A Phase 1 Study to Evaluate the Bioequivalence of Oral Tablet ...

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

in Healthy Adult Subjects Under Fasting Conditions

Robert Croop, MD1; Andrea Ivans, MHS1; David Stock, PhD1; Jennifer Hould, BA1; Beth A. Morris, BA1; Joe Stringfellow, MS1; Julie-Alexandra Moulin, MSc2; Richard Larouche BPharm, MD2; Mario Tanguay, BPharm, PhD2; Vladimir Coric, MD1; Richard B. Lipton, MD3,4,5

1 Biohaven Pharmaceuticals, New Haven, CT, USA; 2 Syneos Health, Quebec, Canada; 3 Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; 4 Montefiore Medical Center, Bronx, NY, USA; 5 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

INTRODUCTION

OBJECTIVES

Assessments

Pharmacokinetics

? Patient preference data can be useful in tailoring

migraine therapy to the needs of individual patients1

? Preference for migraine medications does not always

align with traditional efficacy endpoints (eg, pain

relief)1

? Patients with migraine have consistently expressed a

desire for rapid onset of therapeutic action2-4

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 volunteers under fasting conditions

? Assess the safety, tolerability, and pharmacokinetics

(PK) of rimegepant tablet and ODT

? For analysis of the PK parameters AUC0-t, AUC0-inf, Cmax,

and Tmax, blood samples were collected at predose, 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, the formulations were

considered bioequivalent if the 90% CI for the ratio of

? 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 versus 2 hours for rimegepant

? Evidence indicates that patients with headache

conditions prefer oral formulations when offered a

choice between delivery systems for acute treatment5

? Many patients with migraine prefer orally dissolving

tablets (ODTs) to conventional oral tablets for

convenience and perceived rapid onset of action6-8

? Drug delivery via ODT may improve patient adherence

METHODS

? This single-center, Phase 1, open-label, randomized

study was designed as a 4-period bioequivalence study

? Subjects were screened within 28 days of the

administration of study medications

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 MIXED procedure in SAS?

oral tablet

? A statistical comparison, using Proc Mixed, found the

least-squares means (standard errors) for the ODT and

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 statistically significant (P=0.0021)

to prescribed regimens9

? Following oral administration, ODTs are rapidly

Subjects

? Subjects were members of the community at large who RESULTS

Table 2. Bioequivalence of Rimegepant ODT and Rimegepant Oral Tablet

dissolved and absorbed without the need for additional

fluid, enabling easy administration of pharmaceutical

preparations

? Rimegepant is an orally administered small molecule

calcitonin gene-related peptide (CGRP) receptor

antagonist in development for the acute treatment of

were recruited via advertisements in various media (eg,

radio, newspaper, online)

? Eligible subjects included healthy adult nonsmokers,

aged 18 to 55 years (inclusive), 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

Subjects

? In total, 35 subjects were enrolled, and 34 (97.1%)

completed the study

? The demographic characteristics of the study

population are shown in Table 1

PK Parameter

Ln(AUC0-t) Ln(AUC0-inf) Ln(Cmax)

Ratioa (%)

96.79 96.81 104.65

90% CIb (%) Lower Upper 92.63 101.15 92.66 101.14 97.04 112.84

migraine

? Two formulations of rimegepant are being developed:

? Subjects with a medical history, concurrent illness, or

any physical or laboratory test finding that was likely to Table 1. Demographics (N=35)

PK, pharmacokinetic; CI, confidence interval aCalculated using least squares means according to the formula: e(DIFFERENCE) X 100 b90% Geometric Confidence Interval using log-transformed data

? 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 migraine have been completed (Study 301, NCT03235479; Study 302, NCT03237845)

? A pharmacokinetic (PK) comparison of rimegepant

ODT versus rimegepant tablet is required to define their individual PK profiles and determine bioequivalence

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

interfere with successful completion of the dosing procedure or analysis of results were excluded

Treatments

? Subjects received the 2 following treatments twice: ? 75 mg rimegepant ODT administered sublingually

held under the tongue until fully dissolved 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 5 days

Characteristic Age, years, mean (SD) Sex, n (%)

Male Female Race, n (%) White Non-White BMI, kg/m2 Weight, kg

37.7 (9.5)

28 (80.0) 7 (20.0)

28 (80.0) 7 (20.0)

25.85 76.6

Safety

? Adverse events (AEs) were reported by 17 subjects ? Most AEs were mild, required no treatment, and did not

result in withdrawal from the study

? The only AEs observed in >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) that was considered unrelated to

treatment

? There were no severe or serious AEs

Presented at the 60th Annual Scientific Meeting of the American Headache Society, 29 June 2018, San Francisco, CA (Poster #PF116LB)

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.

CONCLUSIONS

? This study demonstrates that, based on the

rate and extent of absorption, rimegepant ODT administered sublingually and rimegepant oral tablet met criteria for bioequivalence

? Rimegepant ODT and rimegepant oral tablet

were well tolerated

? The earlier Tmax seen with the rimegepant ODT

versus the oral tablet is a PK advantage that might translate into an earlier onset of action for this fast-dissolving ODT formulation

? A Phase 3 clinical trial of rimegepant ODT for

the acute treatment of migraine is ongoing (Study 303, NCT03461757)

REFERENCES

1. Dahl?f 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.

DISCLOSURES

? RC, AI, DS, JH, BAM, JS, 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

To obtain a PDF of this poster and other Biohaven AHS 2018 presentations: Scan the QR code or visit ahs2018

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