Zavegepant Nasal Spray for the Acute Treatment of Migraine

A Phase 2/3 Double-blind, Randomized, Placebo-controlled, Dose-ranging Trial

Robert Croop MD; Jennifer Madonia MS, PA-C; David A. Stock PhD; Alexandra Thiry PhD; Micaela Forshaw MPH; Abigail Murphy BA; Vladimir Coric MD; Richard B. Lipton MD


Headache. 2022;62(9):1153-1163. 

In This Article

Abstract and Introduction


Objective: Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine.

Background: Calcitonin gene-related peptide-targeting agents are a novel class of therapeutics for migraine, but none are currently available as a nonoral option for acute treatment. Zavegepant, a high-affinity, selective, and structurally unique calcitonin gene-related peptide-receptor antagonist in late-stage development, is formulated as a nasal spray for the acute treatment of migraine.

Methods: This randomized, dose-ranging, placebo-controlled, Phase 2/3 trial in adults aged ≥18 years with migraine (NCT03872453) was conducted at US study sites. Participants were randomized by an interactive web response system and treated a single attack of moderate to severe pain intensity with zavegepant nasal spray 5, 10, 20 mg, or placebo. Coprimary efficacy endpoints were pain freedom and freedom from the most bothersome symptom at 2 h postdose.

Results: Of the 1673 participants aged 18 to 79 years who were randomized, 1588 were treated with study medication, and 1581 (mean age 40.8 years, 85.5% female) were analyzed for efficacy: zavegepant 5 mg (n = 387), 10 mg (n = 391), 20 mg (n = 402), and placebo (n = 401). Zavegepant 10 and 20 mg were more effective than placebo on the coprimary endpoints of pain freedom at 2 h postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; p = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; p = 0.0055]) and freedom from the most bothersome symptom at 2 h postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; p = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; p = 0.0094]). Findings for the 5 mg dose were not significant. The most common treatment-emergent adverse events with zavegepant 10 and 20 mg and placebo were dysgeusia (13.5% to 16.1% vs. 3.5%), nausea (2.7% to 4.1% vs. 0.5%), and nasal discomfort (1.3% to 5.2% vs. 0.2%). Most adverse events were mild or moderate and resolved without treatment. There was no signal of hepatotoxicity.

Conclusion: Zavegepant nasal spray, in single doses of 10 or 20 mg, was effective for the acute treatment of migraine, with a favorable safety profile. Additional research is needed to confirm its potential as a nonoral medication for the acute treatment of migraine.


In the acute treatment of migraine, clinicians can choose from a range of medications formulated for oral, parenteral, or intranasal delivery.[1] Although oral formulations are the most widely used, of the nonoral options, nasal sprays are used 2 to 3 times more often than injectables for the acute treatment of migraine.[2] Guidelines recommend nonoral therapies for attacks that include severe nausea or vomiting or rapidly escalating headache pain, as well as for patients in whom oral forms are associated with inadequate response, slow onset of action, or poor tolerability.[1,3,4] At present, approved parenteral or intranasal medications for the acute treatment of migraine include 5-HT1B/1D receptor agonists (sumatriptan, zolmitriptan) and ergot alkaloids (dihydroergotamine mesylate).

Because rapid onset of treatment effect is a priority for many people with migraine and an area of unmet acute treatment need,[5–7] the route of administration influences the onset of treatment effects,[8,9] and most patients prefer nasal sprays to injectables,[2,5] intranasally administered antimigraine drugs can meet an important need in clinical practice. However, triptans are ineffective in approximately one third of those who try them,[10] and cardiovascular contraindications restrict their use in almost 10% of the total migraine population in the United States (~3.5 million people).[11,12] Dihydroergotamine nasal spray is less effective than sumatriptan nasal spray at early time points,[13,14] although new formulations are emerging;[15] it is contraindicated in patients with ischemic heart disease, coronary artery vasospasm, or uncontrolled hypertension, and coadministration with potent cytochrome P450 3A4 inhibitors may lead to potentially fatal cerebral and peripheral ischemia.[16] Gepants may be helpful in people who do not respond to triptans, cannot tolerate them, or who are unable to take them due to cardiovascular contraindications.[4] The available gepants for acute treatment are administered orally. A gepant nasal spray could be advantageous in the groups targeted in guidelines for nonoral therapy: those with gastrointestinal distress, rapidly escalating headache pain, or patients with inadequate response to oral therapy.[1,3,4]

All other things being equal, people with migraine prefer tablets to nasal sprays.[5] But all other things are not always equal. Guidelines for the acute treatment of migraine recommend nonoral agents (injections or nasal sprays) for patients who do not respond to oral agents, patients with prominent nausea or vomiting that interferes with administration or absorption of oral acute treatments, and those for whom oral therapies are intolerable due to treatment-emergent nausea or dysphagia.[1,3] While gepants have many advantages over triptans as acute treatments, including the absence of cardiovascular contraindications and precautions, favorable tolerability, and no evidence of medication-overuse headache, as of this writing there are no marketed gepants available for nonoral administration.

Zavegepant nasal spray—a third-generation, high-affinity, selective and structurally unique, small molecule calcitonin gene-related peptide (CGRP) receptor antagonist—is the first CGRP receptor antagonist for intranasal administration in late-stage development for the acute treatment of migraine. A previous single ascending dose study found that doses of zavegepant nasal spray ranging from 5 to 40 mg were rapidly absorbed (Tmax ~ 30 min) and produced potentially therapeutic systemic exposures.[17] In vitro evaluations have demonstrated that zavegepant has low potential for drug–drug interactions.[18,19] The objective of this study was to evaluate the efficacy, safety, and tolerability of zavegepant nasal spray at dose levels of 5, 10, and 20 mg for the acute treatment of migraine.