Intranasal zavegepant safe and well tolerated in healthy adults

Intranasal zavegepant is in development for the acute treatment of migraine. Escalated to 40 mg/day for up to 14 days, it was safe and well tolerated in healthy adults in 2 sequential phase 1 studies. Doses of ≥10 mg produced exposure that is assumed to be efficacious in adults with migraine.

For acute treatment of migraine, non-oral formulations may be useful in a number of situations, including: acute migraine attacks requiring very rapid onset of efficacy; presence of nausea, vomiting, and/or dysphagia; or when oral medications have previously failed. Zavegepant nasal spray is a third-generation, high-affinity, selective, and structurally unique small molecule calcitonin gene-related peptide receptor (CGRP) antagonist. It is the only intranasal CGRP antagonist in late-stage development for the acute treatment of migraine, as Prof. Richard Bertz (University of Pittsburgh, PA, USA) explained.

At the AAN 2022 meeting, results were shared of 2 single-centre, phase 1, placebo-controlled, randomised, double-blind, sequential zavegepant studies [1]. Participants were non-smokers aged 18–55 years. In the single-dose study, 9 cohorts of 8 adults each received 0.1, 0.3, 1, 3, 5, 10, 20, or 40 mg 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 mg or placebo for 8 or 14 days depending on the cohort.

Intranasal zavegepant was rapidly absorbed, with a median T_max ranging from 0.54 to 0.96 hours across doses. The increase in exposure was slightly less than dose-proportional at doses of 1 to 40 mg. Single doses of ≥10 mg produced an average C_max associated with ≥90% inhibition of CGRP signalling receptors, suggestive of efficacy in migraine.

Single and multiple daily doses of intranasal zavegepant were well tolerated. A maximum tolerated dose was not identified. The most common adverse events were associated with nasal administration and of mild intensity (see Table). No serious adverse events were detected, and no participants had levels of aminotransferases >3x or total bilirubin >2x the upper limit of normal. Effective half-life ranged from 5.0 to 7.6 hours, with little accumulation after multiple daily doses.

Table: Most common adverse events of intranasal zavegepant [1]



 

 

 

 

 

 

 

 

 

 

 

1. Bertz R, et al. Safety, Tolerability, and pharmacokinetics of single and multiple ascending doses of intranasal zavegepant in healthy adults. S31.004, AAN 2022, 02–07 April, Seattle, USA.

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Posted on 2 June 202223 April 2024