Safety, tolerability, and pharmacokinetics of single and multiple ascending doses of zavegepant nasal spray in healthy adults from two phase 1 randomized, placebo-controlled trials.

Abstract

Objective: This study aimed to evaluate the safety and tolerability, and characterize the pharmacokinetic profile, of zavegepant nasal spray in two phase 1 studies.

Background: Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist, approved as a nasal spray for the acute treatment of migraine in adults.

Methods: Two single-site, phase 1, placebo-controlled, randomized, double-blind studies evaluated the safety, tolerability, and pharmacokinetic profile of single ascending doses (SAD) and multiple ascending doses (MAD) of zavegepant nasal spray in healthy adults. The SAD study was conducted from October 18, 2018, to March 15, 2019, and the MAD study from September 2, 2019, to December 14, 2019. Zavegepant SAD were 0.1-20 mg single sprays and 40 mg as two 20-mg sprays. Zavegepant MAD 5-20 mg single sprays once daily (QD) and three 40-mg QD regimens given as two 20-mg sprays were evaluated.

Results: In the SAD study, 72 participants were dosed in nine cohorts, and all participants completed the study. In the MAD study, 72 participants were dosed in six cohorts and 71 (99%) completed the study. In each study, zavegepant was rapidly absorbed, with a median time of maximum observed plasma concentration (T_max) of 0.54 h after a single 10 mg spray (SAD study). Exposure increased with dose, with no evidence of accumulation after repeated QD dosing. In the SAD study, 14 (26%) zavegepant-treated and three (17%) placebo-treated participants reported at least one treatment-emergent adverse events (TEAE). In the MAD study, 42 (75%) zavegepant-treated participants and 10 (63%) placebo-treated participants reported at least one TEAE. In each study, most TEAEs were mild in severity and resolved spontaneously. There was no relevant effect on electrocardiographic parameters. No signal of drug-induced liver injury was identified.

Conclusions: In healthy adults, zavegepant nasal spray was safe and well tolerated at single dose up to 40 mg and in multiple doses up to 40 mg QD. Zavegepant median T_max was approximately 30 min after a single 10 mg dose nasal spray.