Efficacy, Safety, and Tolerability of Rimegepant 75 mg Orally Dissolving Tablet for the Acute Treatment of Migraine: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial (Study 303)

Richard B. Lipton, MD1; Vladimir Coric, MD2; Elyse G. Stock, MD2; David A. Stock, PhD2; Alexandra C. Thiry, PhD2; Charles M. Conway, PhD2;

Gene M. Dubowchik, PhD2; Christopher M. Jensen, PharmD2; Ralph Gosden, MSc3; Marianne Frost, MA2; Kimberly Gentile, BS2; Beth A. Morris, BA2; Micaela Forshaw, MPH2; Robert Croop, MD2

1Albert Einstein College of Medicine, Bronx, NY, USA; 2Biohaven Pharmaceuticals, Inc.,New Haven, CT, USA; 3Catalent UK Swindon Zydis Limited, Swindon, UK

Disclosures: Richard B. Lipton, MD, serves on the editorial board of Neurology and Cephalalgia and as senior advisor to Headache but is not paidfor his roles on Neurology or Headache. He has received research support from the NIH. He also receives support from the Migraine ResearchFoundation and the National Headache Foundation. He receives research grants from Allergan, Amgen, Dr. Reddy’s Laboratories, and Novartis. Hehas reviewed for the NIA and NINDS and serves as consultant, advisory board member, or has received honoraria from Alder, Allergan, Amgen,Autonomic Technologies, Avanir, Biohaven, 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 (8th Edition, Oxford Press University, 2009) andInforma. He holds stock options in eNeura Therapeutics and Biohaven Pharmaceuticals. Vladimir Coric, MD; Elyse G. Stock, MD; David A. Stock,PhD; Alexandra C. Thiry, PhD; Charles M. Conway, PhD; Gene M. Dubowchik, PhD; Christopher M. Jensen, PharmD; Marianne Frost, MA;Kimberly Gentile, BS; Beth A. Morris, BA; Micaela Forshaw, MPH; and Robert Croop, MD, are employed by and hold stock/stock options inBiohaven Pharmaceuticals. Ralph Gosden, MSc, is employed by Catalent Pharma Solutions – Zydis, Swindon, United Kingdom.

Characteristic Overall (N=1351)

Age, years, mean (SD) 40.2 (12.0)Sex, n (%)

Female 1147 (84.9)Male 204 (15.1)

Mean moderate-severe attacks per month, n (SD) 4.6 (1.79)Mean duration of untreated attacks, hr (SD) 29.5 (21.6)Historical MBS, n (%)

Photophobia 770 (57.0)Nausea 317 (23.5)Phonophobia 261 (19.3)

Using concurrent preventive medication, n (%) 187 (13.8)

Background:• Rimegepant is a small molecule calcitonin

gene-related peptide (CGRP) receptor antagonist with demonstrated efficacy in the acute treatment of migraine1,2

• Previous Phase 1 study, Tmax vs tablets3

• 1.5 hours for ODT• 2.0 hours for tablet

Objective:• Compare the efficacy, safety, and tolerability

of rimegepant 75 mg ODT with placebo in the acute treatment of migraine

Subjects:• Aged ≥18 years, with ≥1-year history of ICHD-3

beta migraine• Two to 8 moderate or severe monthly migraine

attacks; <15 monthly headache days (migraine or non-migraine) over the last 3 months

• Preventive migraine medication dose stable for ≥3 months (if using)

Demographics and Baseline Characteristics: Representative of Typical Migraine Patient Population

Methods: • Double-blind, randomized, placebo-controlled,

multicenter Phase 3 trial (Study 303, NCT03461757) • Randomized to rimegepant 75 mg ODT or placebo to treat

1 migraine attack of moderate or severe pain intensity

Rimegepant 75 mg ODT for the Acute Treatment of Migraine

1. Lipton RB et al. N Engl J Med. 2019;381:142-9.; 2. Lipton RB et al. Cephalalgia. 2018;38(1 suppl):123-55 (abstract MTIS2018-171). 2. Croop R et al. Cephalalgia. 2018;38(1 suppl):123-55 (abstract MTIS2018-170).

Superiority Over Placebo

21 Consecutive, Prespecified, Hierarchically-Tested Efficacy

Outcome Measures

Coprimary and Secondary Endpoints Rimegepant N=669

PlaceboN=682 P value

Pain freedom, 2 h (co-primary) 21.2% 10.9% <.0001Freedom from the MBS, 2 h (co-primary) 35.1% 26.8% .0009Pain relief, 2 h 59.3% 43.3% <.0001Ability to function normally, 2 h 38.1% 25.8% <.0001Sustained pain relief, 2–24 h 47.8% 27.7% <.0001Sustained freedom from the MBS, 2–24 h 27.1% 17.7% <.0001Probability of rescue medication use within 24 h 14.2% 29.2% <.0001Sustained ability to function normally, 2–24 h 29.6% 16.9% <.0001Sustained pain relief, 2–48 h 42.2% 25.2% <.0001Sustained freedom from the MBS, 2–48 h 23.2% 16.4% .0018Sustained ability to function normally, 2–48 h 26.0% 15.4% <.0001Freedom from photophobia, 2 ha 33.4% 24.5% .0007Ability to function normally, 90 min 30.2% 21.3% .0002Pain relief, 90 min 49.6% 37.2% <.0001Sustained pain freedom, 2–24 h 15.7% 5.6% <.0001Freedom from the MBS, 90 min 27.4% 21.5% .0128Pain freedom, 90 min 15.1% 7.3% <.0001Freedom from phonophobia, 2 hb 41.7% 30.2% .0003Sustained pain freedom, 2–48 h 13.5% 5.4% <.0001Pain relief, 60 min 36.8% 31.2% .0314Ability to function normally, 60 min 22.3% 15.8% .0025Freedom from nausea, 2 hc 51.0% 45.2% .0898Pain relapse, 2–48 hd,e 36.6% 50.0% .0577 aRimegepant (n=593), placebo (n=611)bRimegepant (n=451), placebo (n=447)cRimegepant (n=397), placebo (n=430)

dRimegepant (n=142), placebo (n=74)eNominal p-value is nominal after the first nonsignificant result

Rimegepant 75 mg ODT

For Pain Relief, Rimegepant 75 mg ODT Achieves Statistical Significance at 60 Minutes Postdose

aDefined as patients who have either mild-pain or no-pain during the specified interval. Estimates computed using the mITT population and CMH methods. Subjects using rescue medications at or before the assessment, and subjects not providing data, are classified as failures.

0

10

20

30

40

50

60

1 2 3 4 5 6

Subj

ects

(%) W

ith P

ain

Rel

ief

Pain Relief 0-2 Hoursa

Minutes

Rimegepant 75 mg (n=669)Placebo (n=682)

19%

59%

37%

50%

8%

28%

**

*P<.05, **P<.0001

**

*

15 30 45 60 90 120

A Single Dose of Rimegepant 75 mg ODT: Early and Sustained Effects on Pain and Return to Normal Functioning

Pain Relief

*60 min *90 min *2 hr *24 hr *48 hr

Sustained Pain Relief

Sustained Pain Relief

Return to Normal Function

*60 min *90 min *2 hr *24 hr *48 hr

Sustained Normal Function

Sustained Normal Function

Pain Freedom

*90 min *2 hr *24 hr *48 hr

Sustained Pain Freedom

Sustained Pain Freedom

*P<.05 vs placebo

Rimegepant-Treated Subjects Were Significantly Less Likely to Use Rescue Medication and Had Delayed Time to Use

<15% Probability That Rimegepant-Treated Patients Used Rescue Medications Within 24 Hours

Data are Kaplan-Meier estimates of Rescue Medicine Use; subjects were censored (not included) at the time of taking rescue medication, and those lost to follow-up were censored at the end of the specified interval. Kaplan-Meier curve is an exploratory analysis.

• The most common AEs were nausea and urinary tract infection (≤1.6%)• Two patients (one in each treatment group) had transaminase elevations >3x ULN

• Both judged not to be drug-related • No subjects experienced elevations in bilirubin >2x the ULN

Rimegepant 75 mg ODTn=682, n (%)

PlaceboN=693, n (%)

Participants with AEs 90 (13.2) 73 (10.5)AEs reported by ≥ 1% of subjects

Nausea 11 (1.6) 3 (.4)Urinary tract infection 10 (1.5) 4 (.6)

AEs related to treatment 47 (6.9) 36 (5.2)Serious AEs 0 (.0) 0 (.0)

Rimegepant 75 mg ODT Safety and Tolerability Were Similar to Placebo

ULN, upper limit of normal

RIMEGEPANT PHASE 3 – STUDY 303, 75 MG ZYDIS ODT

• Met the coprimary endpoints: freedom from pain (P<.0001) and freedom from the most bothersome symptom (P=.0009) at 2 hours

• Early onset of pain relief and return to normal function at 60 minutes• Superior to placebo on 21 consecutive, prespecified, hierarchically-tested

efficacy outcome measures• Clinical effects observed from 2 through 48 hours postdose on:

• Freedom from pain (P<.0001)• Pain relief (P<.0001)• Freedom from most bothersome symptom (P=.0018)• Freedom from functional disability (P<.0001)

• Safety profile similar to placebo, including liver function tests

Conclusions: Phase 3 Rimegepant 75 mg ODTProfile of Early and Sustained Effects in the Acute Treatment of Migraine

Published online today in The Lancet

Croop R et al. Lancet. 2019. http://dx.doi.org/10.1016/S0140-6736(19)31606-X.