Fremanezumab for the Preventive Treatment of Migraine

Expert Opinion on Biological Therapy

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Fremanezumab for the preventive treatment of migraine

Stephen D. Silberstein, Joshua M. Cohen & Paul P. Yeung

To cite this article: Stephen D. Silberstein, Joshua M. Cohen & Paul P. Yeung (2019) Fremanezumab for the preventive treatment of migraine, Expert Opinion on Biological Therapy, 19:8, 763-771, DOI: 10.1080/14712598.2019.1627323 To link to this article: https://doi.org/10.1080/14712598.2019.1627323

Accepted author version posted online: 10 Jun 2019. Published online: 01 Jul 2019.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iebt20 EXPERT OPINION ON BIOLOGICAL THERAPY 2019, VOL. 19, NO. 8, 763–771 https://doi.org/10.1080/14712598.2019.1627323

DRUG EVALUATION Fremanezumab for the preventive treatment of migraine Stephen D. Silbersteina, Joshua M. Cohenb and Paul P. Yeungb aJefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA; bTeva Pharmaceutical Industries Ltd., Frazer, PA, USA

ABSTRACT ARTICLE HISTORY Introduction: The recent approval of monoclonal antibodies targeting the calcitonin gene-related Received 9 April 2019 peptide (CGRP) pathway introduced the first preventive treatments for migraine that were specifically Accepted 31 May 2019 designed to target the underlying pathophysiology of the disease. Fremanezumab, a fully humanized KEYWORDS monoclonal antibody (IgG2Δa) administered via subcutaneous injection, is the first approved mono- Chronic migraine; calcitonin clonal antibody that targets the CGRP ligand and offers both quarterly (once every 3 months) and gene-related peptide monthly dosing. (CGRP); episodic migraine; Areas covered: An introduction to migraine, overview of the migraine preventive treatments that fremanezumab; preventive target CGRP or its receptor, background on CGRP, and details on the fremanezumab clinical develop- treatment ment program in both chronic and episodic migraine. Focus is on the Phase 2b and Phase 3 studies, as well as the recently completed long-term Phase 3 study. Expert opinion: The approval of the first disease-specific preventive treatments for migraine heralds a new era in the treatment of migraine. Fremanezumab has a favorable efficacy and safety profile, which is maintained over the long term. Data from patient subgroups with more-complex disease are promising, and an ongoing study in treatment-refractory patients is evaluating the efficacy of fremanezumab in patients who have failed on multiple prior therapies.

1. Introduction diagnosed, and 12% of EM and 41% of CM patients receive preventive treatment [12]. Experts and treatment guidelines Migraine is a prevalent neurologic disease characterized by recommend preventive treatment in patients with ≥4 head- headaches that can be moderate or severe in intensity, throb- ache days per month and some impairment [13,14]. bing, and accompanied by associated symptoms (nausea, Discontinuation is common with many older preventive thera- vomiting, photophobia, and phonophobia) [1,2]. Migraine pies due to lack of efficacy and intolerable side effects [7]. affects about 40 million people in the United States (US) and Many drugs are used for the prevention of migraine, includ- is the second-leading cause of years lived with disability ing antihypertensives, anticonvulsants, and antidepressants, worldwide [1,3]. Approximately 18% of women and 6% of with most used off-label as they are not indicated for migraine men in the US have migraine, and many experience dimin- [15]. However, these preventive treatments were not devel- ished quality of life, reduced workplace productivity, and lim- oped specifically to treat migraine, and therefore do not ited participation in and enjoyment of social and leisure directly target migraine pathophysiology. These drugs may activities [4–6]. have variable efficacy and intolerable side effects, leading to Most people with migraine have episodic migraine (EM), in nonadherence and poor treatment outcomes [15]. Advances which headache occurs on <15 days per month [7]. People in our understanding of the pathophysiology of migraine have with ≥4 headache days per month are at risk for developing led to the development of the first disease-specific preventive chronic migraine (CM), which is characterized by ≥15 head- migraine therapies: monoclonal antibodies against calcitonin ache days per month for 3 months, with ≥8 migraine days per gene-related peptide (CGRP) or its receptor. These novel thera- month [2,8]. Overuse of acute headache medications, includ- pies, which have recently been approved in the US and the ing analgesics, migraine-specific agents (triptans and ergot European Union, have the potential to treat or prevent the derivatives), and combination products, is also associated most disabling forms of migraine [13,16,17]. While the efficacy with progression from EM to CM [9,10]. Development of CM and safety of these treatments have been established in 12- can result in greater impairment of daily functioning and month clinical trials, longer-term efficacy and safety of CGRP reduced quality of life (QoL) [11]. signaling inhibition in clinical practice have yet to be fully characterized [18]. 2. Overview of market Fremanezumab-vfrm (Box 1) (AJOVY®; Teva Pharmaceuticals) is approved for the preventive treatment of migraine in adults Of an estimated 28,729,000 people with EM and 5,242,000 [19]. Fremanezumab was the first approved monoclonal with CM in the US, 48% of EM and 65% of CM patients are

CONTACT Stephen D. Silberstein [email protected] Jefferson Headache Center, 900 Walnut Street, 2nd Floor, Ste. 200, Philadelphia, PA 19107, USA © 2019 Informa UK Limited, trading as Taylor & Francis Group 764 S. D. SILBERSTEIN ET AL.

humanized monoclonal antibody (IgG1) that targets the CGRP Article Highlights ligand and is administered quarterly (every 3 months) via intravenous infusion [24]. ● Migraine is a prevalent neurologic disease, and experts recommend preventive treatment in patients with ≥4 headache days per month and some impairment ● Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway are promising preventive treatments for migraine 3. Calcitonin gene-related peptide that were specifically designed to target the underlying pathophy- CGRP is a 37–amino acid neuropeptide with two isoforms, siology of the disease ● Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) alpha and beta [25,26]. Alpha-CGRP is a neuromodulator administered via subcutaneous injection, is an approved monoclonal expressed throughout the central and peripheral nervous antibody that targets the CGRP ligand and offers both quarterly and system, while beta-CGRP is mainly found in the enteric monthly dosing ● Fremanezumab demonstrated efficacy across all placebo-controlled nervous system [25]. Pain and other symptoms associated Phase 2b/3 trials in patients with chronic migraine (CM) or episodic with a migraine attack are thought to result from activation migraine (EM), and in certain patient populations with more-complex of the trigeminovascular system [27]. Nociceptive neurons disease ● Fremanezumab was generally safe and well tolerated, with low rates that innervate the dura mater are stimulated and release of serious adverse events and anti-fremanezumab antibody and anti- vasoactive neuropeptides, including CGRP, followed by acti- fremanezumab neutralizing antibody development in the trials vation of meningeal nociceptors, including nonmyelinated This box summarizes key points contained in the article. (C-fibers) and thinly myelinated (Aδ-fibers) axonal projec- tions [27,28]. In vivo data show that activation of meningeal C-fibers causes the release of CGRP, leading to CGRP- dependent activation of Aδ-fibers [29]. Once activated, C-fibers converge on and activate wide dynamic range δ Box 1. Drug summary box. (WDR) neurons and A -fibers converge on WDR and high- threshold (HT) neurons in the spinal trigeminal nucleus, Drug name (generic) Fremanezumab-vfrm which transmit nociceptive signals to the thalamus [29,30]. Phase Approved The efficacy of migraine preventive therapies targeting the Indication Preventive treatment of migraine in adults CGRP pathway suggests that activation of peripheral trige- Pharmacology/ A fully humanized monoclonal antibody that minovascular neurons may be sufficient for the initiation of mechanism of action binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the the headache phase of migraine [29]. receptor Targeting the CGRP ligand versus the receptor may have Chemical structure Monoclonal antibody clinically relevant differences, because CGRP exerts its effects Pivotal trials [HALO CM] Silberstein SD, Dodick DW, Bigal primarily through both the canonical CGRP receptor and the ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med amylin 1 (AMY1) receptor, but also binds and signals through 2017;377:2113–2122. other family receptors with lower affinity [26]. Antibodies [HALO EM] Dodick DW, Silberstein SD, Bigal against the CGRP ligand may result in incomplete blockade ME, et al. Effect of fremanezumab compared with placebo for prevention of episodic at the site of release, while antibodies against the canonical migraine: A randomized clinical trial. JAMA CGRP receptor may not block CGRP activity at the AMY1 2018;319:1999–2008. receptor [31].

4. Fremanezumab antibody targeting the CGRP ligand and is the only member of 4.1. Introduction to compound the class that offers both quarterly (every 3 months) and monthly subcutaneous dosing [19]. Recommended doses are either Fremanezumab is a fully humanized immunoglobulin G2Δa 225 mg monthly or 675 mg (three consecutive injections of (IgG2Δa) monoclonal antibody that contains >95% human pro- 225 mg) every 3 months [19]. tein sequence and is produced in a Chinese hamster ovary (CHO) Erenumab-aooe (Aimovig™; Amgen and Novartis) is an cell expression system [19]. The 2Δa mutation is in the effector approved human immunoglobulin G2 (IgG2) monoclonal anti- domain (CH2 sequence; approximately residues 231–340) of body that binds to the canonical CGRP receptor and prevents IgG2, which results in lack of complement-dependent lysis or CGRP from binding to this receptor [20–22]. Erenumab is cytotoxic activities, while retaining desirable properties such as administered monthly via subcutaneous injection, with a long half-life and reduced immunogenicity [32]. a recommended dosage of 70 mg or 140 mg (two consecutive The relationship between the pharmacodynamic activity and injections of 70 mg) once monthly [20]. Galcanezumab-gnlm mechanisms by which fremanezumab exerts its clinical effects is (Emgality®; Eli Lilly and Company) is an approved humanized unknown [19]. A single subcutaneous injection (225 mg, monoclonal antibody (IgG4) that targets the CGRP ligand and 675 mg, or 900 mg) had a median time to maximum concen- is administered monthly by subcutaneous injection, with trations of 5–7days[19]. Steady state was achieved approxi- a recommended initial loading dose of 240 mg (two consecu- mately 168 days following initiation of 225 mg monthly and tive injections of 120 mg), followed by 120 mg monthly [23]. 675 mg quarterly [19]. Like other monoclonal antibodies, fre- Eptinezumab (Alder BioPharmaceuticals) is an investigational manezumab is degraded by enzymatic proteolysis into small EXPERT OPINION ON BIOLOGICAL THERAPY 765 peptides and amino acids. The estimated half-life is approxi- seen during the first 4 weeks of treatment (675/225 mg: P = mately 30 days [19]. Population pharmacokinetic analyses 0.0035; 900 mg: P < 0.0001) [34]. Improvements were also found no effects of age, race, sex, and weight; no effect of observed in several secondary and a priori exploratory end- hepatic or renal impairment; and no effect of acute or preven- points [34]. tive migraine medication use on drug exposure [19]. In the high-frequency EM trial (NCT02025556) [33,34], Fremanezumab is not metabolized by cytochrome P450 patients were randomized 1:1:1 to receive either 675 mg (n enzymes and therefore not likely to interact with medications = 97), 225 mg (n = 96), or placebo (n = 104), given as four that are substrates, inducers, or inhibitors of cytochrome P450 subcutaneous injections every 4 weeks over a 12-week treat- enzymes [19]. ment period [33]. For the primary endpoint, fremanezumab significantly reduced from baseline the mean number of migraine days during weeks 9–12 (675 mg [least-squares 4.2. Fremanezumab clinical development program mean difference versus placebo]: –2.6 days, P < 0.0001; – P In the migraine clinical program, fremanezumab has been 225 mg: 2.8 days, < 0.0001) [33], with treatment effects P evaluated in 13 clinical trials, eight in healthy volunteers and seen during the first 4 weeks of treatment (675 mg: = 0.0001; P five in patients diagnosed with migraine according to 225 mg: = 0.0007) [33]. Improvements were also observed in International Classification of Headache Disorders, third several secondary and exploratory endpoints [33]. Edition [beta version] (ICHD-3 beta) criteria (Figure 1; Table 1). A total of 2768 patients have been exposed to at 4.3.2. HALO phase 3 trials least one dose of fremanezumab in the migraine clinical Two 12-week, double-blind, placebo-controlled, Phase 3 clinical development program. trials evaluated the efficacy of fremanezumab for the preventive treatment of patients, aged 18–70 years, with CM or EM [35,36]. The concurrent HALO CM (NCT02621931) and EM (NCT02629861) 4.3. Clinical efficacy of fremanezumab trials had innovative design elements. At screening, patients 4.3.1. Phase 2b trials signed consent forms for both studies, and headache day fre- Two 12-week, double-blind, placebo-controlled, Phase 2b clin- quency was confirmed via an electronic headache diary device ical trials assessed the efficacy of two doses of fremanezumab during a 28-day pre-treatment period. Individuals entered rando- for the preventive treatment of CM or high-frequency EM mization into the appropriate study or were excluded if they did (8–14 headache days per month, ≥8 of which are migraine notmeeteligibilitycriteria.This bifurcated screening process days) in patients aged 18–65 years [33,34]. reflected the real-world clinical experience for patients, who may In the CM trial (ClinicalTrials.gov NCT02021773) [34], cycle between CM and EM. To improve generalizability to the real- patients were randomized 1:1:1 to receive either 675/225 mg world clinical setting, up to 30% of patients could use a stable (n = 88), 900 mg (n = 87), or placebo (n = 89), given as four dose of one preventive migraine medication. subcutaneous injections every 4 weeks over a 12-week treat- HALO CM included patients with CM (≥15 headache days ment period [34]. For the primary endpoint, fremanezumab per month with migraine on ≥8 days), 21% of whom used one significantly reduced from baseline the mean number of head- migraine-preventive medication [36]. Patients were rando- ache hours of any severity during weeks 9–12 (675/225 mg mized 1:1:1 to receive either subcutaneous fremanezumab [least-squares mean difference versus placebo]: –22.7 h, P = quarterly (n = 376; 675 mg at baseline, placebo at weeks 4 0.0386; 900 mg: –30.4 h, P = 0.0057) with treatment effects and 8), monthly (n = 379; 675 mg at baseline, 225 mg at weeks

Figure 1. Fremanezumab Migraine Clinical Development Program. IV, intravenous; PBO, placebo; q 3 MO, every 3 months; q MO, every month; SC, subcutaneous. 766 .D IBRTI TAL. ET SILBERSTEIN D. S.

Table 1. Summary of published Phase 2 and 3 trials for fremanezumab in EM and CM. Treatment dose and Number of participants Treatment Study Demographics control drugsa (treated/completed) duration Primary endpoint Phase 2b CM study CM patients PBO/PBO/PBO 89/77 12 weeks Mean change from baseline in the number of headache hours of any severity during Month 3 Bigal et al [34]. Fremanezumab 88/72 675/225/225 mgb Fremanezumab 86/76 900/900/900 mg Phase 2b high-frequency High-frequency EM PBO/PBO/PBO 104/98 12 weeks Mean change from baseline in the number of migraine days during Month 3 EM study patients Fremanezumab 96/83 Bigal et al [33]. 225/225/225 mgc Fremanezumab 96/88 675/675/675 mg Phase 3 HALO CM study CM patients PBO/PBO/PBO 375/342 12 weeks Mean change from baseline in the monthly average number of headache days of at least moderate Silberstein et al [36]. Fremanezumab 376/349 severity during the 12-week treatment period 675 mg/PBO/PBOd Fremanezumab 379/343 675/225/225 mgb Phase 3 HALO EM study EM patients PBO/PBO/PBO 294/265 12 weeks Mean change from baseline in the monthly average number of migraine days during the 12-week Dodick et al [35]. Fremanezumab 291/264 treatment period 675 mg/PBO/PBOd Fremanezumab 290/262 225/225/225 mgc aAll drugs were administered subcutaneously. bSupporting the proposed monthly dosing for patients with CM. cSupporting the proposed monthly dosing in patients with EM. dSupporting the proposed quarterly dosing for patients with CM and EM. CM, chronic migraine; EM, episodic migraine; PBO, placebo. EXPERT OPINION ON BIOLOGICAL THERAPY 767

4 and 8), or placebo (n = 375), over a 12-week period [36]. For taking concomitant preventive migraine medications, disability the primary endpoint, fremanezumab significantly reduced (measured by the Migraine Disability Assessment [MIDAS]), and from baseline the mean number of headache days of at least migraine-associated symptoms (nausea or vomiting, photopho- moderate severity during the 12-week treatment period (quar- bia, and phonophobia; Table 3)[35]. terly: [least-squares mean change]: –4.3 days; monthly: –4.6 days; both P <0.0001vsplacebo:–2.5 days; Figure 2(a))[36]. These treatment effects were seen during the first 4 weeks of 4.3.3. Long-term HALO study treatment (P < 0.0001 for both quarterly and monthly dosing; A 52-week, Phase 3 trial allowed rollover of patients who Figure 2(b)) and as early as the first week of treatment (P < completed the placebo-controlled Phase 3 trials, as well as 0.0001), with a significant difference from placebo the day after 312 new patients (total CM, n = 1110; EM, n = 780). At the first dose (P <0.01)[36]. More patients who received Month 12, CM and EM patients continued to show reductions fremanezumab had a reduction of at least 50% in the mean in the monthly number of headache days of at least moderate monthly number of headache days of at least moderate severity severity and migraine days. than did those given placebo (Table 2)[36]. Reductions were also seen in migraine days, days of acute headache medication 4.3.4. Efficacy in migraine patients with more-complex use, and disability, as measured by the six-item Headache disease Impact Test (HIT-6), and migraine-associated symptoms (nausea In CM patients with prior use of topiramate, fremanezumab or vomiting, photophobia, and phonophobia; Table 2)[36]. significantly reduced the number of headache days of at least HALO EM included patients with EM (6–14 headache days per moderate severity from baseline during the 12-week treatment month with ≥4 migraine days), 21% of whom used one migraine- period (quarterly : –4.4 days; monthly : –4.7 days; both P < preventive medication [35]. Patients were randomized 1:1:1 to 0.0001 vs placebo: –1.7 days). Fremanezumab monthly in CM receive either fremanezumab quarterly (n = 291; 675 mg at patients with prior use of onabotulinumtoxinA had a similar baseline, placebo at weeks 4 and 8), monthly (n = 290; 225 mg treatment effect (P < 0.05). In EM patients with prior use of at baseline, weeks 4 and 8), or placebo (n = 294) over a 12-week topiramate, fremanezumab significantly reduced the number treatment period [35]. For the primary endpoint, fremanezumab of migraine days from baseline during the 12-week treatment significantly reduced from baseline the mean number of period (quarterly: –3.0 days; monthly: –3.0 days; both P <0.001 monthly migraine days during the 12-week treatment period vs placebo: –0.7 days). Fremanezumab monthly was efficacious (quarterly [least-squares mean change]: –3.4 days; monthly: – in CM patients with concomitant preventive medication use, 3.7 days; both P <0.0001vsplacebo:–2.2 days; Figure 3(a)) based on the change from baseline in headache days of at with treatment effects seen during the first 4 weeks of treatment least moderate severity (–4.5 days vs placebo: –2.5 days, P < (P < 0.0001 for both quarterly and monthly dosing; Figure 3(b)), 0.01). Fremanezumab was efficacious in CM patients with med- and the first week of treatment (P <0.001),withasignificant ication overuse at baseline, based on the change from baseline difference from placebo the day after the first dose (P <0.001) in headache days of at least moderate severity (quarterly: –4.7 [35]. More patients who received fremanezumab had a reduction days; monthly: –5.2 days; both P < 0.0001 vs placebo: –2.5 days). of at least 50% in the mean number of monthly migraine days Fremanezumab was efficacious in CM patients with comorbid than did patients given placebo (Table 3)[35]. Reductions were moderate to moderately severe depression (Patient Health also seen in acute headache medication use, migraine-specific Questionnaire scores 10–19) at baseline, based on the change acute headache medication use, migraine days in patients not from baseline in headache days of at least moderate severity

Figure 2. HALO CM Primary Endpoint: Change From Baseline in the Monthly Average Number of Headache Days of At Least Moderate Severity. All P values are compared with placebo. CM, chronic migraine; LSM, least-squares mean; SE, standard error. 768 S. D. SILBERSTEIN ET AL.

Table 2. HALO CM Secondary Endpoints. Fremanezumab Placebo Quarterly (n = 375) Monthly (n = 375) (n = 371) Monthly migraine days, during the 12-week treatment period LSM change ± SE – days –4.9 ± 0.35 –5.0 ± 0.35 –3.2 ± 0.35 Difference vs placebo (P value) –1.7 ± 0.39 (<0.0001) –1.8 ± 0.39 (<0.0001) ≥50% reduction in monthly average headache days of at least moderate severity, during the 12-week treatment period Patients achieving response – no. (%) 141 (37.6) 153 (40.8) 67 (18.1) P value <0.0001 <0.0001 Monthly days of any acute headache medication use, during the 12-week treatment period LSM change ± SE – days –3.7 ± 0.30 –4.2 ± 0.30 –1.9 ± 0.30 Difference vs placebo (P value) –1.8 ± 0.33 (<0.0001) –2.3 ± 0.33 (<0.0001) Monthly headache days of at least moderate severity in patients not receiving concomitant preventive medications, during the 12-week treatment period Patients evaluated – no. (%) 298 (79) 290 (77) 294 (79) LSM change ± SE – days –4.6 ± 0.33 –4.8 ± 0.33 –2.6 ± 0.33 Difference vs placebo (P value) –1.9 ± 0.38 (<0.0001) –2.2 ± 0.39 (<0.0001) HIT-6 score, from baseline to 4 weeks after last dose LSM change ± SE – points –6.4 ± 0.45 –6.8 ± 0.44 –4.5 ± 0.45 Difference vs placebo (P value) –1.9 ± 0.49 (0.0001) –2.4 ± 0.49 (<0.0001) Monthly days with nausea or vomiting, during the 12-week treatment period LSM change ± SE – days –3.3 ± 0.29 –3.2 ± 0.28 –2.2 ± 0.29 Difference vs placebo (P value) –1.0 ± 0.31 (0.0009) –1.0 ± 0.31 (0.0019) Monthly days with photophobia and phonophobia, during the 12-week treatment period LSM change ± SE – days –3.5 ± 0.32 –3.7 ± 0.32 –2.4 ± 0.32 Difference vs placebo (P value) –1.1 ± 0.35 (0.0025) –1.3 ± 0.35 (0.0001) CM, chronic migraine; HIT-6, six-item Headache Impact Test; LSM, least-squares mean; SE, standard error.

Figure 3. HALO EM Primary Endpoint: Change From Baseline in the Monthly Average Number of Migraine Days. All P values are compared with placebo. EM, episodic migraine; LSM, least-squares mean; SE, standard error.

(quarterly: –5.4 days; monthly: –5.6 days; both P <0.001vs in up to 30% of patients (Table 4). Rates of injection-site reactions placebo: – 2.2 days) and migraine days (quarterly: –5.8 days; were higher in the Phase 3 studies than in the Phase 2 studies, monthly: –5.9 days; both P <0.001vsplacebo:–2.3 days). likely due to the thorough injection-site assessments immediately and 1 h after injection in the Phase 3 studies. Two deaths occurred in the clinical development program, 4.4. Safety and tolerability of fremanezumab both unrelated to study drug according to the investigators. In A pooled safety analysis of the placebo-controlled trials has been HALO CM, a 59-year-old patient who received one dose of fre- published previously [37]. Based on these pooled data (N = 2563), manezumab 675 mg died 69 days after study drug exposure adverse events (AEs) were reported for 48–69% of patients in all from chronic obstructive pulmonary disease (COPD) per autopsy. treatment groups (Table 4), most of which were mild to moderate In HALO EM, a 21-year-old patient who received one dose of in severity. Serious AEs and AEs leading to discontinuation were fremanezumab 675 mg withdrew consent due to a family emer- infrequent and had similar incidences across all groups. The most gency and died 110 days after study drug exposure due to commonly reported AEs were injection-site reactions, occurring diphenhydramine overdose (suicide) per autopsy. EXPERT OPINION ON BIOLOGICAL THERAPY 769

Table 3. HALO EM Key Secondary and Exploratory Endpoints. Fremanezumab Placebo Quarterly (N = 288) Monthly (N = 287) (N = 290) ≥50% reduction in monthly average migraine days, during the 12-week treatment period Patients achieving response – no. (%) 128 (44.4) 137 (47.7) 81 (27.9) P value <0.0001 <0.0001 Monthly days of any acute headache medication use, during the 12-week treatment period LSM change ± SE – days –2.9 ± 0.22 –3.0 ± 0.22 –1.6 ± 0.21 Difference vs placebo (P value) –1.3 ± 0.24 (<0.0001) –1.4 ± 0.24 (<0.0001) Monthly days of migraine-specific acute headache medication use in patients who used migraine-specific acute headache medication at baseline, during the 12- week treatment period Patients evaluated – no. (%) 152 (53) 148 (52) 136 (47) LSM change± SE – days –3.1 ± 0.26 –3.1 ± 0.26 –0.9 ± 0.27 Difference vs placebo (P value) –2.2 ± 0.31 (<0.0001) –2.2 ± 0.32 (<0.0001) Monthly migraine days in patients not receiving concomitant preventive migraine medications, during the 12-week treatment period Patients evaluated – no. (%) 230 (80) 225 (78) 230 (79) LSM change ± SE – days –3.5 ± 0.27 –3.7 ± 0.27 –2.4 ± 0.26 Difference vs placebo (P value) –1.1 ± 0.31 (0.0002) –1.3 ± 0.31 (<0.0001) MIDAS score – points LSM change ± SE change – points –23.0 ± 1.60 –24.6 ± 1.59 –17.5 ± 1.57 Difference vs placebo (P value) –5.4 ± 1.78 (0.0023) –7.0 ± 1.78 (<0.0001) Monthly days with nausea or vomiting, during the 12-week treatment period LSM change ± SE – days –1.9 ± 0.19 –2.1 ± 0.19 –1.4 ± 0.19 Difference vs placebo (P value) – 0.5 ± 0.21 (0.0314) –0.7 ± 0.21 (0.0008) Monthly days with photophobia, during the 12-week treatment period LSM change ± SE – days –2.8 ± 0.23 –3.0 ± 0.23 –2.0 ± 0.22 Difference vs placebo (P value) –0.8 ± 0.25 (0.0018) –0.9 ± 0.25 (0.0002) Monthly days with phonophobia, during the 12-week treatment period LSM change ± SE – days –2.7 ± 0.22 –3.0 ± 0.22 –2.1 ± 0.22 Difference vs placebo (P value) –0.6 ± 0.24 (0.0088) –1.0 ± 0.25 (<0.0001) EM, episodic migraine; LSM, least-squares mean; MIDAS, Migraine Disability Assessment; SE, standard error.

Table 4. Overview of AEs for all patients in Phase 2b and 3 trials by treatment group. Fremanezumab 225 mg 675 mg 675/225 mg Placebo monthly monthly quarterly monthlya 675 mg monthly 900 mg monthly Totalb (N = 861) (N = 386) (N = 667) (N = 467) (N = 96) (N = 86) (N = 1702) At least one AE, no. (%) 505 (59) 236 (61) 458 (69) 317 (68) 57 (59) 41 (48) 1109 (65) Mild 290 (34) 129 (33) 264 (40) 175 (37) 31 (32) 17 (20) 616 (36) Moderate 182 (21) 93 (24) 164 (25) 123 (26) 26 (27) 21 (24) 427 (25) Severe 32 (4) 14 (4) 30 (4) 19 (4) 0 3 (3) 66 (4) Missing 1 (<1) 0 0 0 0 0 0 At least one treatment-related AE, no. (%) 307 (36) 164 (42) 323 (48) 219 (47) 24 (25) 28 (33) 758 (45) Mild 220 (26) 111 (29) 236 (35) 154 (33) 18 (19) 14 (16) 533 (31) Moderate 75 (9) 46 (12) 70 (10) 55 (12) 6 (6) 14 (16) 191 (11) Severe 12 (1) 7 (2) 17 (3) 10 (2) 0 0 34 (2) AE leading to discontinuation of the 14 (2) 9 (2) 10 (1) 11 (2) 2 (2) 3 (3) 35 (2) study drug, no. (%) At least one serious AE, no. (%) 14 (2) 5 (1) 6 (<1) 2 (2) 2 (2) 2 (2) 21 (1) At least one treatment-related serious 2 (<1) 1 (<1) 0 0 0 0 1 (<1) AE, no. (%) Injection-site AEs, no. (%) Injection-site pain 189 (22) 96 (25) 200 (30) 105 (22) 4 (4) 8 (9) 413 (24) Injection-site induration 113 (13) 71 (18) 131 (20) 90 (19) 0 0 292 (17) Injection-site erythema 104 (12) 55 (14) 135 (20) 76 (16) 4 (4) 3 (3) 273 (16) Injection-site pruritus 2 (<1) 4 (1) 10 (1) 12 (3) 2 (2) 2 (2) 30 (2) Injection-site hemorrhage 16 (2) 4 (1) 16 (2) 8 (2) 0 0 28 (2) Injection-site edema 0 1 (<1) 1 (<1) 0 0 2 (2) 4 (<1) Injection-site hematoma 1 (<1) 0 0 1 (<1) 2 (2) 0 3 (<1) Injection-site reaction 0 0 0 1 (<1) 0 2 (2) 3 (<1) aPatients received fremanezumab 225 mg monthly with a starting dose of 675 mg. bIncludes patients in all fremanezumab treatment groups, including the 675 mg monthly and 900 mg monthly treatment groups. AE, adverse event.

Cardiovascular events occurred infrequently and at similar events were assessed by the investigator as unrelated to the rates across all groups. Most common events were hyperten- study drug and resolved after appropriate treatment. sion, tachycardia, palpitations, increased blood pressure, and Six of 1701 (0.4%) patients who received fremanezumab had increased heart rate. Two patients who received fremanezu- treatment-emergent anti-fremanezumab antibody responses, mab experienced serious AEs of hypertensive crisis; both of one of whom developed anti-fremanezumab neutralizing anti- whom had a history of hypertension and were taking antibodies; no patients had significant safety or efficacy conse- hypertensives at the time of the event. All cardiovascular quences of anti-fremanezumab antibody development. 770 S. D. SILBERSTEIN ET AL.

No Hy’s law events were reported. Protocol-defined liver with failure of topiramate or onabotulinumtoxinA, medication AEs of special interest (aspartate aminotransferase or alanine overuse, or those taking concomitant preventive medications, aminotransferase ≥3× the upper limit of the normal range are promising. The outcomes of the FOCUS trial in treatment- [ULN], total bilirubin ≥2× the ULN or international normalized refractory patients will determine whether fremanezumab is ratio >1.5) were infrequent and occurred in similar incidences efficacious in those with long-term disease who were not helped across all groups. No events of anaphylaxis or severe hyper- by multiple treatments. sensitivity to the study drug were observed. There were no clinically meaningful changes in serum chemistry, hematology, coagulation, urinalysis assessments, or vital signs. Acknowledgments Safety and tolerability were maintained in the 52-week We thank Kristen Hokenson, PhD (Chameleon Communications International long-term study, with no safety signals to date. with funding from Teva Pharmaceutical Industries Ltd.) for editorial assis- tance in the preparation of this report. 5. Conclusion Funding Across all placebo-controlled Phase 2b/3 trials in patients with CM or EM, fremanezumab demonstrated efficacy, and in This study was funded by Teva Pharmaceutical Industries Ltd., Petach the Phase 3 trials, both quarterly and monthly dosing met all Tikva, Israel. pre-specified primary and secondary efficacy endpoints. Fremanezumab also improved measures of QoL and disability Declaration of interest in these patients. Exploratory and post hoc analyses indicate that certain patient populations with more-complex disease – SD Silberstein provides consultation to Alder, Allergan, Amgen, Avanir, Curelater Inc., Depomed, Dr. Reddy’s Laboratories, Ensured Inc., those with prior topiramate or onabotulinumtoxinA use, using ElectroCore Medical LLC, INSYS Therapeutics, Lilly USA LLC, Supernus concomitant preventive migraine medications, those with Pharmaceuticals Inc., Teva Pharmaceuticals, Theranica, and Trigemina Inc. comorbid depression, or those with medication overuse – JM Cohen is an employee of Teva Branded Pharmaceutical Products R&D, may also benefit from fremanezumab treatment. Inc. PP Yeung is a former employee of Teva Pharmaceutical Industries Ltd. Fremanezumab was generally safe and well tolerated in The authors have no other relevant affiliations or financial involvement with adults with CM and EM. Injection-site reactions occurred at any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those a higher rate in the Phase 3 trials than in the Phase 2b trial, disclosed. likely due to the thorough assessments of injection sites implemented during these trials. There was a low incidence of anti-fremanezumab antibody and anti-fremanezumab neu- Reviewer Disclosures tralizing antibody development in patients in the fremanezu- One of the reviewers has served on advisory board and travel grants from mab trials. The anti-CGRP effect of fremanezumab does not Allergan, Novartis, TEVA, Amgen, Eli Lilly. Other peer reviewers on this appear to raise any cardiovascular concerns. Long-term treat- manuscript have no relevant financial relationships or otherwise to disclose. ment with fremanezumab did not result in any safety signals and was well tolerated. 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