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761077Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 761077Orig1s000 OTHER REVIEW(S) Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research | Office of Surveillance and Epidemiology (OSE) Epidemiology: ARIA Sufficiency Templates Version: 2018-01-24 Date: May 15, 2018 Reviewer(s): Hongliu Ding, MD, PhD, MPH Division of Epidemiology I Team Leader: Kira Leishear, PhD, MS Division of Epidemiology I Division Deputy Director: Sukhminder K. Sandhu, PhD, MS, MPH Division of Epidemiology I Subject: ARIA Sufficiency Memo for Pregnancy Safety Concerns Drug Name(s): Amovig (erenumab) Application Type/Number: BLA 761077 Applicant/sponsor: Amgen Inc. OSE RCM #: 2018-869 Page 1 of 5 Reference ID: 4263424 Expedited ARIA Sufficiency Template for Pregnancy Safety Concerns 1. BACKGROUND INFORMATION 1.1. Medical Product Amovig (erenumab) is a human immunoglobulin G2 (IgG2) monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor. CGRP is a neuropeptide that modulates nociceptive signaling and a vasodilator associated with migraine pathophysiology.1-3 Plasma CGRP levels have been shown to increase significantly during migraine and return to normal when headache is relieved.4, 5 Erenumab competes with the binding of CGRP and inhibits its function at the CGRP receptor, and thus, the proposed indication is for prophylaxis of episodic and chronic migraine in adults. 1.2. Describe the Safety Concern Amovig (erenumab) exposure to women affected by migraine that are pregnant or of childbearing potential is possible. The data from a non-clinical study provided by the sponsor in which female monkeys were administered erenumab (0 or 50 mg/kg) twice weekly by subcutaneous showed that injection throughout pregnancy (gestation day 20-22 to parturition) did not observe adverse effects on offspring. However, several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.6-10 During the clinical trials, 23 pregnancies were reported in female participants with exposure to erenumab. Among the 23 pregnancies, the outcomes of 6 pregnancies were not yet known and 5 pregnant women were lost to follow-up. The remaining pregnancies (N=12) ended with 5 full-term births without complications, 1 full-term birth with complications (no birth complication or congenital anomalies, but admitted to neonatal intensive care for unspecified reasons), 1 preterm birth without complications (infant was born via Caesarean section at 31 weeks due to the mother developing HELLP syndrome), 3 elective terminations, and 2 spontaneous abortions (1 was in a woman with a prior uterine ablation and 1 was in a woman who received a single dose of 140mg of erenumab and miscarried 3 months later). Women of childbearing potential were given monthly pregnancy tests and if the test was positive, they did not receive additional dosings. Therefore, it is likely that exposed pregnancies only received dosings during the first trimester, but the half-life of erenumab is 28 days. Overall, the evidence from animal studies and the clinical trials are limited, and thus, the developmental risk associated with use of erenumab in pregnant women is not known at this time. The goal of this pregnancy safety study is to obtain data on pregnancy and infant outcomes after erenumab exposure during pregnancy to inform prescribing for and counseling of women with migraine who are also pregnant or of childbearing potential. 1.3. FDAAA Purpose (per Section 505(o)(3)(B)) - Please ensure that the selected purpose is consistent with the other PMR documents in DARRTS Page 2 of 5 Reference ID: 4263424 For any checked boxes above, please describe briefly: Study Population and Outcomes: ARIA is insufficient to identify the study population (babies that experienced in utero exposure or postpartum exposure through lactation) because the mother and baby records are not currently linked in Sentinel. Thus, the exposure corresponding to the mother and potential outcomes corresponding to the infant cannot be connected. This lack of linkage between mother and baby records renders ARIA insufficient for both the study population and outcome identification. Analytical Tools: ARIA analytic tools are not sufficient to assess the regulatory question of interest because data mining methods have not been tested for birth defects and other pregnancy outcomes. We did not formally assess the other parameters given that the mother-infant linkage is not currently available in ARIA. 2.5. Please include the proposed PMR language in the approval letter. The following language has been proposed as of May 15, 2018 by the Division of Neurology Products for two PMRs related to pregnancy outcomes: 1. “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 erenumab during pregnancy with two unexposed control populations: one consisting of women with migraine who have not been exposed to erenumab 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.” and 2. “Conduct a pregnancy outcomes study using a different study design than provided for in PMR 3392-5 (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 Amovig (erenumab) during pregnancy compared to an unexposed control population.” The finalized PMR language will be issued upon approval. Page 4 of 5 Reference ID: 4263424 3. References 1. Durham PL. CGRP-receptor antagonists--a fresh approach to migraine therapy? N Engl J Med. 2004;350(11):1073-1075. 2. Edvinsson L, Goadsby PJ. Neuropeptides in migraine and cluster headache. Cephalalgia. 1994;14(5):320-327. 3. Hay DL, Poyner DR. Calcitonin gene-related peptide, adrenomedullin and flushing. Maturitas. 2009;64(2):104-108. 4. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990;28(2):183-187. 5. Raddant AC, Russo AF. Calcitonin gene-related peptide in migraine: intersection of peripheral inflammation and central modulation. Expert Rev Mol Med. 2011;13:e36. 6. Adeney KL, Williams MA, Miller RS, et al. Risk of preeclampsia in relation to maternal history of migraine headaches. J Matern Fetal Neonatal Med. 2005;18(3):167-172. 7. Banhidy F, Acs N, Horvath-Puho E, et al. Pregnancy complications and delivery outcomes in pregnant women with severe migraine. Eur J Obstet Gynecol Reprod Biol. 2007;134(2):157-163. 8. Chen HM, Chen SF, Chen YH, et al. Increased risk of adverse pregnancy outcomes for women with migraines: a nationwide population-based study. Cephalalgia. 2010;30(4):433-438. 9. Marcoux S, Berube S, Brisson J, et al. History of migraine and risk of pregnancy-induced hypertension. Epidemiology. 1992;3(1):53-56. 10. Sanchez SE, Qiu C, Williams MA, et al. Headaches and migraines are associated with an increased risk of preeclampsia in Peruvian women. Am J Hypertens. 2008;21(3):360-364. Page 5 of 5 Reference ID: 4263424 -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ HONGLIU DING 05/15/2018 KIRA N LEISHEAR 05/15/2018 SUKHMINDER K SANDHU 05/16/2018 JUDITH W ZANDER 05/16/2018 MICHAEL D NGUYEN 05/16/2018 ROBERT BALL 05/16/2018 Reference ID: 4263424 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy PATIENT LABELING REVIEW Date: May 3, 2018 To: Billy Dunn, MD Director Division of Neurology Products (DNP) Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Marcia Williams, PhD Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP) From: Aman Sarai, BSN, RN Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Dhara Shah, PharmD Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Patient Package Insert (PPI) and Instructions for Uses (IFUs) Drug Name (established AIMOVIG (erenumab) name): Dosage Form and Route: injection, for subcutaneous use Application 761077 Type/Number: Applicant: Amgen Reference ID: 4257545 1 INTRODUCTION On May 17, 2017, Amgen submitted for the Agency’s review a new BLA submission, request for priority review. AIMOVIG (erenumab) is a potent and selective human IgG2 monoclonal antibody against the calcitonin gene-related peptide receptor. Amgen is seeking to market erenumab for the indication of prophylaxis of migranes
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