N=249) (N=85) (N=127) (N=89) (N=122) LS mean -1.76 (0.30) -3.60 (0.35) -3.19 (0.36) -5.86 (0.42) -2.79 (0.36) -5.87 (0.43) (SE) 95% CI (-2.34, -1.17) (-4.28, -2.91) (-3.90, -2.49) (-6.70, -5.03) (-3.49, -2.09) (-6.72, -5.02) Comparison with Placebo LS mean (SE) -1.44 (0.33) -2.27 (0.42) -1.04 (0.32) -2.27 (0.43) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB

Sensitivity Analyses Several sensitivity analyses were conducted as described in section 11.4.4.1 of the CSR, and the results of these analyses were consistent with the primary efficacy analysis. Additional sensitivity analysis (Table 21) for the primary endpoint excluding patients with monthly baseline headache days >14 was performed, which was an exclusionary criteria (Table 16) and this did not impact study primary efficacy.

Table 21: Study CGAG Mean Change from Baseline in Monthly Headache Days, Sensitivity Analysis

Episodic Migraine Study CGAG Statistic Galcanezumab Placebo (N=379) GMB 120 mg (N=181) GMB 240 mg (N=180) Change from Baseline in Number of Monthly Headache Days LS mean (SE) -2.58 (0.24) -4.45 (0.30) -4.09 (0.30) Comparison with Placebo LS mean (SE) -1.88 (0.29) -1.51 (0.29) 95% CI (-2.46, -1.30) (-2.09, -0.93)

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6.2. Protocol CGAH Phase 3 Episodic Migraine (EVOLVE-2)

6.2.1. Study Design

The EVOLVE-1 (study I5Q-MC-CGAG) and the EVOLVE-2 (study I5Q-MC-CGAH) studies are of identical design in patients with episodic migraine, and are therefore discussed together in the review. Please see section 6.1.

Statistical Analysis Plan (see information for Episodic Migraine Study CGAG in section 6.1.1)

Protocol Amendments

The protocol for study CGAH was approved on 23 September, 2015 and was amended on January 22, 2016 which included clarifying patient selection criteria and additional details regarding statistical control of the familywise type 1 error. There were 5 addenda that were implemented to the protocol to accommodate international regulatory requirements (September 30, 2015 Addendum 1; October 09, 2015 Addendum 2; October 10, 2015 Addendum 4; October 19, 2015 Addendum 5; and March 27, 2017 Addendum 7).

6.2.2. Study Results

Table 22: Study CGAH Summary

CGAH 6 month double-blind treatment phase;5 month post-treatment phase Episodic Migraine Randomized patients with at least 1 injection: 915 (GMB + PBO); EVOLVE-2 Number of patients who completed double-blind treatment: 785

Galcanezumab Doses  single loading dose of 240 mg (two 120 mg subcutaneous injections) followed by 120 mg/month maintenance dose  240 mg/month fixed dose (two 120 mg subcutaneous injections)

Please see discussions for doses selected for the phase 3 studies in section 6.1.2

Compliance with Good Clinical Practices

Lilly provided attestation that the study was conducted in accordance with the CFR governing the protection of human subjects (21 CFR part 50), Institutional Review Boards (21 CFR part 56), and the obligations of clinical investigators (21 CFR 312.50 to 312.70) in accordance with good clinical practice (GCP).

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Financial Disclosure

Lilly provided certification that there was no financial agreement with the clinical investigators defined in 21 CFR part 54.2. Financial disclosure and certification information was submitted in module 1.3.4 included in Form FDA 3454 with Certification from applicant for those investigators (Box 1 checked) with no disclosable financial interests or arrangements. Lilly appended a list of clinical investigators to Form FDA 3454.

Patient Disposition

Screen failures A total of 1696 patients entered the study and 915 patients who received at least 1 dose of IP were included in the ITT population were randomized. The most common reason for screen failure was patients not meeting criteria for study enrollment based on migraine headache information collected in the ePRO diary during the prospective baseline phase.

Table 23: Study CGAH Patient Disposition

Patient Disposition Placebo GMB 120 mg GMB 240 mg (N=461) (N=231) (N=223) Completed DB period 387 (84) 203 (88) 195 (87) Discontinued DB period 74 (16) 28 (12) 27 (12) Adverse Event 8 (2) 5 (2%) 9 (4%) Lack of Efficacy 6 (1%) 1 (0.4%) 1 (0.4%) Lost to Follow-up 10 (2%) 7 (3%) 0 Physician Decision 4 (1%) 0 2 (1%) Protocol Deviation 5 (1%) 2 (1%) 1 (0.4%) Withdrawal by 39 (8%) 11 (5%) 14 (6%) Patient Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (Table CGAH.10.1, CSR for study CGAH) and Module 5.3.5.3 ISE, Table ISE 8.2. Galcanezumab = GMB

Post-Randomization A total of 915 randomized patients received at least 1 dose of investigational product and were included in the ITT population. 785 patients (86%) completed the double-blind treatment phase. Please note that 19 patients (placebo: 11; GMB 120 mg: 5; GMB 240 mg: 3) from study CGAH were excluded from the primary efficacy analysis population due to ePRO compliance <=50%. Several sensitivity analyses on the primary endpoint were conducted for the protocol deviations and the conclusion remained unchanged.

Baseline Demographic and Disease Characteristics

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were similar to study CGAG. The study population included 70% whites with 85% females older than 25, of which over 40% subjects were >45 years old. Between 4-12% of the subjects included patients of Asian or African American race. The demographic characteristics of sex, age, race, and BMI were generally similar across treatment groups with 25% patients classified as obese based on the BMI. 75% of the study participant were from the US and Europe, and the patient population is generally representative of the US migraine population.

The enrolled episodic migraineurs in study CGAH also experienced at baseline on average 9 migraine days and 11 headache days. At baseline about 58% patients experienced between 8-14 mean numbers of monthly migraine headache days and monthly headache days (see definitions Table 9). Overall, treatment groups were balanced with respect to baseline disease characteristics and any treatment group differences were not considered meaningful on the study outcomes (Table 25). Use of concomitant migraine preventive medications was not permitted, and there were no differences across the dose arms in the allowed baseline rescue acute medications. Treatment compliance was high in all groups possibly because the treatments were administered by investigative site personnel.

Reviewer Comment

Exclusionary criteria specified that patients with a history of ≥15 headache days (migraine, probable migraine, or any other headache) per month on average during the past 3 months or were suspected of suffering from chronic migraine as defined per ICHD-3 beta, were to be excluded. 10-13% subjects at baseline experienced over 15 monthly headache days (Table 25). Please see sensitivity analysis for the primary endpoint excluding these patients in Table 30.

Table 24: Study CGAH Episodic Migraine Demographic Characteristics

Placebo Galcanezumab Monthly GMB 120 mg GMB 240 mg Total Demographic Parameters (N=461) (N=231) (N=223) (N=915) n (%) n (%) n (%) n (%) Sex Male 68 (14.75) 34 (14.72) 32 (14.35) 134 (14.64) Female 393 (85.25) 197 (85.28) 191 (85.65) 781 (86.36) Age Mean years (SD) 42.33 (11.30) 40.91 (11.15) 41.91 (10.77) 41.87 (11.14) Median (years) 43 41 42 42 Min, max (years) 18, 65 19, 65 19, 64 18, 65 Age Group < 25 years 35 (7.59) 19 (8.23) 15 (6.73) 69 (7.54) ≥ 25 - < 45 years 217 (47.07) 115 (49.78) 115 (51.57) 447 (48.85) ≥ 45 years 209 (45.34) 97 (41.99) 93 (41.70) 399 (43.61)

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Race White 325 (70.50) 166 (71.86) 152 (68.16) 643 (70.27) Black or African American 36 (7.81) 11 (4.76) 16 (7.17) 63 (6.89) Asian 50 (10.85) 28 (12.12) 24 (10.76) 102 (11.15) American Indian or Alaska Native 20 (4.34) 8 (3.46) 13 (5.83) 41 (4.48) Native Hawaiian or Other Pacific 0 (0.00) 0 (0.00) 2 (0.90) 2 (0.22) Islander Multiple 30 (6.51) 18 (7.79) 16 (7.17) 64 (6.99) Race group Caucasian 325 (70.50) 166 (71.86) 152 (68.16) 643 (70.27) Non-Caucasian 136 (29.50) 65 (28.14) 71 (31.84) 272 (29.73) Ethnicity Not Hispanic or Latino 318 (68.98) 162 (70.13) 151 (67.71) 631 (68.96) Hispanic or Latino 118 (25.60) 58 (25.11) 61 (27.35) 237 (25.90) Unknown or Missing 25 (5.42) 11 (4.76) 11 (4.93) 47 (5.14) BMI Category Underweight (<18.5/Kg/m2) 11 (2.39) 5 (2.16) 4 (1.79) 20 (2.19) normal (≥18.5 and <25/Kg/m2) 186 (40.35) 92 (39.83) 90 (40.36) 368 (40.22) Overweight (≥25 and <30/Kg/m2) 137 (29.72) 76 (32.90) 65 (29.15) 278 (30.38) Obese (≥30 and <40/Kg/m2) 127 (27.55) 58 (25.11) 64 (28.70) 249 (27.21) Region North America (United States) 224 (48.59) 112 (48.48) 110 (49.33) 446 (48.74) Europe 122 (26.46) 60 (25.97) 59 (26.46) 241 (26.34) Czech Republic/CZE 39 (8.46) 19 (8.23) 19 (8.52) 77 (8.42) Germany/DEU 37 (8.03) 19 (8.23) 19 (8.52) 75 (8.20) Netherlands/NLD 24 (5.21) 11 (4.76) 11 (4.93) 46 (5.03) Spain/ESP 14 (3.04) 7 (3.03) 7 (3.14) 28 (3.06) United Kingdom/GBR 8 (1.74) 4 (1.73) 3 (1.35) 15 (1.64) Rest of the World 115 (24.95) 59 (25.54) 54 (24.22) 228 (24.92) Middle East (Israel) 11 (2.39) 5 (2.16) 5 (2.24) 21 (2.30) South/Latin America 58 (12.58) 30 (12.99) 27 (12.11) 115 (12.57) Asia 46 (9.98) 24 (10.39) 22 (9.87) 92 (10.05) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table 14.5 and 14.6 Study CGAH). Galcanezumab = GMB

Table 25: Study CGAH Episodic Migraine Baseline Disease Characteristics

Placebo Galcanezumab Baseline Disease Monthly GMB 120 mg GMB 240 mg Total Characteristics (N=461) (N=231) (N=223) (N=915) n (%) n (%) n (%) n (%) Number of migraine days Mean (SD) 9.19 (2.99) 9.07 (2.87) 9.06 (2.92) 9.13 (2.94) Median (min, max) 9 (4, 18) 9 (4, 14) 9 (4, 14) 9 (4, 18)

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≤ 8 days 197 (42.73) 96 (41.56) 94 (42.15) 387 (42.30) 8< and ≤ 14 days 262 (56.83) 135 (58.44) 129 (57.85) 526 (57.49) 14< and ≤ 22 days 2 (0.43) 0 (0.00) 0 (0.00) 2 (0.22) Number of headache days Mean (SD) 10.68 (3.53) 10.56 (3.42) 10.74 (3.70) 10.66 (3.54) Median (min, max) 11 (4, 28) 10.34 (4, 30) 10.34 (4, 30) 10.71 (4, 30) ≤ 8 days 130 (28.20) 69 (29.87) 60 (26.91) 259 (28.31) 8< and ≤ 14 days 283 (61.39) 135 (58.44) 134 (60.09) 552 (60.33) 14< and ≤ 22 days 45 (9.76) 26 (11.26) 28 (12.56) 99 (10.82) >22 days 3 (0.65) 1 (0.43) 1 (0.45) 5 (0.55) Number of headache days of at least moderate severity Mean (SD) 7.56 (3.10) 7.58 (2.93) 7.76 (3.16) 7.61 (3.07) Median (min, max) 8 (0, 17) 7.24 (0, 15.52) 7.5 (0, 15.52) 7.5 (0, 17) ≤ 8 days 278 (60.30) 144 (62.34) 129 (57.85) 551 (60.22) 8< and ≤ 14 days 180 (39.05) 86 (37.23) 92 (41.26) 358 (39.13) 14< and ≤ 22 days 3 (0.65) 1 (0.43) 2 (0.90) 6 (0.66) Number of headache hours Mean (SD) 59.84 (40.86) 58.56 (41.43) 63.63 (62.31) 60.44 (47.10) Median (min, max) 50 (7, 322) 48.62 (6.56, 296.79) 49 (4, 686) 49 (4, 686) Number of migraine headache days acute headache medications/ Abortive Medication Use Mean (SD) 7.62 (3.40) 7.47 (3.34) 7.47 (3.25) 7.54 (3.34) Median (min, max) 7.24 ( 0, 17) 7.27 ( 0, 14) 7.24 ( 0, 14) 7.24 ( 0, 17) Number of days of use of Triptan Mean (SD) 4.57 (4.59) 4.63 (4.61) 4.53 (4.53) 4.58 (4.57) Median (min, max) 4.14 (0, 17) 5 (0, 14) 4 (0, 13.64) 4.14 (0, 17) Number of days of use of NSAID/Aspirin use Mean (SD) 5.77 (4.42) 5.57 (4.26) 5.91 (4.28) 5.75 (4.34) Median (min, max) 6 (0, 14.44) 6 (0, 14) 6 (0, 14) 6 (0, 14.44) MSQ Role Function Restrictive score Mean (SD) 51.35 (15.73) 52.47 (14.76) 51.71 (16.31) 51.72 (15.62) Median (min, max) 51.43 (0, 100) 54.29 (5.71, 94.29) 51.43 (0, 100) 51.43 (0, 100) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table 14.5 and Table 14.6 study CGAG). Galcanezumab = GMB; N/A=No data available **No Concomitant preventive migraine medications permitted in study CGAG and CGAH Episodic migraine population

Efficacy Results – Primary Endpoint

Efficacy analysis following the methods specified in the SAP was performed, and the results reported by the sponsor in the analyses of the primary endpoint were confirmed. The primary efficacy endpoint analysis is shaded in gray (Table 26). The treatment effect across the multiple post-baseline assessment times (months) are also included in Table 26.

Similar to the primary efficacy results observed for the study CGAG in episodic migraineurs,

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there was statistically significant mean between-group difference favoring both galcanezumab dose groups compared to placebo in the overall mean reduction in the number of monthly migraine headache days with onset of effect as early as month 1 (Table 26, Figure 9). The overall LS mean reduction from baseline in the number of monthly MHDs during the double-blind treatment phase was 4.3 days for galcanezumab 120 mg and 4.2 days for galcanezumab 240 mg compared with 2.3 days for placebo (LS mean change difference from placebo: -2 and -1.9; p<.001 for each dose group versus placebo). Please note that patients in the galcanezumab 120 mg treatment group received a loading dose of galcanezumab 240 mg at the first injection followed by monthly galcanezumab 120 mg injection, which provides information for efficacy at month 1. Therefore, the initial treatment effect observed at month 1 was based on galcanezumab 240 mg dose (Figure 9). The higher maintenance dose of galcanezumab 240 mg does not seem to provide better efficacy than the initial dose of galcanezumab 240 mg followed by lower monthly galcanezumab 120 mg SC injections during the monthly intervals.

Table 26: Study CGAH Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM

Episodic Migraine Study CGAH Statistic Galcanezumab Placebo (N=450) GMB 120 mg (N=226) GMB 240 mg (N=220) Overall LS mean (SE) -2.28 (0.20) -4.29 (0.25) -4.18 (0.26) 95% CI (-2.67, -1.88) (-4.79, -3.80) (-4.68, -3.67) Comparison with Placebo LS mean (SE) -2.02 (0.27) -1.90 (0.27) 95% CI (-2.55, -1.48) (-2.44, -1.36) p-value <.001 <.001 Month 1 LS mean (SE) -1.17 (0.22) -3.90 (0.29) -3.23 (0.30) 95% CI (-1.60, -0.73) (-4.47, -3.33) (-3.81, -2.65) Comparison with Placebo LS mean (SE) -2.74 (0.32) -2.06 (0.33) 95% CI (-3.37, -2.10) (-2.70, -1.42) p-value <.001 <.001 Month 2 LS mean (SE) -2.16 (0.23) -4.01 (0.29) -3.76 (0.30) 95% CI (-2.60, -1.71) (-4.59, -3.44) (-4.34, -3.18) Comparison with Placebo LS mean (SE) -1.86 (0.33) -1.60 (0.33) 95% CI (-2.51, -1.21) (-2.25, -0.96) p-value <.001 <.001 Month 3 LS mean (SE) -2.19 (0.23) -3.81 (0.30) -4.49 (0.30)

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95% CI (-2.64, -1.73) (-4.40, -3.22) (-5.08, -3.89) Comparison with Placebo LS mean (SE) -1.62 (0.34) -2.30 (0.34) 95% CI (-2.28, -0.95) (-2.96, -1.63) p-value <.001 <.001 Month 4 LS mean (SE) -2.42 (0.24) -4.51 (0.31) -4.32 (0.32) 95% CI (-2.90, -1.95) (-5.13, -3.90) (-4.94, -3.70) Comparison with Placebo LS mean (SE) -2.09 (0.36) -2.30 (0.34) 95% CI (-2.79, -1.39) (-2.96, -1.63) p-value <.001 <.001 Month 5 LS mean (SE) -2.88 (0.23) -4.94 (0.29) -4.70 (0.30) 95% CI (-3.33, -2.43) (-5.52, -4.36) (-5.28, -4.12) Comparison with Placebo LS mean (SE) -2.06 (0.33) -1.82 (0.33) 95% CI (-2.71, -1.41) (-2.48, -1.17) p-value <.001 <.001 Month 6 LS mean (SE) -2.85 (0.24) -4.59 (0.32) -4.56 (0.32) 95% CI (-3.33, -2.37) (-5.21, -3.96) (-5.19, -3.93) Comparison with Placebo LS mean (SE) -1.73 (0.36) -1.71 (0.36) 95% CI (-2.44, -1.03) (-2.42, -1.00) p-value <.001 <.001 Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAH 11.3). Galcanezumab = GMB **No Concomitant preventive migraine medications permitted in study CGAG and CGAH Episodic migraine population The primary endpoint was the average change from baseline in the number of MHDs over the entire double-blind treatment period, denoted as overall mean change. This endpoint is the treatment main effect from the primary MMRM model, averaged across the multiple post-baseline assessment times (months).

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Figure 9: Study CGAH Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Figure CGAH 11.1). Galcanezumab = GMB

Post Hoc Empirical Distribution Analysis of Primary Endpoint (Figure 10) Distribution of the average change from baseline in migraine headache days (MHDs) The sponsor’s Figure 10 plotted post hoc as histogram by dose (placebo, 120 mg and 240 mg) based on the distribution of the average change from baseline in migraine headache days (MHDs). Although there appears to be a shift to the left favoring galcanezumab, there were greater reductions in migraine days in those patients’ experiences changes of at least 6-8 days.

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Figure 10: Study CGAH Histogram Mean Change from Baseline in Migraine Headache Days

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0013. Module 1.11.3, Figure 2.2. LY = Galcanezumab For calculation of "Average Change from Baseline in Number of Migraine Headache Days over Months 1 to 6", it is the average of non-missing change value among 6 months.

Efficacy Results – Key Secondary endpoints

Efficacy analysis following the methods specified in the SAP was performed, and the results reported by the sponsor in the analyses of the secondary endpoints were confirmed. The key secondary endpoints shown in Table 27 were pre-specified and adjusted for multiplicity, and there was statistically significant difference compare to placebo in both dose groups.

Similar to the observations based on the primary efficacy analysis, for the key secondary efficacy variables the higher maintenance dose of galcanezumab 240 mg did not seem to provide better efficacy than the initial dose of galcanezumab 240 mg followed by lower monthly galcanezumab 120 mg SC injections during the monthly intervals.  The mean percentage of patients with ≥50%, ≥75%, and 100% reduction from baseline in monthly MHDs during the 6 month treatment phase was statistically significantly greater in both the galcanezumab 120 mg and 240 mg treatment groups compared with placebo. The response rates in Table 27 and in Figure 11 show that about 1/3rd of the responders in both galcanezumab treated groups (34%) experienced a 75% reduction in migraine headache days and after considering the placebo response rate there was on average 16% treatment difference. Hence, a 100% responder had no migraines over the study CDER Clinical Review Template 67 Version date: September 6, 2017 for all NDAs and BLAs

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period (galcanezumab 12-14% compared to placebo response 6%).  Compared to the baseline use of acute medications there was statistically significant and clinically meaningful reduction in both the galcanezumab 120 mg and 240 mg treatment groups compared with placebo (-1.8 days for both galcanezumab doses).  The functional impact of migraine in this study was measured by the Role Function- Restrictive domain of the Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1 over the final 3 months of double-blind treatment (average of months 4 to 6). See reviewer discussions with Table 9. Even though there were statistically significant differences from placebo in favor of galcanezumab, any meaningful inferences cannot be made at this time. The reader is referred to Sarrit Kovacs, COA review for details.

Table 27: Study CGAH Key Secondary Efficacy Analyses

Episodic Migraine Study CGAH (Months 1 to 6) Statistic Galcanezumab Placebo (N=450) GMB 120 mg (N=226) GMB 240 mg (N=220) Reduction of at least 50% in monthly average number of migraine days % responder, SE 36.0 (1.7) 59.3 (2.4) 56.5 (2.5) p-value <.001 <.001 Reduction of at least 50% in monthly average number of migraine days % responder, SE 17.8 (1.3) 33.5 (2.3) 34.3 (2.3) p-value <.001 <.001 100% Reduction in monthly average number of migraine days % responder, SE 5.7 (0.7) 11.5 (1.4) 13.8 (1.5) p-value <.001 <.001 mean change from baseline in monthly migraine headache days using acute medication Placebo (N=450) GMB 120 mg (N=226) GMB 240 mg (N=220) LS mean change (SE) -1.85 (0. 18) -3.67 (0.22) -3.63 (0.23) Comparison with Placebo LS mean (SE) -1.82 (0.24) -1.78 (0.24) 95% CI (-2.29, -1.36) (-2.25, -1.31) p-value <.001 <.001 Change from Baseline in MSQ Role Function-Restrictive Domain (months 4 to 6) Placebo (N=396) GMB 120 mg (N=213) GMB 240 mg (N=210) LS mean (SE) 19.65 (0.92) 28.47 (1.15) 27.04 (1.17) Comparison with Placebo LS mean (SE) 8.82 (1.27) 7.39 (1.28) 95% CI (6.33, 11.31) (4.88, 9.90) p-value <.001 <.001 Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAH 11.4, 11.8, ISE Table 8.5). Galcanezumab = GMB *Responders are defined as patients whose change from baseline to average of month 4, 5 and 6 in MSQ role function restrictive >=25 on the transformed 100-point scale. The value of 25 corresponds to a change of 9 points on the raw scale.

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Efficacy Results –other relevant endpoints

Additional variables were considered that were not pre-specified with a priori statistical methods applied to control for multiplicity. The nominal p-values were <0.001 for these endpoint in Table 28. All results should be interpreted in the context that the results are from post hoc analysis without adjusting for multiplicity.

The mean change from baseline in the monthly average number of headache days of any severity, and for at least moderate severity during the study period showed similar reductions in both dose groups from placebo in favor of galcanezumab, and there appeared to be at least a 40% reduction in the mean numbers of headache hours in the galcanezumab treated population.

Table 28: Study CGAH Additional Secondary Efficacy Analyses

Episodic Migraine Study CGAH Statistic Galcanezumab Placebo (N=450) GMB 120 mg (N=226) GMB 240 mg (N=220) Change from Baseline in Number of Monthly Headache Days LS mean (SE) -2.30 (0.22) -4.31 (0.28) -4.30 (0.28) Comparison with Placebo LS mean (SE) -2.00 (0.30) -2.00 (0.30) Change from Baseline in Number of Monthly Headache Days of at least Moderate Severity LS mean (SE) -2.31 (0.18) -3.90 (0.22) -3.78 (0.22) Comparison with Placebo LS mean (SE) -1.59 (0.23) -1.47 (0.24) Change from Baseline in Number of Monthly Headache Hours LS mean (SE) -10.89 (1.92) -26.07 (2.41) -24.44 (2.44) Comparison with Placebo LS mean (SE) -15.19 (2.59) -13.56 (2.60) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAH 11.5, Table CGAH.14.35). Estimates were obtained using unstructured covariance structure. MMRM model. Galcanezumab = GMB This analysis model includes an additional fixed effect: grouped baseline monthly migraine headache days compared with the primary efficacy analysis model.

Post Hoc Analysis of Distribution of specified percentage levels of reduction for the average change from baseline in migraine headache days (MHDs) (Figure 11) The sponsor’s post hoc analysis of responder rates for the percent reduction from baseline in the monthly average number of migraine days is shown in Figure 11 for the distribution analysis presented as a histogram by dose (placebo, 120 and 240 mg) based on the average change from baseline in migraine headache days (MHDs) displayed as “bins” of either 0 ≤ 25% reduction of migraine days/month from baseline, >25 - ≤ 50%, >50% - ≤ 75% and >75- 100% reduction. The y- axis represents the mean percentages of patients within each category for each treatment arm. Please see earlier discussion regarding responders.

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Figure 11: Study CGAH Histogram Percent Change from Baseline in Migraine Headache Days

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0013. Module 1.11.3, Figure 2.5. LY = Galcanezumab Example, Mean percentages of patients with ≥0% to <25% is equal to values from "≥0% decrease" minus values from "≥25% decrease".

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Additional Analyses Conducted

The overall mean difference from placebo was reduction of about 2 migraine days in both the galcanezumab treated groups from an average of 9 migraine days at baseline (Table 26). At baseline, 60% subjects experienced >8 migraine days. A sub analyses showed that there were nominally greater mean reductions in the patients with between 8-14 migraine days (5-6 days reduction) in both galcanezumab dose groups over placebo compared to the patients with <8 migraine days monthly (2-3 day reduction) (Table 29, Figure 10) suggestive that the galcanezumab treatment efficacy was greater in the episodic migraine patients experiencing more frequent migraines.

Table 29: Study CGAH Mean Change from Baseline in Monthly Migraine Headache Days

Episodic Migraine Study CGAH Galcanezumab Placebo GMB 120 mg GMB 240 mg Statistic ≤8 days >8-14 days ≤8 days >8-14 days ≤8 days >8-14 days (N=197) (N=262) (N=96) (N=135) (N=94) (N=129) LS mean -0.54 (0.25) -3.58 (0.30) -2.61 (0.33) -5.57 (0.38) -2.64 (0.33) -5.35 (0.38) (SE) 95% CI (-1.04, -0.04) (-4.18, -2.99) (-3.25, -1.97) (-6.31, -4.83) (-3.29, -1.99) (-6.10, -4.59) Comparison with Placebo LS mean (SE) -2.07 (0.36) -1.99 (0.40) -2.10 (0.36) -1.76 (0.40) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB Sensitivity Analysis Several sensitivity analyses were conducted as described in section 11.4.4.1 of the CSR, and the results of these analyses were consistent with the primary efficacy analysis. Additional sensitivity analysis (Table 30) for the primary endpoint excluding patients with monthly baseline headache days >14 was performed, which was an exclusionary criteria (Table 25) and this did not impact study primary efficacy.

Table 30: Study CGAH Mean Change from Baseline in Monthly Headache Days, Sensitivity Analysis

Episodic Migraine Study CGAH Statistic Galcanezumab Placebo (N=403) GMB 120 mg (N=201) GMB 240 mg (N=191) Change from Baseline in Number of Monthly Headache Days LS mean (SE) -2.06 (0.21) -4.03 (0.26) -3.99 (0.27) Comparison with Placebo LS mean (SE) -1.97 (0.29) -1.93 (0.29) 95% CI (-2.53, -1.40) (-2.50, -1.36)

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6.3. Protocol CGAI Phase 3 Chronic Migraine (REGAIN)

6.3.1. Study Design

Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 in Patients with Chronic Migraine – REGAIN study

Trial Design for CM Study CGAI

Study CGAI (REGAIN) was a phase 3, multicenter, randomized, stratified, double blind, placebo- controlled, parallel-group study in subjects with chronic migraine.

REGAIN included up to 12 months on investigational product (3 months of double-blind treatment and 9 months of open-label treatment) with 5 periods, including a prospective baseline phase to determine patient eligibility, followed by 4 months of posttreatment observation (Figure 12).

Figure 12: BLA 761063 CM Study Design for Galcanezumab Migraine Prophylaxis

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0008. Module 5.3.5.3 Figure ISE 5.2. *Eligibility period determined between a minimum of 30 days and a maximum of 40 days. Investigators may have up to 5 additional days (beyond the 40 days) if needed to schedule patients’ Visit 3 appointment. aPatients randomized to the 120 mg dose will receive a loading dose of 240 mg at the first injection only (Visit 3) . bAt Visit 7, all patients who enter the open-label extension will receive LY2951742 at a dose of 240 mg. cAt Visit 8, all patients will receive LY2951742 at a dose of 120 mg. dStarting at Visit 9, dosing will be flexible (LY2951742 120 mg or 240 mg) at the discretion of the investigator Abbreviations: LY2951742 = galcanezumab; OLE = open-label extension; SP = Study Period.

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Table 31 provides an overview of the key study design characteristics for the 2 episodic migraine studies CGAG and CGAH, and for the chronic migraine study CGAI, highlighting any similarities and differences. See details explained below. As per the ISE, the criteria for migraine headache were adapted from the IHS ICHD-3. The only modification from the original criteria was a reduction in required minimum duration from “4 hours untreated” to “30 minutes.” This reduction was made so that patients would not feel compelled to delay taking acute medications to relieve the oncoming migraine headache (Table 9), and in that case the 4 hour duration was not applicable. In general, this was acceptable and was discussed with FDA. In this BLA, 30 minute migraine headache was counted as an event even when the patients did not take acute migraine medications. Apart from the differences in the EM and CM study populations and the 3 month study duration in chronic migraineurs where up to 1/3rd patients were allowed concomitant prophylactic migraine medications, the doses evaluated were no different in studies CGAG, CGAH, and CGAI, including the similar endpoint definitions and primary efficacy variables (Table 9, Table 31).

Table 31: BLA 761063 Overview of Study Design EM Study CGAG and CGAH, and CM Study CGAI

I5Q-MC-CGAG (Episodic migraine) I5Q-MC-CGAI (Chronic migraine) I5Q-MC-CGAH (Episodic migraine) Study Phase 3, multicenter randomized, double- Phase 3, multicenter randomized, double-blind, placebo- Design blind, placebo-controlled, parallel group trial controlled, parallel group trial with 5-study periods: with 4-study periods:  SP I- Screening and washout (3-45 days)  SP I- Screening and washout (3-45 days)  SP II- Prospective Baseline (30-40 days)  SP II- Prospective Baseline (30-40 days)  SP III- Double-Blind Treatment (3 months)  SP III- Double-Blind Treatment (6 months)  SP IV- Open-Label Extension (9 months)  SP IV- ADA Follow-up (galcanezumab  SP V- Follow-up (galcanezumab washout phase; 4 washout phase; 4 months) months) Up to 1/3rd of study patients enrolled using concomitant prophylactic medications Study Drug

Key  ICHD-3 diagnosis of migraine with or  ICHD-3 diagnosis of chronic migraine Inclusion without aura  For at least 3 months, history of 15 or more headaches Criteria  History of 4 to 14 MHDs prior to Visit 1 and per month, of which at least 8 have features of at least 2 migraine attacks per month on migraine, and at least 1 headache-free day per month

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average within the past 3 months  15 to 29 headache days per 30-day period in the  4 to 14 MHDs and at least 2 migraine prospective baseline period, of which at least 8 are attacks per month during the prospective MHDs baseline period Primary  mean change from baseline in the average mean change from baseline in the average (number of) Endpoint (number of) monthly migraine headache monthly migraine headache days (≥30 minutes duration) days (≥30 minutes duration) during the during the double-blind treatment period double-blind treatment period Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1 (CSR for study CGAG, CGAH, and CGAI) and Module 5.3.5.3 ISE Galcanezumab = GMB or LY2951742; ICHD-3 = International Classification of Headache Disorders – 3rd edition, beta; SP = Study Period ***As per the ISE, the criteria for migraine headache were adapted from the Standard (IHS) ICHD-3. The only modification from the original criteria is a reduction in required minimum duration from “4 hours untreated” to “30 minutes.” This reduction was made so that patients would not feel compelled to delay taking acute medications to relieve the oncoming migraine headache.

Reviewer Comment Please see galcanezumab development discussions with the Division in Table 5 regarding acceptability of the study design including the patient selection criteria, concomitant prophylactic medications during the study and limiting this to 1/3rd of the sample, the controlled study duration, the definitions of the primary endpoint and any pre-specified key secondary endpoints, and the sponsors statistical analysis plan.

Trial Population 18 to 65 year old patients were enrolled with a diagnosis of chronic migraine as defined by International Headache Society (IHS) International Classification of Headache Disorders – 3rd edition, beta (ICHD-3) (1.3) (ICHD-3 2013), a headache occurring on 15 or more days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month, Or, if the headache is believed by the patient to be migraine at onset and is relieved by a triptan or ergot derivative (Table 6).

The Study Period I and Study Period II schedules were similar to the information previously explained in section 6.1.1 for study CGAG. The following differences are listed below for study CGAI.  Unlike Studies CGAG and CGAH, study CGAI allowed up to one-third of enrolled patients to continue migraine prophylactic treatment with either topiramate or propranolol if the patient had been on a stable dose for at least 2 months prior to Visit 2 and if dosing remained stable throughout the double-blind treatment period. Otherwise, all migraine preventive treatments had to be discontinued at least 30 days prior to Visit 2 (or 4 months for botulinum toxin).  Patients with history of persistent daily headache, cluster headache, or migraine subtypes including hemiplegic (sporadic or familial) migraine, ophthalmoplegic migraine, and migraine with brainstem aura (basilar-type migraine) were excluded as defined by ICHD-3 beta. Patients experiencing tension-type headache and medication overuse headache (stratified randomization) were permitted in the study. Acute headache medication overuse patients were permitted (based on Section 8.2 of the ICHD-3

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guidelines) after determining the frequency of specific drug classes reported in the ePRO diary during the prospective baseline period.  Patients with ECGs showing abnormalities compatible with acute cardiovascular events and/or serious cardiovascular risk, including but not limited to a corrected QT (QTcB [Bazett's]) interval >470 msec for women and >450 for men, or have had myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or deep vein thrombosis/pulmonary embolism within 6 months of screening, or have planned cardiovascular surgery or percutaneous coronary angioplasty, or a lifetime history of stroke were excluded Study Period III (3 month double-blind treatment phase study CGAI)

Table 32: BLA 761063 Chronic Migraine Study CGAI Planned Sample Size

Eligible for Randomization (n=1113) Placebo 558 Screen (n=1903) 120 mg 278 240 mg 277

Study Period IV: Patients who completed the double-blind treatment phase (study Period III) could opt to enter an open-label treatment period (study Period IV) for up to 9 months of treatment with galcanezumab. Study Period V: Patients who discontinued from study Period III or IV entered directly into study Period V for assessment during washout of investigational study drug.

Doses - Phase 3 Episodic Migraine Study CGAG and CGAH, and for Chronic Migraine Study CGAI

The galcanezumab doses administered in study CGAI were identical to the regimens in study CGAG and CGAH. Please see discussions for doses and the justification for dose selection for phase 3 studies in sections 6.1.1 and 6.1.2.

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Table 33: CM Study CGAI Schedule of Assessments Double-Blind Treatment Phase (3 months)

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Abbreviations: AE = adverse event; CGRP = Calcitonin-gene related peptide; C-SSRS = Columbia-Suicide Severity Rating Scale; ePRO = electronic patient reported outcomes; ET = early termination; FSH = follicle stimulating hormone; HDL = High-density lipoprotein; MIDAS = Migraine Disability Assessment test; MSQ (v2.1) = Migraine Specific Quality of Life Questionnaire; PGI-I = Patient Global Impression of Improvement; PGI- S = Patient Global Impression of Severity; PK = pharmacokinetics; RNA = ribonucleic acid; SHSF = Self-harm supplement form; SHFU = Self-harm follow-up form. Note: Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may be required in follow-up with patients in consultation with the Lilly, or its designee, clinical research physician. See Appendix 4 for more details regarding specific hepatic monitoring tests. If the patient has discontinued the trial and returns for hepatic follow-up, the site should use the recommended visit designation. a The eligibility period of the prospective baseline assessment will last from 30 to 40 days. Investigators and patients may have up to an additional 5 days to schedule their Visit 3 appointment (beyond the 40 days); however, eligibility will be based on the 30-40 day period. b Visit is to include a review of any spontaneously reported adverse events and collection of blood samples for immunogenicity, PK, and CGRP plasma. c A neurological exam will be conducted at screening, Month 3 (final visit of double-blind treatment), Months 6, 9, and 12 (open-label treatment), and Month 16/early termination in order to assess for any signs of pre-existing or treatment-emergent neurological abnormalities such as stroke or other cerebrovascular events.

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d Electrocardiograms (ECGs) will be performed at Visit 1, Visit 3, Visit 12, and Visit 14 or early termination. Note: The Visit 3 ECG should be collected prior to blood draws and dosing. Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection. e Vital signs will include body temperature, blood pressure, and pulse. Blood pressure and pulse will be measured in triplicate in the sitting position and should be measured prior to blood draws. Blood pressure will be assessed by utilizing a calibrated machine. f Chemistry samples collected at Visit 3, Visit 7, Visit 10, Visit 13, Visit 16, and Visit 18 or early termination must be fasting. Fasting is defined as no food or drink, except water, for at least 8 hours prior to testing. g In the event of a positive urine leukocyte esterase result, a repeat urine sample will be collected and shipped to the central laboratory. h A positive urine test must be followed by a serum pregnancy test for confirmation. i Immunogenicity, CGRP plasma sample, and PK sampling to be performed at the indicated visits and prior to dose administration if the visit is a dosing visit. Samples will be taken in the event of early termination. Immunogenicity samples also may be collected in the event of a systemic allergic/hypersensitivity reaction (see Section 8.4.3). The timing of samples will be recorded. j Patients will receive injections of placebo or LY2951742 after all other visit procedures are completed. Following the first dose at Visit 3, patients will be observed for at least 30 minutes in the office. k Questionnaire administered by clinician to assess other chronic pain conditions. l The C-SSRS and SHSF (and SHFU when applicable) will be completed at scheduled and unscheduled office visits.

Efficacy Endpoints

Please see summary information for migraine day and headache day endpoint definitions in Table 9.

Please note that the primary efficacy endpoint and the key secondary endpoints were similar for all studies CGAG, CGAH, and CGAI, except that the endpoint evaluation was at 3 months as opposed to 6 months in the episodic migraine studies (CGAG and CGAH).

Primary Efficacy Endpoint (Chronic Migraine Study CGAI)

 mean change from the baseline period in the number of monthly migraine headache days during the 3 month double-blind treatment phase

The primary endpoint treatment main effect is estimated from the primary MMRM model. The treatment main effect is, by definition, the treatment effect averaged across the multiple post- baseline assessment times (months).

Key Secondary Efficacy Endpoints (Chronic Migraine Study CGAI)

The following key secondary endpoints were pre-specified and adjusted for multiplicity  The proportion of patients with reduction from baseline ≥50%, (≥75% and 100%) in monthly migraine headache days during the 3 month double-blind treatment phase  mean change from baseline in monthly migraine headache days that acute medication was taken  functional impact of migraine on usual activities assessed by the Role Function- Restrictive domain of the Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1

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The overall mean change (applicable to the primary endpoint variable) also applied to the secondary study endpoints, estimated as the main effect of treatment from the MMRM analysis averaged across the multiple post-baseline assessment times during the 3 month double-blind treatment phase.

Statistical Analysis Plan

The following information was abstracted from the ISE, and the CSR.

The statistical analysis plan (SAP) finalized for study CGAI was Version 4 (25 April 2017) Version 1 November 23, 2015 (first approved) Version 2 September 13, 2016 Version 3 January 16, 2017

The reporting database was validated and locked for analysis on May 5, 2017. The database lock date was determined based on the last patient visit date of March 16, 2017 for the double- blind treatment phase. The additional time to the data lock date was needed to resolve and close all queries, process laboratory samples, and complete signoff by investigators. Any data after this cutoff date were excluded from the study data tabulation model/analysis data model (SDTM/ADaM) dataset.

For study CGAI, randomization was stratified within country and by acute headache medication overuse (yes versus no), and use of concurrent migraine prophylactic medication (yes versus no).

General Statistical Issues Applied to Study CGAI

The general issues defined or specified in the Statistical Analysis Plan (SAP) for chronic migraine study CGAI were similar to the information provided for episodic migraine studies (CGAG and CGAH) with regard to the analysis population, specification of baseline calculations, ePRO diary reporting, methods for handling of missing data, and missing at random (MAR) assumptions. See section 6.1.1.

Primary Efficacy Analyses The primary analysis evaluated the efficacy of 2 doses of galcanezumab compared with placebo on the overall mean change from baseline in the number of monthly MHDs during the 3 month double-blind treatment phase. A mixed model repeated measures (MMRM) analysis was applied. The MMRM model include the fixed, categorical effects of treatment, pooled country, month, baseline medication overuse (yes versus no), concurrent prophylaxis (yes versus no), and treatment-by-month interaction, as well as the continuous, fixed covariates of baseline value and baseline value-by-month interaction. The type I error rate for the study was controlled at a 2-sided 0.05 level (equivalently, 1-sided 0.025 level). Table 10 summarizes key CDER Clinical Review Template 79 Version date: September 6, 2017 for all NDAs and BLAs

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and other secondary analyses and analysis methods used in the phase 3 confirmatory studies.

Secondary Efficacy Analyses If secondary endpoints were continuous, repeated measures analyses as described for the primary efficacy analysis were used. For repeated binary endpoints, a categorical, pseudo- likelihood-based repeated measures analysis was implemented using the GLIMMIX procedure in SAS to compare treatments and include the fixed, categorical effects of treatment, month, baseline medication overuse (yes versus no), concurrent prophylaxis (yes versus no), and treatment-by-month interaction, as well as the continuous, fixed covariate of baseline value. For non-repeated binary endpoints, a logistic regression analysis with the main effect of treatment, baseline medication overuse (yes versus no), concurrent prophylaxis use (yes versus no) and pooled country, and appropriate baseline value as a covariate.

Multiplicity Adjustment Please see discussion in section 6.1.1 for similar multiplicity adjustment procedures for chronic migraine study CGAI, which also applied to episodic migraine studies CGAG and CGAH. The procedure for study CGAI was different from (study CGAG and CGAH) in that the order of the final 2 measures (PGI-S and 100% response rate) in the procedures was reversed.

Sample Size Determination Based on the observation of 2 double-blind, placebo-controlled, phase 2 studies, a 15% discontinuation rate and an effect size of 0.30 in the last month of the 3 month treatment phase were assumed. It would need approximately 1140 to provide approximately 95% power that at least 1 dose of galcanezumab would separate from placebo at a one-sided 0.025 significance level based on simulations using Dunnett test.

Protocol Amendments

The protocol for study CGAI was approved on September 23, 2015 and was amended on January 22, 2016 which included clarifying patient selection criteria and additional details regarding statistical control of the familywise type 1 error. There were 5 addenda that were implemented to the protocol to accommodate international regulatory requirements (October 09, 2015 Addendum 1&2; October 10, 2015 Addendum 4; and March 27, 2017 Addendum 7).

6.3.2. Study Results

Table 34: Study CGAI Summary

CGAI 3 month double-blind treatment phase; Chronic Migraine Randomized patients with at least 1 injection: 1113 (GMB + PBO); REGAIN Number of patients who completed double-blind treatment: 1037

Galcanezumab Doses

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 single loading dose of 240 mg (two 120 mg subcutaneous injections) followed by 120 mg/month maintenance dose  240 mg/month fixed dose (two 120 mg subcutaneous injections) CGAI 9 month open-label long-term repeat FLEXIBLE dosing phase ongoing; Chronic Migraine  first open-label visit - initial dose of 240 mg; 9 month OPEN-LABEL long-  At the second open-label visit, all patients received a 120 mg dose of term repeat dosing phase galcanezumab  subsequent visits - FLEXIBLE dosing (either 120 mg or 240 mg/month), at the discretion of the investigator Investigators were allowed flexible dosing to optimize the dose of galcanezumab based on their clinical judgment, without knowing patients’ previous treatment assignment.

Please see discussions for doses selected for the phase 3 studies in section 6.1.2

Compliance with Good Clinical Practices

Lilly provided attestation that the study was conducted in accordance with the CFR governing the protection of human subjects (21 CFR part 50), Institutional Review Boards (21 CFR part 56), and the obligations of clinical investigators (21 CFR 312.50 to 312.70) in accordance with good clinical practice (GCP).

Financial Disclosure

Lilly provided certification that there was no financial agreement with the clinical investigators defined in 21 CFR part 54.2. Financial disclosure and certification information was submitted in module 1.3.4 included in Form FDA 3454 with Certification from applicant for those investigators (Box 1 checked) with no disclosable financial interests or arrangements. Lilly appended a list of clinical investigators to Form FDA 3454.

Patient Disposition

Screen failures A total of 1903 patients entered the study and 1113 patients who received at least 1 dose of IP were included in the ITT population were randomized. The most common reason for screen failure was patients not meeting criteria for study enrollment based on migraine headache information collected in the ePRO diary during the prospective baseline phase.

Table 35: Chronic Migraine Study CGAI Patient Disposition

Patient Disposition Placebo GMB 120 mg GMB 240 mg (N=558) (N=278) (N=277) Completed DB period 508 (91%) 263 (95%) 266 (96%) Discontinued DB period 49 (9%) 15 (5%) 11 (4%) Adverse Event 6 (1%) 3 (1%) 2 (0.7%)

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Lack of Efficacy 4 (0.7%) 0 0 Lost to Follow-up 10 (2%) 4 (1%) 1 (0.4%) Physician Decision 2 (0.4%) 1 (0.4%) 1 (0.4%) Protocol Deviation 6 (1%) 1 (0.4%) 0 Withdrawal by 19 (3%) 4 (1%) 7 (3%) Patient Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (Table CGAI.10.1, CSR for study CGAI) and Module 5.3.5.3 ISE, Table ISE 8.2. Galcanezumab = GMB

Post-Randomization A total of 1113 randomized patients received at least 1 dose of investigational product and were included in the ITT population. 1037 patients (93%) completed the double-blind treatment phase.

In the chronic migraine study up to 1/3rd of patients were permitted in the study with concurrent migraine prophylaxis medication use, and these patients were to be stratified at randomization. However, because of errors with the IWRS data entry (e.g., stating Yes when meant No, and No when meant Yes), incorrect entry of whether the patient was or was not receiving concurrent prophylaxis or incorrect entry of the assigned randomization authorization code, which also reflected presence or absence of baseline medication overuse. The IWRS data entry error impacted patient stratification in 5-6% patients in each treated group. 2-5% patients took concomitant mediations like opioids or barbiturates for beyond the 3 doses or 7 days permitted, or additional concomitant migraine prophylaxis medications permitted that could not be switched during the study (study CGAI CSR Table 10.4 and Table 14.3). Between 4- 7% subjects were dosed outside the specified limits (<21 days or >37 days between injections), although considering the long half-life of galcanezumab it is unlikely to impact the efficacy outcomes. The other protocol deviations identified affected small numbers of patients relative to the study population, or that had minimal impact on study efficacy. 28 patients (placebo: 20; GMB 120 mg: 5; GMB 240 mg: 3) from study CGAI were excluded from the primary efficacy analysis population due to ePRO compliance <=50% and missing post-baseline primary efficacy data. Several sensitivity analyses were conducted removing patients with important protocol deviations as described in section 11.4.1.3.1 of the CSR. The conclusions remained unchanged and indicated no significant change to the overall findings, and the results of these analyses were consistent with the primary efficacy analysis.

Baseline Demographic and Disease Characteristics

There were no significant differences between the treatment groups with respect to their baseline demographic characteristics, Table 36. Overall, the study population was representative of the US migraine population with over 80% white females older than 25, of which at least 40% subjects were >45 years old. Between 3-6% of the subjects included patients of Asian or African American race. The demographic characteristics of sex, age, race,

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and BMI were generally similar across treatment groups with 25% patients classified as obese based on the BMI. 80% of the study participant were from the US and Europe.

The representative sample of chronic migraine population (Table 37) included patients with 20 days of migraine (75% patients experienced up to 21 migraine days and there were 25% chronic migraineurs experiencing more than 22 monthly migraine days. See definitions Table 9). Headache days of any severity were experienced on average 21 days monthly, with 40% patients experiencing >22 days monthly. Chronic migraineurs experienced on average 145 hours of headache compared to 60 hours in episodic migraineurs (Table 16 and Table 25). Study CGAI permitted concomitant preventive migraine medication use of either topiramate or propranolol, and this included 15% subjects at baseline. Overall, treatment groups were balanced with respect to baseline disease characteristics and any treatment group differences were not considered meaningful on the study outcomes.

At baseline, the mean MSQ v2.1 ePRO RR domain scores was 38.7, (Table 37) in comparison to 51.5, 51.7, in the CGAG and CGAH studies (Table 16 and Table 25). The lower scores observed in the chronic migraine trial, as compared to the episodic migraine trials, is suggestive of greater disease burden and lower health status for chronic migraine patients, as per the PRO dossier.

Table 36: Study CGAI Chronic Migraine Demographic Characteristics

Placebo Galcanezumab Monthly GMB 120 mg GMB 240 mg Total Demographic Parameters (N=558) (N=278) (N=277) (N=1113) n (%) n (%) n (%) n (%) Sex Male 75 (13.44) 41 (14.75) 51 (18.41) 167 (15) Female 483 (86.56) 237 (85.25) 226 (81.59) 946 (85) Age Mean years (SD) 41.62 (12.08) 39.66 (11.88) 41.05 (12.4) 40.99 (12.12) Median (years) 42.5 40 42 42 Min, max (years) 17, 66 17, 64 18, 65 17, 66 Age Group < 25 years 56 (10.04) 35 (12.59) 36 (13.00) 127 (11.41) ≥ 25 - < 45 years 257 (46.06) 135 (48.56) 125 (45.13) 517 (46.45) ≥ 45 years 245 (43.91) 108 (38.85) 116 (41.88) 469 (42.14) Race* White 432 (77.42) 223 (80.22) 224 (81.16) 879 (79.05) Black or African American 39 (6.99) 16 (5.76) 17 (6.16) 72 (6.47) Asian 26 (4.66) 13 (4.68) 14 (5.07) 53 (4.77) American Indian or Alaska 4 (0.72) 2 (0.72) 0 (0.00) 6 (0.54) Native

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Native Hawaiian or Other 1 (0.18) 0 (0.00) 0 (0.00) 1 (0.09) Pacific Islander Multiple 56 (10.04) 24 (8.63) 21 (7.61) 101 (9.08) Race group* Caucasian 432 (77.42) 223 (80.22) 224 (81.16) 879 (79.05) Non-Caucasian 126 (22.58) 55 (19.78) 52 (18.84) 233 (20.95) Ethnicity Not Hispanic or Latino 401 (71.86) 195 (70.14) 192 (69.31) 788 (70.80) Hispanic or Latino 122 (21.86) 66 (23.74) 70 (25.27) 258 (23.18) Unknown or Missing 35 (6.27) 17 (6.12) 15 (5.42) 67 (6.02) BMI Category Underweight (<18.5/Kg/m2) 20 (3.58) 14 (5.04) 6 (2.17) 40 (3.59) normal (≥18.5 and 223 (39.96) 104 (37.41) 117 (42.24) 444 (39.89) <25/Kg/m2) Overweight (≥25 and 172 (30.82) 93 (33.45) 83 (29.96) 348 (31.27) <30/Kg/m2) Obese (≥30 and <40/Kg/m2) 143 (25.63) 67 (24.10) 71 (25.63) 281 (25.25) Region North America 321 (57.53) 161 (57.91) 159 (57.40) 641 (57.59) United States and PRI 313 (56.09) 157 (56.47) 156 (56.32) 626 (56.24) Canada 8 (1.43) 4 (1.44) 3 (1.08) 15 (1.35) Europe 140 (25.09) 68 (24.46) 70 (25.27) 278 (24.98) Czech Republic/CZE 25 (4.48) 10 (3.60) 10 (3.61) 45 (4.04) Germany/DEU 28 (5.02) 13 (4.68) 13 (4.69) 54 (4.85) Spain/ESP 24 (4.30) 13 (4.68) 12 (4.33) 49 (4.40) United Kingdom/GBR 15 (2.69) 7 (2.52) 9 (3.25) 31 (2.79) Italy/ITA 27 (4.84) 14 (5.04) 15 (5.42) 56 (5.03) Netherlands/NLD 21 (3.76) 11 (3.96) 11 (3.97) 43 (3.86) Rest of the World 97 (17.38) 49 (17.63) 48 (17.33) 194 (17.43) Middle East (ISR) 20 (3.58) 10 (3.60) 10 (3.61) 40 (3.59) South/Latin America 53 (9.50) 27 (9.71) 26 (9.39) 106 (9.52) (ARG and MEX) Asia (TWN) 24 (4.30) 12 (4.32) 12 (4.33) 48 (4.31) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table 14.6 and 14.7 Study CGAI). Galcanezumab = GMB (b) (6) * race for subject n the GMB 240 mg group is missing

Table 37: Study CGAI Chronic Migraine Baseline Disease Characteristics

Placebo Galcanezumab Monthly GMB 120 mg GMB 240 mg Total Baseline Disease Characteristics (N=558) (N=278) (N=277) (N=1113) n (%) n (%) n (%) n (%) Number of migraine days Mean (SD) 19.55 (4.59) 19.36 (4.27) 19.17 (4.60) 19.41 (4.52) CDER Clinical Review Template 84 Version date: September 6, 2017 for all NDAs and BLAs

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Median (min, max) 19 (8, 29) 19 (9.31, 29) 19 (8.25, 29) 19 (8, 29) <8 days 2 (0.36) 0 (0.00) 0 (0.00) 2 (0.18) 8≤ and ≤ 14 days 60 (10.75) 32 (11.51) 33 (11.91) 125 (11.23) 14< and ≤ 22 days 335 (60.04) 178 (64.03) 174 (62.82) 687 (61.73) >22 days 161 (28.85) 68 (24.46) 70 (25.27) 299 (26.86) Number of headache days Mean (SD) 21.54 (4.10) 21.24 (3.97) 21.44 (4.10) 21.44 (4.06) Median (min, max) 21 (15, 29) 21 (14, 29) 21 (15, 29) 21 (14, 29) 14< and ≤ 22 days 324 (58.06) 173 (62.23) 161 (58.12) 658 (59.12) >22 days 234 (41.94) 105 (37.77) 116 (41.88) 455 (40.88) Number of headache days of at least moderate severity Mean (SD) 16.33 (5.47) 16.13 (5.14) 16.03 (5.47) 16.20 (5.38) Median (min, max) 16 (0, 29) 16 (3, 29) 16 (1, 29) 16 (0, 29) Number of headache hours Mean (SD) 145.05 (95.07) 144.69 (85.35) 145.87 145.17 (92.23) (93.37) Median (min, max) 119.58 (15, 126.70 (15, 123 (24, 124 (15, 664) 664) 582.22) 526.76) Number of migraine headache days acute headache medications/ Abortive Medication Use Mean (SD) 15.51 (6.57) 15.12 (6.25) 14.49 (6.25) 15.16 (6.42) Median (min, max) 16 (0, 29) 15 (0, 29) 15 (0, 29) 15 (0, 29) Number of days of use of Triptan Mean (SD) 9.53 (9.18) 9.60 (8.98) 9.08 (8.76) 9.44 (9.02) Median (min, max) 10 (0, 29) 11.38 (0, 28) 10 (0, 29) 10.34 (0, 29) Number of days of use of NSAID/Aspirin use Mean (SD) 12.24 (8.53) 11.32 (8.47) 10.88 (8.08) 11.67 (8.42) Median (min, max) 14 (0, 29) 13 (0, 29) 12 (0, 28) 13 (0, 29) Concomitant preventive medication use (Yes) (limited to 1/3rd of study 82 (14.70) 37 (13.31) 43 (15.52) 162 (14.56) patients) Topiramate 59 (10.57) 26 (9.35) 30* (10.83) 115 (10.33) Propranolol 23 (4.12) 11 (3.96) 14* (5.05) 48 (4.31) MSQ Role Function Restrictive score Mean (SD) 38.37 (17.18) 39.29 (17.30) 38.93 (17.31) 38.74 (17.23) Median (min, max) 37.14 (0, 40 (0, 91.43) 37.14 (0, 37.14 (0, 94.29) 91.43) 94.29) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table 14.6 and Table 14.7 study CGAI). Galcanezumab = GMB; N/A=No data available **No Concomitant preventive migraine medications permitted in study CGAG and CGAH Episodic migraine population *one patient on the GMB 240 mg group used both Topiramate and Propranolol.

Efficacy Results – Primary Endpoint

Efficacy analysis following the methods specified in the SAP was performed, and the results

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reported by the sponsor in the analyses of the primary endpoint were confirmed. The primary efficacy endpoint analysis is shaded in gray (Table 38). The treatment effect across the multiple post-baseline assessment times (months) are also included in Table 38.

There was statistically significant mean between-group difference favoring both galcanezumab dose groups compared to placebo in the overall mean reduction in the number of monthly migraine headache days with onset of effect as early as month 1 (Table 38, Figure 13). The overall LS mean reduction from baseline in the number of monthly MHDs during the double- blind treatment phase was 4.8 days for galcanezumab 120 mg and 4.6 days for galcanezumab 240 mg compared with 2.8 days for placebo (LS mean change difference from placebo: -2 and - 1.9; p<.001 for each dose group versus placebo). Please note that patients in the galcanezumab 120 mg treatment group received a loading dose of galcanezumab 240 mg at the first injection followed by monthly galcanezumab 120 mg injection, which provides information for efficacy at month 1. Therefore, the initial treatment effect observed at month 1 was based on galcanezumab 240 mg dose (Figure 13).

The higher monthly maintenance dose of galcanezumab 240 mg did not seem to provide better efficacy than the group with initial dose of galcanezumab 240 mg followed by lower monthly galcanezumab 120 mg SC injections during the monthly intervals. In addition, there appeared to be a slight loss of efficacy after month 1 numerically for the galcanezumab 240 mg group as compared to the lower monthly galcanezumab 120 mg dose group (see Figure 13 below); that is maintained and showing reductions in endpoint variables through month 3. There was no nominal statistically significant difference between the doses studied. The numerical trends in the differences in the results are suggestive that lower monthly galcanezumab 120 mg after the first galcanezumab 240 mg loading dose might provide continued benefit to maintain the efficacy as shown in Figure 13.

Table 38: Study CGAI Chronic Migraine Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 6 month Treatment Period - MMRM

Chronic Migraine Study CGAI Statistic Galcanezumab Placebo (N=538) GMB 120 mg (N=273) GMB 240 mg (N=274) Overall LS mean (SE) -2.74 (0.36) -4.83 (0.44) -4.62 (0.43) 95% CI (-3.45, -2.03) (-5.69, -3.97) (-5.47, -3.76) Comparison with Placebo LS mean (SE) -2.09 (0.42) -1.88 (0.42) 95% CI (-2.92, -1.26) (-2.71, -1.05) p-value <.001 <.001 Month 1 LS mean (SE) -1.78 (0.36) -4.06 (0.44) -4.22 (0.43)

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95% CI (-2.49, -1.07) (-4.92, -3.20) (-5.07, -3.37) Comparison with Placebo LS mean (SE) -2.28 (0.42) -2.44 (0.42) 95% CI (-3.10, -1.45) (-3.27, -1.61) p-value <.001 <.001 Month 2 LS mean (SE) -3.04 (0.38) -5.01 (0.47) -4.51 (0.47) 95% CI (-3.79, -2.29) (-5.93, -4.09) (-5.42, -3.59) Comparison with Placebo LS mean (SE) -1.97 (0.47) -1.47 (0.47) 95% CI (-2.90, -1.04) (-2.39, -0.54) p-value <.001 .002 Month 3 LS mean (SE) -3.39 (0.40) -5.41 (0.50) -5.12 (0.50) 95% CI (-4.18, -2.59) (-6.40, -4.42) (-6.10, -4.14) Comparison with Placebo LS mean (SE) -2.03 (0.52) -1.73 (0.52) 95% CI (-3.05, -1.00) (-2.76, -0.71) p-value <.001 <.001 Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAI 11.3). Galcanezumab = GMB **Up to 1/3rd patients permitted to use concomitant preventive migraine medications in study CGAI chronic migraine population The primary endpoint was the average change from baseline in the number of MHDs over the entire double-blind treatment period, denoted as overall mean change. This endpoint is the treatment main effect from the primary MMRM model, averaged across the multiple post-baseline assessment times (months).

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Figure 13: Study CGAI Chronic Migraine Change from Baseline in the Monthly Average Number of Migraine Headache Days during the 3 month Treatment Period - MMRM

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Figure CGAI 11.1). Galcanezumab = GMB

Post Hoc Empirical Distribution Analysis of Primary Endpoint (Figure 14) Distribution of the average change from baseline in migraine headache days (MHDs) The sponsor’s Figure 14 plotted post hoc as histogram by dose (placebo, 120 and 240 mg) based on the distribution of the average change from baseline in migraine headache days (MHDs). Both galcanezumab 120 mg and 240 mg dosing regimens appear to have greater reduction in the monthly number of migraine days as indicated by a slight shift to the left in the active treatment groups as compared to placebo group and in particular in those patients who experienced at least 6 day reduction, which indicates more improvement with the active treatment than with placebo.

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Figure 14: Study CGAI Histogram Mean Change from Baseline in Migraine Headache Days

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0013. Module 1.11.3, Figure 2.3. LY = Galcanezumab For calculation of "Average Change from Baseline in Number of Migraine Headache Days over Months 1 to 3", it is the average of non-missing change value among 3 months.

Efficacy Results – Key Secondary endpoints

Efficacy analysis following the methods specified in the SAP was performed, and the results reported by the sponsor in the analyses of the secondary endpoints were confirmed. The key secondary endpoints shown in Table 39 were pre-specified and adjusted for multiplicity.

 For galcanezumab 240 mg dose group, all key secondary objectives of the study were met after multiplicity adjustment except for 100% response rate, although the response was not much improved compared to the placebo response.

 For galcanezumab 120 mg dose group, only the key secondary objective of ≥50% response rate remained statistically significant after multiplicity adjustment albeit with similar response observed in the 240 mg dose. Chronic migraine may be more difficult condition considering the response rates for the various thresholds in comparison to the episodic migraine studies (Figure 8 and Figure 11), or that 75% patients enrolled had fewer than 21 migraine days at baseline including 10% patients meeting EM criteria further indicating a less burdened population enrolled in study CGAI. In addition, it is CDER Clinical Review Template 89 Version date: September 6, 2017 for all NDAs and BLAs

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not known whether the modified definition of >30 minute migraine duration used to define the migraines versus using longer duration of headaches or the recommended duration in the guidelines for controlled trials of prophylactic treatment of chronic migraine in adults may have provided further predictive enrichment of the study population 13.

 Per the prespecified multiple testing procedure, because the p-value observed for the comparison of 75% response rate for the 120 mg dose versus placebo (p=.031) was higher than the multiplicity-adjusted alpha level (0.025), and because no alpha could be recycled from galcanezumab 240 mg to 120 mg as the result for galcanezumab 240 mg 100% response rate was nonsignificant, all further multiple testing for the 120 mg dose was stopped. Thus, all remaining items in the 120 mg testing sequence (MHD with acute medication use, MSQ Role Function-Restrictive, PGI-S, and 100% response rate) are considered not statistically significant after multiplicity adjustment regardless of p- value.

Compared to the baseline use of acute medications there was nominally significant and clinically meaningful reduction in both the galcanezumab 120 mg and 240 mg treatment groups compared with placebo of at least 2 days for both galcanezumab doses. Similar to the observations based on the primary efficacy analysis , for the key secondary efficacy variables the higher maintenance dose of galcanezumab 240 mg did not seem to provide better efficacy than the initial dose of galcanezumab 240 mg followed by lower monthly galcanezumab 120 mg SC injections during the monthly intervals.

Table 39: Study CGAI Key Secondary Efficacy Analyses

Chronic Migraine Study CGAI (Months 1 to 3) Statistic Galcanezumab Placebo (N=538) GMB 120 mg (N=273) GMB 240 mg (N=274) Reduction of at least 50% in monthly average number of migraine days % responder, SE 15.4 (1.6) 27.6 (2.7) 27.5 (2.6) p-value <.001 <.001 Reduction of at least 75% in monthly average number of migraine days % responder, SE 4.5 (0.9) 7.0 (1.4) 8.8 (1.7) p-value .031 (NS @ >0.025) <.001 Percentage of ≥100% Responders reduction from baseline for Migraine Headache Days % responder, SE 0.5 (0.3) 0.7 (0.4) 1.3 (0.6) p-value .597 (Not tested)$$ .058 mean change from baseline in monthly migraine headache days using acute medication Placebo (N=538) GMB 120 mg (N=273) GMB 240 mg (N=274) LS mean (SE) -2.23 (0.33) -4.74 (0.40) -4.25 (0.40) Comparison with Placebo

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LS mean (SE) -2.51 (0.38) -2.01 (0.38) 95% CI (-3.27, -1.76) (-2.77, -1.26) p-value <.001 (Not tested)$$ <.001 Change from Baseline in MSQ Role Function-Restrictive Domain (at month 3) Placebo (N=494) GMB 120 mg (N=252) GMB 240 mg (N=253) LS mean (SE) 16.76 (1.18) 21.81 (1.41) 23.05 (1.63) Comparison with Placebo LS mean (SE) 5.06 (1.50) 6.29 (1.66) 95% CI (2.12, 7.99) (3.03, 9.55) p-value <.001 (Not tested)$$ <.001 Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAI 11.4, 11.7, ISE Table 8.5). Galcanezumab = GMB *Responders are defined as patients whose change from baseline to month 3 in MSQ role function restrictive >=17.14 on the transformed 100-point scale. The value of 17.14 corresponds to a change of 6 points on the raw scale. $$ = Because of the nonsignificant result observed for the 75% response rate for the 120 mg dose in Study CGAI and because no alpha can be recycled from galcanezumab 240 mg to 120 mg since the result for galcanezumab 240 mg 100% response rate was nonsignificant, all remaining items in the testing sequence (migraine headache days with acute medication use, MSQ-Role Function-Restrictive, PGI-S, and 100% response rate) for the 120 mg dose for Study CGAI are considered not statistically significant regardless of nominal p-value

Efficacy Results –other relevant endpoints

Additional variables were considered that were not pre-specified with a priori statistical methods applied to control for multiplicity. The nominal p-values were <0.001 for these endpoint in Table 40, except for the 15% of chronic migraineurs in the study allowed concomitant migraine preventive medication use. There was nominal reduction by 1 day in the mean migraine days compared to the placebo treated patients using migraine prophylactic medications, irrespective of being on topiramate or propranolol, however, these results should be interpreted in the context that the results are from post hoc analysis without adjusting for multiplicity and when the study was not designed to show an effect on concomitant migraine prophylactic medication use with galcanezumab. Similar results were observed regardless of the chronic migraine patient’s baseline status for medication overuse (data not shown), and galcanezumab showed nominal reduction by 1-2 days in the mean migraine days compared to the placebo treated patients.

The mean change from baseline in the monthly average number of headache days of any severity, and for at least moderate severity during the 12 week study period showed similar reductions in both dose groups from placebo in favor of galcanezumab, and there appeared to be at least a 20-25% reduction in the mean numbers of headache hours in the galcanezumab treated population.

Table 40: Study CGAI Additional Secondary Efficacy Analyses

Statistic Chronic Migraine Study CGAI

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Galcanezumab Placebo (N=538) GMB 120 mg (N=273) GMB 240 mg (N=274) Change from Baseline in Number of Monthly Headache Days LS mean (SE) -3.01 (0.35) -4.84 (0.43) -4.61 (0.43) Comparison with Placebo LS mean (SE) -1.84 (0.42) -1.60 (0.42) Change from Baseline in Number of Monthly Headache Days of at least Moderate Severity LS mean (SE) -2.92 (0.33) -4.90 (0.40) -4.64 (0.39) Comparison with Placebo LS mean (SE) -1.98 (0.38) -1.72 (0.38) Change from Baseline in Number of Monthly Headache Hours LS mean (SE) -13.44 (3.91) -36.15 (4.74) -31.53 (4.70) Comparison with Placebo LS mean (SE) -22.71 (4.60) -18.09 (4.58) Change from Baseline in Migraine Days with Concomitant Preventive Medication Use Placebo (N=80) GMB 120 mg (N=37) GMB 240 mg (N=41) LS mean (SE) -1.41 (0.99) -2.27 (1.10) -2.58 (1.11) Comparison with Placebo LS mean (SE) -0.86 (1.07) -1.18 (1.00) Change from Baseline in Migraine Days with NO Concomitant Preventive Medication Use Placebo (N=485) GMB 120 mg (N=236) GMB 240 mg (N=233) LS mean (SE) -3.34 (0.35) -5.66 (0.43) -5.42 (0.44) Comparison with Placebo LS mean (SE) -2.32 (0.46) -2.08 (0.46) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Modified format. Module 5.3.5.1 (CSR Table CGAI 11.5, Table CGAI 14.78). Galcanezumab = GMB Estimates were obtained using unstructured covariance structure. MMRM model. Galcanezumab = GMB This analysis model includes an additional fixed effect: grouped baseline monthly migraine headache days compared with the primary efficacy analysis model.

Post hoc analysis distribution of specified percentage levels of reduction for the average change from baseline in migraine headache days (MHDs) (Figure 15) The sponsors post hoc analysis of the responder rates for the percent reduction from baseline in the monthly average number of migraine days is shown in Figure 15 for the distribution analysis presented as a histogram by dose (placebo, 120 and 240 mg) based on the average change from baseline in migraine headache days (MHDs) displayed as “bins” of either 0 ≤ 25% reduction of migraine days/month from baseline, >25 - ≤ 50%, >50% - ≤ 75% and >75- 100% reduction. The y-axis represents the mean percentages of patients within each category for each treatment arm. Please see earlier discussion regarding responders.

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Figure 15: Study CGAI Histogram Percent Change from Baseline in Migraine Headache Days

Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0013. Module 1.11.3, Figure 2.6. LY = Galcanezumab Example, Mean percentages of patients with ≥0% to <25% is equal to values from "≥0% decrease" minus values from "≥25% decrease".

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Sensitivity Analysis Several sensitivity analyses were conducted as described in section 11.4.1.3.1 of the CSR, and the results of these analyses were consistent with the primary efficacy analysis.

Additional Analyses Conducted

The overall mean difference from placebo was reduction of about 2 migraine days in both the galcanezumab treated groups based on an average of 20 migraine days at baseline (Table 38). 70-75% subjects experienced <22 migraine days at baseline. A sub analyses showed that there were nominally greater reductions in the chronic migraine patients of 5 days reduction regardless of the galcanezumab dose and for the number of migraine days that the patients experienced at baseline, compared to 3 days in the placebo group (Table 41, Figure 14).

Table 41: Study CGAI Mean Change from Baseline in Monthly Migraine Headache Days

Chronic Migraine Study CGAI Statistic Galcanezumab Placebo GMB 120 mg GMB 240 mg ≤22 days >22-28 days ≤22 days >22-28 days ≤22 days >22-28 days (N=395) (N=161) (N=210) (N=68) (N=207) (N=70) LS mean (SE) -2.68 (0.43) -3.43 (0.68) -4.79 (0.50) -5.14 (0.87) -4.50 (0.51) -5.53 (0.86) 95% CI (-3.53, -1.83) (-4.77, -2.08)) (-5.77, -3.80) (-6.85, -3.43) (-5.49, -3.50) (-7.23, -3.84)) Comparison with Placebo LS mean (SE) -2.11 (0.49) -1.71 (0.84) -1.82 (0.49) -2.11 (0.82) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB

7. Integrated Review of Effectiveness

7.1. Assessment of Efficacy Across Trials

7.1.1. Primary Endpoints

Table 42 provides an overview of the primary efficacy endpoints measured in the two phase 3 episodic migraine studies (CGAG and CGAH), and results from the chronic migraine study (CGAI) shown (in bold) for each of the studies. Additionally information for the pre-specified key secondary endpoints is included.

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approved products for migraine prophylaxis, and the endpoint is well-established for migraine prophylaxis (section 2.2 and Table 4).

7.1.2. Secondary and Other Endpoints

Lilly is seeking labeling claims based on the protocol specified key secondary endpoints (Table 42) that were controlled for type -1 error, and the endpoints are discussed in section 6.1.2 (CGAG), 6.2.2 (CGAH), and 6.3.2 (CGAI). The episodic migraineurs (study CGAG and CGAH) and chronic migraineurs (study CGAI) used acute medications on fewer days for their migraine, and these results were statistically significant and clinically meaningful in both dose groups compared to placebo treatment. The distribution of specified percentage levels of reduction for the primary endpoint is shown in Figure 8, Figure 11, and Figure 15. One third to half of the responders with episodic migraine in both galcanezumab treated groups experienced a 75% response to reduction in migraine headache days, and 12-15% patients had complete response in study CGAG and CGAH compared to the placebo group. The response rates for the thresholds were much lower in the chronic migraineurs (Figure 13, Figure 14). In addition, both galcanezumab doses (120 mg or 240 mg) showed numerically improved efficacy over placebo regardless of concomitant medications use status in the chronic migraine study CGAI (Table 40). There was also a reduction from baseline in number of monthly headache hours compared to placebo in studies CGAG, CGAH, CGAI.

7.1.3. Subpopulations

Studies CGAG, GGAH and CGAI were not designed to compare efficacy between these subgroups discussed below; this is particularly important for subgroup analyses based on study CGAI, which had a higher underlying variability and a smaller sample size relative to the combined samples from Studies CGAG and GGAH in episodic migraineurs. Overall, the subgroup analyses suggest there were larger differences in magnitude of effect between galcanezumab and placebo in some subgroups, and there appeared to be consistent directional differences of effect for galcanezumab compared with placebo. Even though with the slight differences in response rates in some subgroups there were no differences in the efficacy analysis between the various subgroups analyzed that were considered persuasive for labeling.

Age There were mean reductions of migraine days in the different age groups in either galcanezumab treated group when compared to placebo among episodic migraineurs with <14 monthly migraine headache days or in chronic migraineurs (Table 43, Table 44). These results should be interpreted in the context that the results are from post hoc analysis without adjusting for multiplicity.

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Table 43: Study CGAG and CGAH Subgroup Analysis - Age (Pooled ITT; MMRM)

Episodic Migraine Pooled Subgroup Analysis Age Group Placebo (N=875) GMB 120 mg (N=436) GMB 240 mg (N=428) < 25 years Overall n (%) 59 (6.74) 39 (8.94) 39 (9.11) LS mean (SE) -3.49 (0.49) -4.66 (0.62) -4.41 (0.59) 95% CI (-4.47, -2.52) (-5.89, -3.43) (-5.59, -3.24) Comparison with Placebo LS mean (SE) -1.17 (0.68) -0.92 (0.69) 95% CI (-2.51, 0.17) (-2.28, 0.44) ≥ 25 - < 45 years Overall n (%) 440 (50.29) 214 (49.08) 222 (51.87) LS mean (SE) -2.43 (0.22) -4.28 (0.27) -4.20 (0.27) 95% CI (-2.85, -2.00) (-4.80, -3.76) (-4.73, -3.67) Comparison with Placebo LS mean (SE) -1.85 (0.28) -1.77 (0.28) 95% CI (-2.40, -1.31) (-2.31, -1.23) ≥ 45 years Overall n (%) 376 (42.97) 183 (41.97) 167 (39.02) LS mean (SE) -2.60 (0.24) -4.86 (0.30) -4.74 (0.31) 95% CI (-3.07, -2.13) (-5.46, -4.26) (-5.35, -4.13) Comparison with Placebo LS mean (SE) -2.26 (0.31) -2.14 (0.32) 95% CI (-2.87, -1.66) (-2.77, -1.52) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB

Table 44: Study CGAI Subgroup Analysis - Age (ITT; MMRM)

Chronic Migraine Subgroup Analysis Age Group Placebo (N=538) GMB 120 mg (N=273) GMB 240 mg (N=274) < 25 years Overall n (%) 50 (9.29) 32 (11.72) 36 (13.14) LS mean (SE) -2.29 (1.62) -2.88 (1.93) -3.15 (1.65) 95% CI (-5.51, 0.93) (-6.70, 0.94) (-6.42, 0.12) Comparison with Placebo LS mean (SE) -0.59 (1.49) -0.87 (1.38) 95% CI (-3.55, 2.36) (-3.61, 1.88) ≥ 25 - < 45 years Overall n (%) 247 (45.91) 133 (48.72) 123 (44.89) LS mean (SE) -3.52 (0.58) -5.50 (0.66) -5.47 (0.67) 95% CI (-4.66, -2.38) (-6.80, -4.19) (-6.79, -4.14) Comparison with Placebo

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Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

LS mean (SE) -1.98 (0.62) -1.94 (0.63) 95% CI (-3.19, -0.77) (-3.18, -0.70) ≥ 45 - < 65 years Overall n (%) 241 (44.80) 108 (39.56) 115 (41.97) LS mean (SE) -2.15 (0.51) -4.56 (0.65) -4.08 (0.64) 95% CI (-3.15, -1.15) (-5.83, -3.29) (-5.34, -2.83) Comparison with Placebo LS mean (SE) -2.41 (0.65) -1.93 (0.64) 95% CI (-3.69, -1.12) (-3.19, -0.67) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB

Race There were mean reductions of migraine days in either galcanezumab treat group when compared to placebo among white and non-white episodic migraineurs (Table 45, Table 46). The sample sizes of the African American and Asian subgroups included in the episodic and chronic migraine populations were too small to infer any clinically meaningful differences in the specific subpopulations (data not shown).

Table 45: Study CGAG and CGAH Subgroup Analysis - Race (Pooled ITT; MMRM)

Episodic Migraine Pooled Subgroup Analysis Race Placebo (N=875) GMB 120 mg (N=436) GMB 240 mg (N=428) White Overall n (%) 667 (76.23) 328 (75.23) 313 (73.13) LS mean (SE) -2.42 (0.18) -4.43 (0.22) -4.42 (0.22) 95% CI (-2.77, -2.08) (-4.86, -4.00) (-4.86, -3.98) Comparison with Placebo LS mean (SE) -2.01 (0.22) -2.00 (0.23) 95% CI (-2.45, -1.57) (-2.44, -1.56) Non-White Overall n (%) 208 (13.77) 108 (24.77) 115 (26.87) LS mean (SE) -3.06 (0.40) -4.87 (0.47) -4.25 (0.47) 95% CI (-3.85, -2.26) (-5.79, -3.95) (-5.18, -3.33) Comparison with Placebo LS mean (SE) -1.82 (0.41) -1.20 (0.41) 95% CI (-2.62, -1.01) (-1.99, -0.40) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB

Table 46: Study CGAI Subgroup Analysis - Race (ITT; MMRM)

Chronic Migraine Subgroup Analysis Race Placebo (N=538) GMB 120 mg (N=273) GMB 240 mg (N=274)

CDER Clinical Review Template 98 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

White Overall n (%) 418 (77.70) 218 (79.85) 222 (81.32) LS mean (SE) -2.47 (0.43) -4.91 (0.51) -4.31 (0.50) 95% CI (-3.32, -1.63) (-5.90, -3.91) (-5.30, -3.33) Comparison with Placebo LS mean (SE) -2.44 (0.47) -1.84 (0.47) 95% CI (-3.36, -1.51) (-2.75, -0.92) Non-White Overall n (%) 120 (22.30) 55 (21.15) 52 (18.68) LS mean (SE) -4.16 (0.92) -5.08 (1.04) -6.44 (1.09) 95% CI (-5.97, -2.35) (-7.13, -3.02) (-8.58, -4.30) Comparison with Placebo LS mean (SE) -0.92 (0.93) -2.28 (0.95) 95% CI (-2.75, 0.92) (-4.14, -0.41) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB

Sex/Gender The mean reductions of migraine days in either galcanezumab treated group was about 1-2 days when compared to placebo in males and females without any notable differences, Table 47, Table 48.

Table 47: Study CGAG and CGAH Subgroup Analysis - Gender (Pooled ITT; MMRM)

Episodic Migraine Pooled Subgroup Analysis Gender Placebo (N=875) GMB 120 mg (N=436) GMB 240 mg (N=428) Female Overall n (%) 739 (84.46) 370 (84.86) 361 (84.35) LS mean (SE) -2.55 (0.17) -4.65 (0.21) -4.42 (0.21) 95% CI (-2.87, -2.22) (-5.05, -4.24) (-4.84, -4.01) Comparison with Placebo LS mean (SE) -2.10 (0.21) -1.88 (0.21) 95% CI (-2.52, -1.68) (-2.29, -1.46) Male Overall n (%) 136 (15.54) 66 (15.14) 67 (15.65) LS mean (SE) -2.76 (0.49) -3.79 (0.58) -4.26 (0.56) 95% CI (-3.73, -1.80) (-4.93, -2.64) (-5.35, -3.16) Comparison with Placebo LS mean (SE) -1.03 (0.52) -1.49 (0.52) 95% CI (-2.05, -0.00) (-2.51, -0.47) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0008. Module 5.3.5.3.Table ISE.APP.15.8 Galcanezumab = GMB

CDER Clinical Review Template 99 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

Table 48: Study CGAI Subgroup Analysis - Gender (ITT; MMRM)

Chronic Migraine Subgroup Analysis Gender Placebo (N=538) GMB 120 mg (N=273) GMB 240 mg (N=274) Female Overall n (%) 466 (86.62) 233 (85.35) 223 (81.39) LS mean (SE) -2.78 (0.39) -4.82 (0.46) -4.59 (0.47) 95% CI -3.54, -2.02 (-5.73, -3.91) (-5.51, -3.68) Comparison with Placebo LS mean (SE) -2.04 (0.45) -1.81 (0.46) 95% CI (-2.93, -1.15) (-2.72, -0.91) Male Overall n (%) 72 (13.38) 40 (14.65) 51 (18.61) LS mean (SE) -2.78 (1.07) -5.12 (1.35) -5.14 (1.24) 95% CI -4.89, -0.67 (-7.78, -2.46) (-7.60, -2.68) Comparison with Placebo LS mean (SE) -2.34 (1.21) -2.36 (1.12) 95% CI (-4.73, 0.05) (-4.57, -0.15) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0008. Module 5.3.5.3. CSR Table CGAI 14.71 Galcanezumab = GMB

BMI Category In the episodic migraineur populations the efficacy was consistent in magnitude and direction for the BMI categories similar to the primary efficacy analysis (Table 49). Among the chronic migraineurs administered galcanezumab 240 mg in the obese BMI category (25% patients at baseline), there was about 3 days reduction in the mean migraine days compared to the 1-2 days seen in general (Table 50).

Table 49: Study CGAG and CGAH Subgroup Analysis - BMI (Pooled ITT; MMRM)

Episodic Migraine Pooled Subgroup Analysis BMI Category Placebo (N*=875) GMB 120 mg (N*=436) GMB 240 mg (N*=428) normal (≥18.5 and <25/Kg/m2) Overall n (%) 291 (33.26) 154 (35.32) 153 (35.75) LS mean (SE) -1.83 (0.27) -4.41 (0.33) -4.07 (0.33) 95% CI (-2.36, -1.29) (-5.06, -3.77) (-4.72, -3.43) Comparison with Placebo LS mean (SE) -2.59 (0.34) -2.25 (0.34) 95% CI (-3.25, -1.92) (-2.91, -1.58) Overweight (≥25 and <30/Kg/m2) Overall n (%) 270 (30.86) 152 (34.86) 124 (28.97) LS mean (SE) -2.67 (0.24) -4.53 (0.31) -4.55 (0.31) 95% CI (-3.15, -2.19) (-5.14, -3.93) (-5.17, -3.94) Comparison with Placebo CDER Clinical Review Template 100 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

LS mean (SE) -1.86 (0.33) -1.88 (0.34) 95% CI (-2.52, -1.21) (-2.55, -1.22) Obese (≥30 and <40/Kg/m2) Overall n (%) 294 (33.60) 125 (28.67) 144 (33.64) LS mean (SE) -3.24 (0.28) -4.55 (0.30) -4.56 (0.35) 95% CI (-3.78, -2.69) (-5.15, -3.95) (-5.24, -3.88) Comparison with Placebo LS mean (SE) -1.31 (0.32) -1.33 (0.35) 95% CI (-1.95, -0.68) (-2.01, -0.64) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB *subjects with BMI < 18.5 were not included in the analyses; total number of ITT population per treatment group is the denominator.

Table 50: Study CGAI Subgroup Analysis - BMI (ITT; MMRM)

Chronic Migraine Subgroup Analysis BMI Category Placebo (N*=538) GMB 120 mg (N*=273) GMB 240 mg (N*=274) normal (≥18.5 and <25/Kg/m2) Overall n (%) 216 (40.15) 103 (37.73) 117 (42.70) LS mean (SE) -2.44 (0.57) -4.48 (0.68) -4.53 (0.68) 95% CI (-3.56, -1.33) (-5.82, -3.14) (-5.86, -3.20) Comparison with Placebo LS mean (SE) -2.04 (0.68) -2.09 (0.65) 95% CI (-3.37, -0.70) (-3.36, -0.81) Overweight (≥25 and <30/Kg/m2) Overall n (%) 166 (30.86) 90 (32.97) 82 (29.93) LS mean (SE) -2.95 (0.67) -4.97 (0.77) -4.21 (0.80) 95% CI (-4.28, -1.63) (-6.49, -3.45) (-5.79, -2.63) Comparison with Placebo LS mean (SE) -2.02 (0.77) -1.26 (0.79) 95% CI (-3.53, -0.50) (-2.81, 0.30) Obese (≥30 and <40/Kg/m2) Overall n (%) 137 (25.46) 66 (24.18) 69 (25.18) LS mean (SE) -3.69 (1.01) -5.66 (1.18) -6.54 (1.11) 95% CI (-5.67, -1.71) (-7.98, -3.34) (-8.71, -4.36) Comparison with Placebo LS mean (SE) -1.97 (0.88) -2.85 (0.87) 95% CI (-3.70, -0.24) (-4.56, -1.13) Source: BLA 761063 \\cdsesub1\evsprod\BLA761063\0001. Module 5.3.5.1. Galcanezumab = GMB * subjects with BMI < 18.5 were not included in the analyses; total number of ITT population per treatment group is the denominator.

CDER Clinical Review Template 101 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

7.1.4. Dose and Dose-Response

Please see justification for dose selection for phase 3 Studies CGAG, CGAH and CGAI in 6.1.2 section of the review. While two monthly dosing options were considered, patients in the galcanezumab 120 mg treatment group received a loading dose of galcanezumab 240 mg at the first injection followed by monthly galcanezumab 120 mg injection, which provided information for efficacy at month 1. Therefore, any initial treatment effect observed at month 1 was based on galcanezumab 240 mg dose.

In episodic migraine study CGAG and CGAH, the higher maintenance dose of galcanezumab 240 mg did not seem to provide better efficacy than the initial dose of galcanezumab 240 mg followed by lower monthly galcanezumab 120 mg SC injections during the monthly intervals.

In chronic migraine study CGAI, the higher maintenance dose of galcanezumab 240 mg did not appear to provide better efficacy than the initial dose of galcanezumab 240 mg followed by lower monthly galcanezumab 120 mg SC injections during the monthly intervals. In addition, there appeared to be a slight loss of efficacy after month 1 numerically for the galcanezumab 240 mg group as compared to the lower monthly galcanezumab 120 mg dose group (see Figure 13); that is maintained and showing reductions in endpoint variables through month 3. There was no nominal statistically significant difference between the doses studied. The results are suggestive that lower monthly galcanezumab 120 mg after the first galcanezumab 240 mg loading dose might provide continued benefit to maintain the efficacy as shown in Figure 13.

7.1.5. Onset, Duration, and Durability of Efficacy Effects

In general, consistent with the primary efficacy data, the onset of efficacy appeared as early as month 1 for the primary efficacy variables including the secondary measures and with no reportable differences between the dosing regimens through the treatment period in the episodic migraine population. As discussed in section 7.1.4, there was slight loss of efficacy with repeated monthly galcanezumab 240 mg dose in the chronic migraine study population. The overall results were fairly consistent showing persistence of treatment effect over 6 months in the episodic migraine population and during 3 months in the chronic migraineurs across multiple endpoints with statistically convincing evidence of clinically meaningful treatment effect.

7.2. Additional Efficacy Considerations

Please see discussion in section 7.3

CDER Clinical Review Template 102 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

7.3. Integrated Assessment of Effectiveness

Lilly’s application included clinical studies in episodic migraine population (study CGAG and CGAH) and chronic migraineurs (study CGAI) for evaluation of efficacy from adequately designed and well-controlled studies of sufficient study duration, that were based on prior discussions including agreements with the FDA for assessing clinical meaningfulness using clinically relevant endpoints meeting regulatory standards (section 3.2). Table 9 and Table 31 provides an overview of the key study design characteristics including the similar endpoint definitions and primary efficacy variables for the 2 episodic migraine studies CGAG and CGAH, and for chronic migraine study CGAI highlighting any similarities and differences. Lilly modified the original ICHD-3 criteria for migraines from a reduction in required minimum duration from 4 hours untreated to 30 minutes (Table 9) after discussions with the Division and the phase 3 clinical studies were capable of demonstrating efficacy.

There were highly statistically significant primary and secondary efficacy outcomes after correction for multiplicity across multiple headache symptom measures with independently substantive results across study subsets in the episodic migraine population (study CGAG and CGAH) and the chronic migraine population (study CGAI) with results favoring galcanezumab treatment group across clinically relevant endpoints.

The treatment effects observed with galcanezumab is similar to available prophylactic therapies (Table 4). Galcanezumab treatment demonstrated onset of efficacy during the 1st month after the initial subcutaneous injection and with a reduction in use of acute medications for the chronic intermittent migraine attacks, along with reductions in the migraines and the hours of overall moderate to severe headaches experienced; all measures with clinically meaningful impact. While there is no clear demonstration of dose response, there is some evidence based on the efficacy outcomes suggesting that the galcanezumab 120 mg monthly interval dosing injections may provide maintenance of efficacy in the chronic migraine population. The (b) (4) and the information reviewed in BLA 761063 aligns with Lilly’s determination. In addition, Lilly’s intention to select similar dosing regimen in the episodic migraine and chronic migraine populations provides for consistent dosing with monthly galcanezumab 120 mg dose after a loading dose of galcanezumab 240 mg because there is possibility to revert to less frequent symptoms with better managed migraines as migraine evolves from episodic migraine to chronic migraine or when there is transition to episodic migraine showing improvement.

While the reviews from the disciplines of Clinical Pharmacology, Office of Scientific Investigations, and the Clinical Outcomes Assessments are pending, based on the available information reviewed for the determination of efficacy in BLA 761063, Lilly’s application appears to provide substantial evidence supporting galcanezumab for migraine prophylaxis indication based on clinically significant endpoints.

CDER Clinical Review Template 103 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

The efficacy data submitted in BLA 761063 provides for a reasonable assessment of benefit supporting effectiveness for the proposed indication, prophylaxis of migraine, with reference to 21 CFR 601.25 (d)(2) and 21 CFR 314.126.

8. Review of Safety

Please refer to the clinical safety review of Dr. Lourdes Villalba, MD for BLA 761063, Galcanezumab.

9. Advisory Committee Meeting and Other External Consultations

Not applicable.

10. Labeling Recommendations

10.1. Prescription Drug Labeling

Please see edits proposed for labeling in separate labeling review.

11. Risk Evaluation and Mitigation Strategies (REMS)

At the time of this review completion, no REMS have been determined for BLA 761063.

12. Postmarketing Requirements and Commitments

A pregnancy registry and pediatric PMRs are being considered for BLA 761063.

13. Appendices

13.1. References

CDER Clinical Review Template 104 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 BLA 761063 Statistical & Clinical Efficacy Review Junshan Qiu, Ph.D. Suhail Kasim, M.D., M.P.H. Emgality (galcanezumab) Injection

13.2. Financial Disclosure

Covered Clinical Studies: I5Q-MC-CGAG, I5Q-MC-CGAH, I5Q-MC-CGAI

Was a list of clinical investigators provided: Yes No (Request list from Applicant) Total number of investigators identified: CGAG=92; CGAH=119; CGAI=121 Number of investigators who are sponsor employees (including both full-time and part-time employees): None identifed

Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): Form FDA 3454 attached with Certification from applicant for those investigators (Box 1 checked) with no disclosable financial interests or arrangements If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: Significant payments of other sorts: Proprietary interest in the product tested held by investigator: Significant equity interest held by investigator in S Sponsor of covered study: Is an attachment provided with details Yes No (Request details from of the disclosable financial Applicant) interests/arrangements: Is a description of the steps taken to Yes No (Request information minimize potential bias provided: from Applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3) None Is an attachment provided with the Yes No (Request explanation reason: from Applicant)

CDER Clinical Review Template 105 Version date: September 6, 2017 for all NDAs and BLAs

Reference ID: 4241559 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------

SUHAIL KASIM 03/29/2018 BLA 761063 Emgality (galcanezumab) LILLY Combined STAS-Clinical Efficacy review

JUNSHAN QIU 03/30/2018

KUN JIN 03/30/2018 I concur with the statistical review.

HSIEN MING J HUNG 03/30/2018

HEATHER D FITTER 06/13/2018

Reference ID: 4241559