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Abstract Details

Concentration QT Interval Modeling of Intranasally Administered Zavegepant in Healthy Subjects
Headache
P9 - Poster Session 9 (5:30 PM-6:30 PM)
2-004

Calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. Zavegepant (BHV-3500/formerly vazegepant) is a high-affinity, selective, small molecule CGRP receptor antagonist in development for migraine treatment.

To evaluate the cardiovascular safety of single and multiple ascending doses (SAD/MAD) of zavegepant nasal spray.

Two Phase 1, single-center, randomized, double-blind, placebo-controlled, sequential studies were conducted in healthy adults. The SAD study participants were administered with 0.1, 0.3, 1, 3, 5, 10, 20, 20 (2×10), or 40 (2×20) mg zavegepant nasal spray or placebo. The MAD study participants received 5, 10, or 20 mg zavegepant nasal spray once daily (QD) for 14 days, 40 mg (2×20, 2-hour interval) QD for 8 days, 40 mg (2×20, 30-min interval) or 40 mg (2×20, nose blow with 5-min interval) for 1 day or matching placebo. Plasma zavegepant pharmacokinetics and ECG parameters (heart rate, Fridericia-corrected QT interval [QTcF], PR interval, ventricular depolarization [QRS], T-wave morphology) were analyzed pre- and post-zavegepant administration. Furthermore, a pooled SAD/MAD plasma zavegepant concentration-QTcF assessment using the linear mixed-effects model was done (SAD: 1218 and MAD: 1600 PK-QTcF pairs).
In total, 72 subjects (SAD: 54 active/18 placebo) and 71 subjects (MAD: 56 active/16 placebo) were dosed. The mean change (Δ)/placebo-corrected change (ΔΔ) from the baseline heart rate (ΔΔHR) and the QTcF (ΔQTcF) was similar to placebo; ΔΔQTcF was not dose-dependent. Homogeneity testing showed no group variance, indicating pooled analysis was appropriate for concentration-QTcF assessment. The estimated slope of the plasma zavegepant concentration-QTcF model was negative and not statistically significant (-0.044 msec per ng/mL [90%CI: -0.1231 to 0.0346]). A QT interval exceeding 10 msec can be excluded for plasma zavegepant up to 214 ng/mL. No changes in T-morphology were noted.

Based on pooled analysis of intranasal SAD/MAD data, zavegepant has no clinically relevant effect on ECG parameters.

Authors/Disclosures
Jing Liu
PRESENTER
Jing Liu has received personal compensation for serving as an employee of Pfizer, Inc.. Jing Liu has stock in Pfizer, Inc. .
Richard Bertz (Biohaven Pharmaceuticals) Richard Bertz has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Richard Bertz has stock in Biohaven Pharmaceuticals.
Joseph Stringfellow Joseph Stringfellow has nothing to disclose.
Rajinder K. Bhardwaj, PhD (Certara) The institution of Dr. Bhardwaj has received personal compensation in the range of $0-$499 for serving as a Consultant for Certara.
Mary Kathleen Donohue, Other (Biohaven Pharmaceuticals, Inc.) Ms. Donohue has received personal compensation for serving as an employee of Biohaven Pharmaceuticals, Inc.. Ms. Donohue has stock in Biohaven Pharmaceuticals, Inc..
Jennifer Madonia (Biohaven Pharmaceuticals) Jennifer Madonia has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Jennifer Madonia has stock in Biohaven Pharmaceuticals.
Matt Anderson Matt Anderson has received personal compensation for serving as an employee of Certara. An immediate family member of Matt Anderson has received personal compensation for serving as an employee of Bristol Myers Squibb. Matt Anderson has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Certara Strategic Consulting. An immediate family member of Matt Anderson has received stock or an ownership interest from Bristol Myers Squibb.
Beth Morris Beth Morris has received personal compensation for serving as an employee of Biohaven Pharmaceuticals Inc. Beth Morris has received stock or an ownership interest from Biohaven Pharmaceuticals Inc.
Vladimir Coric Vladimir Coric has received personal compensation for serving as an employee of Biohaven. Vladimir Coric has received personal compensation in the range of $1,000,000+ for serving as an officer or member of the Board of Directors for Bioahven. Vladimir Coric has stock in Biohaven. Vladimir Coric has received intellectual property interests from a discovery or technology relating to health care.
Robert Croop, MD Dr. Croop has received personal compensation for serving as an employee of Biohaven Pharmaceuticals, Inc. Dr. Croop has received personal compensation for serving as an employee of Pfizer Inc.. Dr. Croop has stock in Biohaven Pharmaceutical Holding Co Ltd. Dr. Croop has stock in Biohaven Ltd.. Dr. Croop has received intellectual property interests from a discovery or technology relating to health care.