Concentration QT Interval Modeling of Intranasally Administered Zavegepant in Healthy Subjects
Richard Bertz1, Joseph Stringfellow2, Rajinder Bhardwaj3, Mary Donohue1, Jennifer Madonia1, Matt Anderson3, Beth Morris1, Vladimir Coric1, Robert Croop1
1Biohaven Pharmaceuticals, 2Navitas Data Sciences, 3Certara USA
Objective:
To evaluate the cardiovascular safety of single and multiple ascending doses (SAD/MAD) of zavegepant nasal spray.
Background:
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.
Design/Methods:
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).
Results:
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.
Conclusions:
Based on pooled analysis of intranasal SAD/MAD data, zavegepant has no clinically relevant effect on ECG parameters.