Evaluate the safety, tolerability, and pharmacokinetics of intranasal zavegepant—a third-generation, high-affinity, selective and structurally unique, small molecule calcitonin gene-related peptide receptor (CGRP) antagonist—after administration of ascending single and multiple doses in healthy fasted adults.

In the acute treatment of migraine, nonoral formulations may be useful for patients with nausea, vomiting, and/or dysphagia, as well as for those in whom oral medications have failed or those seeking very fast relief. Intranasal zavegepant is in development for the acute treatment of migraine.

Two single-center, phase 1, placebo-controlled, randomized, double-blind, sequential zavegepant studies were conducted in nonsmoking adults aged 18-55 years, with body mass index of 18.5 to 30.0 kg/m² and body weight ≥50.0 kg for men and ≥45.0 kg for women. In the single-dose study, 9 cohorts of 8 adults each received 0.1, 0.3, 1, 3, 5, 10, 20, or 40 (2x20) mg of intranasal zavegepant or placebo. In the multiple-dose study, 6 cohorts of 12 adults each received a daily dose of 5, 10, 20, or 40 (2x20) mg of intranasal zavegepant or placebo for up to 14 days.

Single and multiple daily doses of intranasal zavegepant up to 40 mg for 8-14 days were well tolerated. A maximum tolerated dose was not identified. No serious adverse events were reported, and no participants had levels of aminotransferases >3x or total bilirubin >2x the upper limit of normal. Effective half-life ranged from 5.0-7.6 hours with little accumulation after multiple daily doses. C_max and area under the curve were approximately dose proportional from 5-40 mg. Single doses ≥10 mg produced an average C_max associated with ≥90% inhibition of CGRP signaling.

Intranasal zavegepant escalated to 40 mg/d for up to 14 days was safe and well tolerated in healthy adults. Doses ≥10 mg produced exposures predictive of efficacy in adults with migraine.