Effects of Zavegepant and Concomitant Sumatriptan on Blood Pressure and Pharmacokinetics in Healthy Adult Participants
Richard Bertz1, Rajinder Bhardwaj2, Mary Donohue1, Jennifer Madonia1, Joseph Stringfellow3, Matt Anderson2, Beth Morris1, Vladimir Coric1, Robert Croop1
1Biohaven Pharmaceuticals, 2Certara USA, 3Navitas Data Sciences
Objective:
Evaluate co-administration of zavegepant+sumatriptan on resting blood pressure (BP); pharmacokinetics (PK) of sumatriptan and zavegepant alone and combined; zavegepant effects on resting BP vs placebo; safety and tolerability of zavegepant+sumatriptan in healthy participants.
Background:
Zavegepant (BHV-3500; formerly vazegepant) is a high-affinity, selective, small-molecule CGRP receptor antagonist in development for migraine.
Design/Methods:
In a Phase 1, single-center, randomized, partially blind, placebo-controlled, one-arm study, participants received 2 sumatriptan 6mg subcutaneous (SC) injections ~1 hour apart (12mg; Days [D] 1,4) and zavegepant 10mg nasal spray or placebo (20mg; 1 per each nostril; D2-4), immediately after the second sumatriptan dose on D4. BP was recorded manually predose, then via ambulatory monitoring for 13 hours. Blood samples for pharmacokinetics (PK) were collected predose and postdose D1,3,4. Individual time-weighted average (TWA) of mean arterial pressure (MAP) was calculated. Treatment effects on BP and PK were compared via random effects repeated measures ANOVA.
Results:
Forty-two participants were dosed (36 zavegepant; 6 placebo) and 41 completed the study. The overall median (range) age was 31.0 (20 to 49) years. The difference in TWA of MAP between zavegepant+sumatriptan and sumatriptan was 0.04 mmHg; the upper bound of the comparison 90% confidence interval (CI) (-0.69, 0.77) was <5 mmHg, indicating similar MAP. The comparison ratios (90% CI) for sumatriptan with and without zavegepant were Cmax: 104.13% (98.03%, 110.61%); AUC0-inf: 102.46% (100.73%, 104.21%). The comparison ratios (90% CI) for zavegepant with and without sumatriptan were Cmax:112.43% (103.36%, 122.29%); AUC0-24: 96.74% (88.93%, 105.23%). Overall, 38 (90.5%) participants experienced ≥1 treatment-emergent adverse event (AE), with no deaths, serious AEs, or treatment-emergent AEs leading to dose discontinuation.
Conclusions:
Co-administration of zavegepant+sumatriptan resulted in no significant changes in BP compared to sumatriptan alone and no clinically meaningful change in the PK of sumatriptan or zavegepant. Overall, all treatments were well tolerated and exhibited a favorable safety profile.