CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761089Orig1s000 CLINICAL / STATISTICAL REVIEW(S) Safety Team Leader Review BLA 761089 Ajovy (Fremanezumab) Safety Team Leader Review Date September 14, 2018 From Sally Usdin Yasuda Subject Safety Team Leader Review NDA/BLA # BLA 761089 Supplement# Applicant Teva Pharmaceuticals USA, Inc. Date of Submission October 16, 2017 PDUFA Goal Date June 16, 2018 Proprietary Name / Non- Ajovy/Fremanezumab Proprietary Name Dosage form(s) / Strength(s) Solution for subcutaneous injection, 225 mg/1.5 ml Applicant Proposed Preventive treatment of migraine in adult patients Indication(s)/Population(s) There do not appear to be safety concerns that would preclude approval. If efficacy is demonstrated and the Recommendation on benefits of fremanezumab for prevention of migraine Regulatory Action outweigh the risks, then I recommend that approval include appropriate labeling language addressing any adverse reactions of concern. Recommended Indication(s)/Population(s) (if applicable) 1 Reference ID: 4320823 Safety Team Leader Review BLA 761089 Ajovy (Fremanezumab) 1. Background This memorandum summarizes the primary concerns from the safety review conducted by Dr. Lourdes Villalba of the fremanezumab BLA 761089 and provides my conclusions and recommendations regarding the safety findings and management of the risks. I also discuss the consultant reviews from Dr. Wiley Chambers (Division of Transplant and Ophthalmology Products). The product information and the applicant’s proposals Fremanezumab is a humanized monoclonal IgG2 antibody that, according to the Sponsor, is a calcitonin gene-related peptide (CGRP) binder that blocks both CGRP isoforms (α- and β) so that CGRP is blocked from binding to the CGRP receptor. According to the Sponsor, fremanezumab is specific for CGRP (and does not bind to closely related family members such as amylin, calcitonin, adrenomedullin, and intermedin). The Sponsor states that mutations introduced into the molecule limit antibody effector functions, preventing fremanezumab from stimulating antibody-dependent cell-mediated toxicity and triggering complement-mediated lysis. I note that α- CGRP is found in spinal afferents from sensory ganglia, and β-CGRP is primarily found in the enteric nervous system.1 According to a recent review, CGRP, a vasodilator, may maintain cardiovascular homeostasis in the setting of pathophysiology.2 This leads to questions (in the literature and raised by Dr. Villalba) as to the effect of chronic antagonism of CGRP in patients with vascular and cardiovascular risk factors. The proposed indication for fremanezumab is preventive treatment of migraine in adult patients. The proposed doses (to be given subcutaneously) are: 225 mg monthly or 675 mg every 3 months (quarterly).3 The Sponsor included as events of special interest adverse ophthalmic events of at least moderate intensity, possible drug-induced liver injury, and events of suspected anaphylaxis and severe hypersensitivity reactions, based on potential risks identified in preliminary preclinical studies, small molecule CGRP antagonist development programs, and intrinsic factors for biological molecules. The Sponsor’s evaluation of cardiovascular effects involved an evaluation of cardiovascular adverse events in the database and an evaluation of ECGs and vital signs measurements. (b) (4) 1 Deen et al. The Journal of Headache and Pain (2017) 18:96 2 MaassenVanDenBrink A, et al. Trends in Pharmacological Sciences, September 2016, Vol. 37, No. 9 http://dx.doi.org/10.1016/j.tips.2016.06.002 3 In the amendment of 5/14/18 (b) (4) . 2 Reference ID: 4320823 Safety Team Leader Review BLA 761089 Ajovy (Fremanezumab) Therapeutic context Migraine, often disabling, is characterized by recurrent episodes of headache attacks accompanied by symptoms such as nausea, vomiting, photophobia, and phonophobia. Migraine affects more than 10% of adults globally. Dr. Villalba notes that the prevalence of migraine in the U.S. is 3:1 for females vs males and that the peak incidence is 30 to 49 years of age. Dr. Villalba provides a list of the 5 products already approved for prophylaxis of migraine in the United States. She 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. According to the Sponsor, although 39-50% of migraine patients are candidates for prophylactic therapy, only 13% of United States patients with migraine are on prophylactic therapy. 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. Villalba notes that a toxicology study in cynomolgus monkey identified a potential risk of ophthalmic related events in a 3-month study, consisting of inflammation of ciliary vessels of the eye, although the finding was not reproduced in a 1-month study or in a 6-month chronic toxicity study. In an email communication to me (April 16, 2018), Dr. Barbara Wilcox in the Division of Neurology Products clarified that the vascular inflammation noted in the 3 month monkey study was most likely due to immunogenicity. She wrote that immunogenicity in animals is not considered to be predictive of the human response. 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 fremanezumab could be designed and conducted that would 3 Reference ID: 4320823 Safety Team Leader Review BLA 761089 Ajovy (Fremanezumab) provide useful information; therefore, no postmarketing study to further assess the cardiovascular safety of fremanezumab 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 5 to 7 days after a single subcutaneous dose. Median elimination half-life is 31 days. The total drug accumulation ratio is 2.3 and 1.2 for monthly and quarterly regimens, respectively. Steady state is expected to be achieved by approximately 6 months. 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 Cohorts 1 through 7 were the pools agreed upon by the Sponsor and the Division during August 31, 2017, pre-BLA meeting for the analysis of fremanezumab clinical safety. The pools have the following characteristics, as presented by Dr. Villalba: Safety cohorts as per original application in patients with migraine Cohorts Description Studies Safety Population* All patients in the placebo-controlled phase 2 & 3 021, 022, 049, and 2563 1 studies for migraine (EM and CM) 050 2 All patients with CM in the placebo-controlled studies 021 and 049 1393 3 All patients with EM in the placebo-controlled studies 022 and 050 1170 All FRMB-treated patients in phase 2 & 3 studies for 021, 022, 049, 050, 2512 4 migraine (EM or CM) and 051 5 All FRMB-treated patients with CM 021, 049, and 051 1411 6 All FRMB-treated patients with EM 022, 050, and 051 1107 7 All patients in pivotal studies (CM or EM) 049 and 050 2004 Source: ISS ADSL database, original submission. *Cohorts 1, 2, 3 and 7 include placebo patients. Placebo- 4 Reference ID: 4320823 Safety Team Leader Review BLA 761089 Ajovy (Fremanezumab) controlled studies: 12-week treatment with 4-week post-treatment FU (Completed). Study 051 double blind (no placebo) up to 48 weeks with 7.5-month post-treatment FU (Ongoing). (Half-life of FRMB is 31 days). EM: Episodic migraine. CM: Chronic migraine. Dr. Villalba primarily used Cohorts 1 and 4 throughout her review as do I. The Cohort 7 results will be used for the common AE table. The placebo controlled studies included 12 weeks of treatment and 4 weeks of follow-up. Study 051 included 48 weeks of treatment and 7.5 months of follow-up (ongoing). I agree with Dr. Villalba’s use of “actual dose” by treatment group for treatment emergent AEs. The primary data (the safety population)