A Phase 1 Study to Evaluate the Bioequivalence of Oral Tablet and Orally Dissolving Tablet Formulations of Rimegepant, a Small M

A Phase 1 Study to Evaluate the Bioequivalence Poster No. MTIS2018-170 of Oral Tablet and Orally Dissolving Tablet Formulations of Rimegepant, a Small Molecule CGRP Receptor Antagonist Robert Croop, MD1; Andrea Ivans, MHS1; David Stock, PhD1; Jennifer Hould, BA1; Beth A. Morris, BA1; Joe Stringfellow, MS1; Christopher M. Jensen, PharmD1; Julie-Alexandra Moulin, MSc2; Richard Larouche, BPharm, MD2; Mario Tanguay, BPharm, PhD2; Vladimir Coric, MD1; Richard B. Lipton, MD3 1Biohaven Pharmaceuticals, New Haven, CT, USA; 2Syneos Health, Quebec, Canada; 3Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA Introduction Results • Patient preference is an important component of drug selection in the acute treatment Subjects of migraine1 • A total of 35 subjects was enrolled, and 34 subjects (97.1%) completed the study • In some patients, the affinity for a particular type of migraine treatment does not • The demographic characteristics of the study population are shown in Table 1 completely align with standard efficacy endpoints, such as pain relief,1 that might be expected to predict preference Table 1. Demographics (N=35) • This helps to explain why a rapid onset of relief is consistently ranked among the most 2-4 important attributes of acute migraine medications Characteristic • When offered a choice between delivery systems for acute treatment, the vast majority of patients with headache conditions (~90%) prefer oral formulations5 Age, years, mean (SD) 37.7 (9.5) • Because of the convenience and perceived rapid onset of action with Orally Dissolving Sex, n (%) Tablet (ODT) formulations, patients with migraine have been shown to prefer them to Male 28 (80.0) traditional oral tablets6-8 Female 7 (20.0) • Adherence to drug therapy is generally poor in migraine,5 and drug delivery via ODT may improve patient adherence to prescribed regimens9 Race, n (%) • Following oral administration, ODTs are rapidly dissolved and absorbed without the White 28 (80.0) need for additional fluid, which facilitates easy administration of acute treatment to Non-White 7 (20.0) headache patients BMI, kg/m2 25.85 • Rimegepant is an orally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine Weight, kg 76.6 • Two formulations of rimegepant are being developed: Pharmacokinetics – A conventional oral tablet – An ODT utilizing the Zydis® fast-dissolve technology • Statistical comparisons of the ln-transformed AUC0-t, AUC0-inf, and Cmax of rimegepant ODT administered sublingually versus rimegepant tablet showed that all 90% CIs of • Two Phase 3 clinical trials of rimegepant oral tablet for the acute treatment of migraine geometric mean ratios were within the predefined range (80%-125%) for bioequivalence have been completed (Study 301, NCT03235479; Study 302, NCT03237845) (Table 2) • A pharmacokinetic (PK) comparison of rimegepant ODT versus rimegepant tablet is • Median Tmax was 1.5 hours for rimegepant ODT administered sublingually versus required to characterize their individual PK profiles and ascertain bioequivalence 2 hours for rimegepant oral tablet • A statistical comparison, using Proc Mixed, found the least-squares means (standard Objectives errors) for rimegepant ODT and oral tablet to be 1.48 (0.098) hours and 1.92 (0.163) • The objectives of this study were to: hours, respectively – Compare the rate and extent of absorption of rimegepant ODT administered • The difference in time to peak concentration, 0.44 hours (26 minutes), was statistically sublingually versus rimegepant oral tablet administered as 1 x 75 mg in healthy, significant (P=0.0021) fasted volunteers – Assess the safety, tolerability, and PK of rimegepant ODT and rimegepant oral tablet Table 2. Bioequivalence of Rimegepant ODT and Rimegepant Oral Tablet Methods PK Parameter Ratioa (%) 90% CIb (%) • This was a single-center, Phase 1, open-label, randomized 4-period bioequivalence Lower Upper study Ln(AUC ) 96.79 92.63 101.15 • Subjects were screened within 28 days of the administration of study medications 0-t Ln(AUC ) 96.81 92.66 101.14 Subjects 0-inf

• The study population included members of the community at large who were recruited Ln(Cmax) 104.65 97.04 112.84 via advertisements in various media (eg, radio, newspaper, online) PK, pharmacokinetic; CI, confidence interval a (DIFFERENCE) 2 Calculated using least squares means according to the formula: e X 100 • Healthy adult nonsmokers, aged 18 to 55 years, with BMI between 18.5 and 30.0 kg/m b90% Geometric Confidence Interval using ln-transformed data and weight of at least 50.0 kg for males and 45.0 kg for females were eligible to participate Safety • Any subject with a medical history, concurrent illness, or any physical or laboratory test • Seventeen subjects experienced adverse events (AEs) finding that was likely to interfere with successful completion of the dosing procedure or analysis of results was excluded • Most AEs were mild, required no treatment, and did not result in withdrawal from the study Treatments • The only AEs reported by more than 1 subject were constipation (n=6); increased level • Subjects were given the 2 following treatments twice: of alanine transaminase (n=3, none >3x ULN); heart rate increase (n=2); headache (n=2); cold symptoms (n=2); and back pain (n=2) – 75 mg rimegepant ODT administered sublingually held under the tongue until fully dissolved then swallowed without water • One subject discontinued due to a moderate AE (external otitis), which was considered unrelated to treatment – 75 mg rimegepant oral tablet swallowed with water • No severe or serious AEs were reported • Doses were administered after a 10-hour overnight fast • Treatments were separated by washouts of at least 5 days Assessments Conclusions • For analysis of the PK parameters AUC0-t, AUC0-inf, Cmax, and Tmax, blood samples were • This study demonstrates that, based on the rate and extent of absorption, collected at baseline, 5, 10, 20, 30, 40, 50 minutes and 1, 1.5, 2, 2.5, 5, 8, 12, 24, 48, rimegepant ODT administered sublingually and rimegepant oral tablet are and 72 hours bioequivalent • Following analyses of AUC0-t, AUC0-inf, and Cmax — the primary PK endpoints — the • Rimegepant ODT and rimegepant oral tablet were well tolerated formulations were considered bioequivalent if the 90% CI for the ratio of geometric means was within 80% to 125% • The earlier Tmax seen with rimegepant ODT versus oral tablet is a PK advantage that might translate into an earlier onset of action for this Pharmacokinetic and Statistical Analyses fast-dissolving ODT formulation • The PK analysis was performed using Phoenix® WinNonlin® • The results of a Phase 3 clinical trial of rimegepant ODT for the acute • Inferential statistical analyses were performed using ln-transformed data and the MIXED treatment of migraine are pending (Study 303, NCT03461757) procedure in SAS®

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References: 1. Dahlöf C et al. J Headache Pain. 2004;5:115-122.; 2. Lipton RB et al. Headache. 1999;39(s2):S20-S26.; 3. Lipton RB et al. Headache. 2002;42 Suppl 1:3-9.; 4. Malik SN et al. Headache. 2006;46(5):773-780.; 5. Mitsikostas DD et al. J Headache Pain. 2017;18(1):102.; 6. Loder E et al. Headache. 2001;41(8):745-753.; 7. Dowson AJ et al. Curr Med Res Opin. 2005;21 Suppl 3:S13-17.; 8. Dowson AJ et al. Int J Clin Pract. 2003;57(7):573-576.; 9. Delini-Stula A et al. Int J Psychiatry Clin Pract. 2009;13(2):109-116. Acknowledgments RC, AI, DS, JH, BAM, JS, CJ, and VC are employees and stockholders in Biohaven Pharmaceuticals; J-AM, RL, and MT are employees of Syneos Health; RBL has received honoraria and research support from Biohaven Pharmaceuticals; he is also a stockholder

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. To download a copy of 17th Biennial Migraine Trust International Symposium | 6-9 September 2018 | London, UK this poster, scan code.