a phase 1 study to evaluate the bioequivalence of oral tablet … · 2018-09-21 · a phase 1 study...

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

• Patient preference is an important component of drug selection in the acute treatmentof migraine1

• In some patients, the affinity for a particular type of migraine treatment does notcompletely align with standard efficacy endpoints, such as pain relief,1 that might beexpected to predict preference

• This helps to explain why a rapid onset of relief is consistently ranked among the mostimportant attributes of acute migraine medications2-4

• When offered a choice between delivery systems for acute treatment, the vast majorityof patients with headache conditions (~90%) prefer oral formulations5

• Because of the convenience and perceived rapid onset of action with Orally DissolvingTablet (ODT) formulations, patients with migraine have been shown to prefer them totraditional oral tablets6-8

• Adherence to drug therapy is generally poor in migraine,5 and drug delivery via ODTmay improve patient adherence to prescribed regimens9

• Following oral administration, ODTs are rapidly dissolved and absorbed without theneed for additional fluid, which facilitates easy administration of acute treatment toheadache patients

• Rimegepant is an orally administered small molecule calcitonin gene-related peptide(CGRP) receptor antagonist in development for the acute treatment of migraine

• Two formulations of rimegepant are being developed:– A conventional oral tablet– An ODT utilizing the Zydis® fast-dissolve technology

• Two Phase 3 clinical trials of rimegepant oral tablet for the acute treatment of migrainehave been completed (Study 301, NCT03235479; Study 302, NCT03237845)

• A pharmacokinetic (PK) comparison of rimegepant ODT versus rimegepant tablet isrequired to characterize their individual PK profiles and ascertain bioequivalence

Introduction

Objectives

• A total of 35 subjects was enrolled, and 34 subjects (97.1%) completed the study• The demographic characteristics of the study population are shown in Table 1

Results

Characteristic

Age, years, mean (SD) 37.7 (9.5)Sex, n (%)

Male 28 (80.0)Female 7 (20.0)

Race, n (%)White 28 (80.0)Non-White 7 (20.0)

BMI, kg/m2 25.85Weight, kg 76.6

Conclusions• This study demonstrates that, based on the rate and extent of absorption,

rimegepant ODT administered sublingually and rimegepant oral tablet arebioequivalent

• Rimegepant ODT and rimegepant oral tablet were well tolerated• 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 fast-dissolving ODT formulation

• The results of a Phase 3 clinical trial of rimegepant ODT for the acutetreatment of migraine are pending (Study 303, NCT03461757)

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

A Phase 1 Study to Evaluate the Bioequivalence of Oral Tablet and Orally Dissolving Tablet Formulations of Rimegepant, a Small Molecule CGRP Receptor AntagonistRobert 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, MD31Biohaven Pharmaceuticals, New Haven, CT, USA; 2Syneos Health, Quebec, Canada; 3Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA

• The objectives of this study were to:– Compare the rate and extent of absorption of rimegepant ODT administered

sublingually versus rimegepant oral tablet administered as 1 x 75 mg in healthy,fasted volunteers

– Assess the safety, tolerability, and PK of rimegepant ODT and rimegepant oral tablet

Methods• This was a single-center, Phase 1, open-label, randomized 4-period bioequivalence

study• Subjects were screened within 28 days of the administration of study medications

Subjects• The study population included members of the community at large who were recruited

via advertisements in various media (eg, radio, newspaper, online)• Healthy adult nonsmokers, aged 18 to 55 years, with BMI between 18.5 and 30.0 kg/m2

and weight of at least 50.0 kg for males and 45.0 kg for females were eligible toparticipate

• Any subject with a medical history, concurrent illness, or any physical or laboratory testfinding that was likely to interfere with successful completion of the dosing procedureor analysis of results was excluded

Safety• Seventeen subjects experienced adverse events (AEs)• Most AEs were mild, required no treatment, and did not result in withdrawal from the

study• The only AEs reported by more than 1 subject were constipation (n=6); increased level

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)

• One subject discontinued due to a moderate AE (external otitis), which was consideredunrelated to treatment

• No severe or serious AEs were reported

Treatments• Subjects were given the 2 following treatments twice:

– 75 mg rimegepant ODT administered sublingually held under the tongue until fullydissolved then swallowed without water

– 75 mg rimegepant oral tablet swallowed with water• Doses were administered after a 10-hour overnight fast• Treatments were separated by washouts of at least 5 days

Assessments• For analysis of the PK parameters AUC0-t, AUC0-inf, Cmax, and Tmax, blood samples were

collected at baseline, 5, 10, 20, 30, 40, 50 minutes and 1, 1.5, 2, 2.5, 5, 8, 12, 24, 48, and 72 hours

• Following analyses of AUC0-t, AUC0-inf, and Cmax — the primary PK endpoints — theformulations were considered bioequivalent if the 90% CI for the ratio of geometric means was within 80% to 125%

Pharmacokinetic and Statistical Analyses• The PK analysis was performed using Phoenix® WinNonlin®

• Inferential statistical analyses were performed using ln-transformed data and the MIXEDprocedure in SAS®

Zydis is a registered trademark of R.P. Scherer Technologies, Inc.

Table 1. Demographics (N=35)

PK Parameter Ratioa (%) 90% CIb (%)

Lower Upper

Ln(AUC0-t) 96.79 92.63 101.15

Ln(AUC0-inf) 96.81 92.66 101.14

Ln(Cmax) 104.65 97.04 112.84PK, pharmacokinetic; CI, confidence intervalaCalculated using least squares means according to the formula: e(DIFFERENCE) X 100b90% Geometric Confidence Interval using ln-transformed data

Table 2. Bioequivalence of Rimegepant ODT and Rimegepant Oral Tablet

Subjects

Pharmacokinetics• 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 geometric mean ratios were within the predefined range (80%-125%) for bioequivalence (Table 2)

• Median Tmax was 1.5 hours for rimegepant ODT administered sublingually versus2 hours for rimegepant oral tablet

• A statistical comparison, using Proc Mixed, found the least-squares means (standarderrors) for rimegepant ODT and oral tablet to be 1.48 (0.098) hours and 1.92 (0.163)hours, respectively

• The difference in time to peak concentration, 0.44 hours (26 minutes), was statisticallysignificant (P=0.0021)

Poster No. MTIS2018-170

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.