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FDA Accepts New Drug Application for Intranasal Zavegepant to Treat Acute Migraine

SAP Partner | <b>Montefiore Health System</b>

In 2 pivotal trials, the agent showed statistically significant superiority over placebo at 2 hours on coprimary end points of pain freedom and freedom from the most bothersome symptom.

The FDA has filed and accepted a new drug application for Biohaven’s calcitonin gene-related peptide (CGRP) receptor antagonist, zavegepant, for the acute treatment of migraine, with a Prescription Drug User Fee Act action date set for Q1 2023. If approved, zavegepant nasal spray would be the only FDA-approved medication to target CGRP in an intranasal formulation, giving patients a new treatment option that provides ultra-rapid pain relief.1

Zavegepant, a third generation, high affinity, selective and structurally unique agent, had its NDA backed by 2 pivotal double-blind, placebo-controlled studies. In both trials, zavegepant demonstrated statistically significant differences in comparison to placebo on the coprimary regulatory end points of superiority at 2 hours for pain freedom and freedom from the most bothersome symptom (MBS).

"People with migraine want an acute treatment that provides fast, lasting relief from the debilitating symptoms of this disease. If approved, zavegepant would provide a new treatment option for patients who need ultra-rapid relief, in as early as 15 minutes, and for those that experience nausea or vomiting and need a non-oral treatment option," Vlad Coric, MD, chief executive officer and chairman, Biohaven, said in a statement.1 "We have generated robust data from two intranasal zavegepant pivotal trials that were submitted with our NDA and look forward to bringing this new treatment option to people suffering from migraine."

The first study (BHV3500-201; NCT03872453), evaluated zavegepant in forms of 5-, 10-, and 20-mg doses vs placebo in 1673 patients with migraine. In addition to meeting the coprimary end points, the agent demonstrated a duration and sustained effect profile through 48 hours (nominal P <.05). This included sustained pain freedom 2 to 24 hours (5 mg, 10 mg, and 20 mg), sustained pain freedom 2 to 48 hours (5 mg, 10 mg, and 20 mg), sustained pain relief 2 to 24 hours (5 mg, 10 mg, and 20 mg), and sustained pain relief 2 to 48 hours (5 and 10 mg).2

WATCH NOW: Acute and Preventive Treatment Options for Migraine

Announced in December 2021, the second pivotal trial (NCT04571060) not only achieved coprimary end points of pain freedom (24% vs 15%; P <.0001) and freedom from MBS (40% vs 31%; P = .0012), but also showed statistically significant differences relative to placebo across a total of 15 prespecified primary and secondary outcome measures. In the study, patients achieved return to normal function as early as 30 minutes after dosing (P <.006). Zavegepant also showed a durable efficacy profile that was superior to placebo (P <.05) on sustained pain freedom 2 to 24 hours; sustained pain freedom 2 to 48 hours; sustained pain relief 2 to 24 hours; and sustained pain relief 2 to 48 hours.3

"Many patients with migraine need treatments other than pills for at least some of their attacks. Swallowing a pill may make nausea worse and if the patient vomits, medication cannot be absorbed. Nasal sprays are a favored option to tablets in many situations,” Richard B. Lipton, MD, professor and vice chair of neurology, Albert Einstein College of Medicine, and director, Montefiore Headache Center, said in a statement.1

Lipton added that "many patients dissatisfied with their current acute treatments want faster relief so they can get back to their plans without missing life's important moments. Zavegepant nasal spray will be an important option for patients seeking nonoral therapies and faster relief. Though head-to-head studies are lacking, relative to triptan nasal sprays, zavegepant should provide favorable safety and tolerability, lack of cardiovascular contraindications and precautions and a reduced risk of medication overuse."1

The second pivotal study included 1405 adults with at least 1 year of migraine, with or without aura, and had migraine attacks lasting, on average, 4 to 72 hours if untreated. The drug continued to show a safe and tolerable profile, with abnormal taste (21% vs 5%) representing the most common adverse event (AE) reported. The majority of AEs were mild in intensity.3

In April 2021, Biohaven announced the first patient had been dosed in a separate phase 2/3 clinical trial of zavagepant. The pivotal double-blind, placebo-controlled study aimed at evaluating the safety and efficacy of 100-mg and 200-mg zavegapant over a 12-week study period, is expected to be completed in the second half of 2022. Approximately 2900 participants will be evaluated on mean reduction in the number of monthly migraine days during weeks 9 to 12 as the primary end point. Rimegepant (Nurtec ODT), which was approved in February 2020 for the acute treatment of migraine in adult patients, was Biohaven’s first approved medication and was crucial in better constructing the zavegepant clinical trial process.4

REFERENCES
1. FDA accepts for review Biohaven’s new drug application (NDA) filing of intranasal zavegepant for the acute treatment of migraine. News release. Biohaven Pharmaceuticals. May 23, 2022. Accessed May 24, 2022. https://www.prnewswire.com/news-releases/us-fda-accepts-for-review-biohavens-new-drug-application-nda-filing-of-intranasal-zavegepant-for-the-acute-treatment-of-migraine-301552566.html
2. Biohaven achieves positive topline results in pivotal phase 2/3 study of vazegepant, the first and only intranasal CGRP receptor antagonist in clinical development for the acute treatment of migraine. News release. December 17, 2019. Accessed May 24, 2022. https://www.biohavenpharma.com/investors/news-events/press-releases/12-17-2019
3. Biohaven reports positive topline results from pivotal migraine trial of intranasal zavegepant demonstrating ultra-rapid pain relief by 15 minutes; prepares for submission of new drug application. News release. Biobaven Pharmaceuticals. December 6, 2021. Accessed May 24, 2022. https://www.biohavenpharma.com/investors/news-events/press-releases/12-06-2021-0
4. Biohaven enrolls first patient in phase 2/3 trial of oral zavegepant, prompting $100 million milestone funding payment from Royalty Pharma. News release. March 29, 2021. Accessed May 24, 2022. https://www.prnewswire.com/news-releases/biohaven-enrolls-first-patient-in-phase-23-trial-of-oral-zavegepant-prompting-100-million-milestone-funding-payment-from-royalty-pharma-301257256.html