Efficacy, Safety, and Tolerability of Rimegepant 75 mg, an Oral CGRP Receptor Antagonist, for the Acute Treatment of Migraine: Results from a Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial, Study 302 Richard B. Lipton, MD 1,2,3 ; Vladimir Coric, MD 4 ; Elyse G. Stock, MD 4 ; David Stock, PhD 4 ; Beth A. Morris, BA 4 ; Timothy J. McCormack, BA 4 ; Marianne Frost, MA 4 ; Kimberly Gentile, BS 4 ; Gene M. Dubowchik, PhD 4 ; Charles M. Conway, PhD 4 ; Robert Croop, MD 4 1 Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; 2 Montefiore Medical Center, Bronx, NY, USA; 3 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; 4 Biohaven Pharmaceuticals, Inc., New Haven, CT, USA
Disclosures Biohaven Pharmaceuticals funded the study, was responsible for study oversight, and performed data management and analysis Richard B. Lipton, MD, serves on the editorial board of Neurology and Cephalalgia and as senior advisor to Headache but is not paid for his roles on Neurology or Headache. He has received research support from the NIH. He also receives support from the Migraine Research Foundation and the National Headache Foundation. He receives research grants from Allergan, Amgen, Dr. Reddy s Laboratories, and Novartis. He has reviewed for the NIA and NINDS and serves as consultant, advisory board member, or has received honoraria from Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Boston Scientific, CoLucid, Dr. Reddy s Laboratories, electrocore, Eli Lilly, eneura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, and Vedanta. He receives royalties from Wolff s Headache (8 th Edition, Oxford Press University, 2009) and Informa. He holds stock options in eneura Therapeutics and Biohaven Pharmaceuticals. All other authors are employed by and hold stock/stock options in Biohaven Pharmaceuticals Rimegepant is an investigational new drug, not approved or authorized for marketing in the U.S. or any country for any indication or treatment of any disease or condition. This material is being made available for informational purposes only. 2
Triptans: Nonresponse, Recurrence, and Serious AEs for Many Patients Serotonin 5-HT 1B/1D receptor agonists (triptans) have been the most widely prescribed acute treatment of migraine for decades 1 34% 30%-40% ~3.5 million Do not respond 2 Have attack recurrence 3 Contraindicated or use with caution 4,5 1. Loder E. NEJM. 2010;363:63-70.; 2. Lipton RB et al. Headache. 2017;57:1026-40.; 3. Cameron C et al. Headache. 2015;55 Suppl 4:221-35.; 4. Buse DC et al. Headache. 2017;57:31-44.; 5. Lipton RB et al. Headache. 2017;57:1507-21. 3
Study Design Double-blind, randomized, placebo-controlled, multicenter Phase 3 study Eligible subjects: At least 18 years of age At least a 1-year history of migraine (ICHD-3 beta 1 ) 2-8 migraine attacks of moderate or severe intensity per month Fewer than 15 days with headache per month (migraine or non-migraine) over the last 3 months Any preventive migraine medication had to be stable for at least 3 months Randomized to receive rimegepant 75 mg or placebo Instructed to treat a single migraine attack ICHD-3 beta. Cephalalgia. 2013;33(9):629-808. 4
Subject Demographics Characteristic Rimegepant 75 mg Placebo Total N=537 N=535 N=1072 Age, years (SD) 40.2 (11.9) 40.9 (12.1) 40.6 (12.0) Female, n (%) 479 (89.2) 472 (88.2) 951 (88.7) Body mass index, kg/m 2 (SD) 30.1 (7.9) 31.8 (8.5) 31.4 (8.2) Attacks per month, n (SD) 4.5 (1.9) 4.6 (1.8) 4.6 (1.8) Duration of untreated attacks, hr (SD) 32.0 (22.5) 32.9 (21.7) 32.5 (22.1) Historical MBS, n (%) Photophobia 316 (58.8) 303 (56.6) 619 (57.7) Phonophobia 79 (14.7) 90 (16.8) 169 (15.8) Nausea 142 (26.4) 142 (26.5) 284 (26.5) SD, Standard Deviation MBS, most bothersome symptom 5
Subject Disposition Rimegepant 75 mg Placebo Randomized 594 592 Received study treatment 543 543 Did not receive study treatment a 51 49 Completed acute phase 538 542 Discontinued a 5 1 Analyzed Safety 543 543 Modified intent-to-treat 537 535 a Most common reasons were lost to follow-up and no qualifying migraine attack 6
Superior to Placebo on Both Coprimary Efficacy Endpoints 70 60 Rimegepant Placebo N=537 N=535 Proportion of Subjects 50 40 30 20 10 19.6 P=0.0006 12.0 37.6 P<0.0001 25.2 0 Pain Freedom at 2 hours postdose Freedom from the MBS at 2 hours postdose MBS, most bothersome symptom 7
Significant Superiority on Key Secondary Endpoints Durability Evident from 2 through 48 Hours Endpoints Rimegepant 75 mg N=537, n (%) Placebo N=535, n (%) P-value a Photophobia-free at 2 hours b 183 (37.4) 106 (22.3) <0.0001 Phonophobia-free at 2 hours c 133 (36.7) 100 (26.8) 0.0039 Pain relief at 2 hours 312 (58.1) 229 (42.8) <0.0001 Nausea-free at 2 hours d 171 (48.1) 145 (43.3) 0.2084 Rescue medication within 24 hours 113 (21.0) 198 (37.0) <0.0001 Sustained pain-free, 2-24 hours 66 (12.3) 38 (7.1) 0.0040 Sustained pain relief, 2-24 hours 229 (42.6) 142 (26.5) <0.0001 Sustained pain-free, 2-48 hours 53 (9.9) 32 (6.0) 0.0181 Sustained pain relief, 2-48 hours 195 (36.3) 121 (22.6) <0.0001 Pain relapse from 2 to 48 hours e 52 (49.6) 32 (50.0) 0.9648 Ability to function normally at 2 hours 175 (32.6) 125 (23.4) 0.0007 Nausea-free at 3 hours d,f 209 (58.8) 167 (49.7) 0.0156 Sustained ability to function normally, 2-48 hours f 105 (19.6) 67 (12.5) 0.0016 Sustained freedom from the MBS, 2-48 hours f 112 (20.9) 65 (12.2) 0.0001 a Secondary endpoints were tested hierarchically in the order shown at P=0.05 b Rimegepant n=489, placebo n=477; c Rimegepant n=362, placebo n=374; d Rimegepant n=355, placebo n=336; e Rimegepant n=105, placebo n=64 f Exploratory endpoint 8
Pain Freedom with Single Dose: Increasing Benefit Over Time Pain Freedom 2-8 Hours Post-Single Dosing with Rimegepant 75 mg % of Patients Pain Free 100 80 60 40 20 Rimegepant 75 mg (n=537) Percent (%) difference versus placebo at each time point Placebo (n=535) Single Dose of Rimegepant, No Rescue Meds 48% 43% 37% 30% 20% 0 2 hr 3 hr 4 hr 6 hr 8 hr Time Pain Freedom represents subjects that report no pain at the timepoint of interest. Percentages represent Non-Completer = Failure (NC=F) estimates of pain freedom, and were based on the mitt population. 9
Greater Proportion of Subjects Achieving Pain Relief and Normal Function Without Additional Dosing or Rescue Medications Pain Relief up to 8 Hours Postdose Disability Freedom up to 8 Hours Postdose Pain Relief represents the first report of either mild pain or no pain. Probabilities are Kaplan-Meier estimates; subjects were censored (not included) at the time they took rescue medication or provided their last data point. Four-point scale: 0=normal function, 1=mild impairment, 2=severe impairment, 3=required bedrest Data are Kaplan-Meier estimates of the first report of Normal Function. Subjects were censored (not included) at the time they took rescue medication or provided their last data point. 10
Safety Profile Similar to Placebo Adverse Event Rimegepant 75 mg N = 543, n (%) Placebo N = 543, n (%) Subjects with AE 93 (17.1) 77 (14.2) AEs reported by 1% of subjects a Nausea 10 (1.8) 6 (1.1) Urinary tract infection 8 (1.5) 6 (1.1) AEs related to treatment 10 (1.8) 3 (.6) Serious AEs 1 (0.2) b 2 (0.4) AEs leading to discontinuation 0 0 AE, adverse event; a In either treatment group; b Back pain; unrelated to treatment 11
Liver Safety Liver Function Tests Rimegepant 75 mg N = 543, n (%) Placebo N = 543, n (%) Serum AST or ALT > ULN 13 (2.4) 12 (2.2) Serum AST or ALT > 3x ULN 0 0 Serum AST or ALT > 5x ULN 0 0 Bilirubin elevations > 2x ULN 0 0 AST, aspartate transaminase; ALT, alanine transaminase; ULN, upper limit of normal 12
Conclusions Coprimary endpoints met Pain Freedom at 2 hours postdose Freedom From the Most Bothersome Symptom at 2 hours postdose Broad and clinically important drug benefit with single dose of rimegepant Majority of patients achieve Pain Relief Durability of benefit (24 and 48 hours) Lower use of rescue meds Greater proportion of patients achieving normal function Excellent safety profile similar to placebo including liver function tests Tolerability profile similar to placebo and favorable compared to historical triptan experience Consistent results across endpoints and all efficacy trials Phase 3 Study 301 is presented as a late-breaking poster (PS123LB) 13
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