Zavegepant Is A Promising Frontier in Acute Migraine Treatment

Migraine is a debilitating neurological condition characterized by recurrent and severe headaches that pose a significant challenge for those affected. The search for effective and well-tolerated treatments has led to the development of novel options.

Zavegepant (Zavzepret; Pfizer) is a novel receptor antagonist for the calcitonin gene-related peptide (CGRP) indicated for the acute treatment of migraine with or without aura.¹ Medication is delivered as nasal spray and provides a notable advancement for individuals experiencing migraines seeking relief from acute pain, especially those who prefer alternatives to oral medications or unable to take oral medications because of nausea or vomiting.²

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Although complete understanding of migraine pathophysiology remains elusive, certain vasoactive substances and neurotransmitters, including CGRP, neurokinin A, nitric oxide, and substance P are thought to play a role in neurovascular and cortical spreading depression mechanisms. In the acute phase of migraine, the release of CGRP leads to increased vasodilation and modulation of neuronal excitability. This, in turn, facilitates pain responses in structures involved in migraine pain transmission, such as the trigeminal system. Zavegepant's mechanism of action centers around inhibiting the CGRP receptor, effectively disrupting the cascade of events that contribute to migraine attacks.¹

One distinctive feature of zavegepant is its focus on acute migraine treatment. As a CGRP receptor antagonist, it intervenes during the active phase of migraine, providing a targeted and prompt response to alleviate symptoms. This acute treatment approach distinguishes zavegepant from preventive measures, offering an alternative for individuals seeking relief specifically during migraine episodes.

Clinical trials evaluating zavegepant have demonstrated promising results in efficacy and tolerability. The drug's ability to inhibit vasodilation mechanisms and desensitize neuronal circuits contributes to its effectiveness in alleviating migraine symptoms. In addition to its impact on pain relief, zavegepant has shown potential in reducing the frequency and severity of migraine attacks, enhancing the overall quality of life for patients.³

The medication was tested in multicenter, double-blind, randomized, and placebo-controlled phase 3 trial, conducted across 90 academic medical centers, headache clinics, and independent research facilities in the United States. Adults with a history of 2 to 8 moderate or severe migraine attacks per month were recruited. The participants were randomly assigned in a 1:1 ratio to receive either zavegepant 10 mg nasal spray or a placebo. They self-treated a single migraine attack characterized by moderate or severe pain intensity. The randomization process was stratified based on the use or non-use of preventive medication.³

Study center personnel enrolled eligible participants through an interactive web response system, which was operated and managed by an independent contract research organization. The group assignment was concealed from all participants, investigators, and the funder through masking. The coprimary endpoints—freedom from pain and freedom from the most bothersome symptom at 2 hours after the treatment dose—were evaluated in all randomly assigned participants who took the study medication, experienced a migraine attack of moderate or severe pain intensity at baseline, and provided at least 1 assessable post-baseline efficacy datapoint. Safety analysis included all randomly assigned participants who received at least 1 dose.³

Out of 1978 participants initially recruited and assessed for eligibility, 1405 individuals were eligible (703 assigned to zavegepant, 702 to placebo). The efficacy analysis set included 1269 participants (623 in the zavegepant group, 646 in the placebo group). At the 2-hour mark following the treatment dose, a higher proportion of participants in the zavegepant group experienced pain freedom (147 [24%] out of 623 vs. 96 [15%] out of 646; risk difference 8.8 percentage points, 95% CI 4.5-13.1; p<0.0001) and freedom from their most bothersome symptom (247 [40%] vs. 201 [31%]; risk difference 8.7 percentage points, 3.4-13.9; p=0.0012).³

The most prevalent adverse events in either treatment group (≥2%) included dysgeusia (21% in the zavegepant group vs. 5% in the placebo group), nasal discomfort (4% vs. 1%), and nausea (3% vs. 1%).

Zavegepant may interact with OATP1B3 inhibitors/inducers, NTCP transporters, and intranasal decongestants. Additionally, it should be avoided in cases of severe renal or hepatic impairment.^3,4

One notable aspect of zavegepant is its potential appeal to individuals who prefer alternatives to oral medications. As a CGRP receptor antagonist administered through non-oral routes, such as intranasal or injectable formulations, zavegepant offers flexibility in treatment options, accommodating diverse patient preferences and needs.^2,3

One spray in one nostril is the recommended dose, without the need for priming. Zavegepant comes as a ready-to-use, single-dose disposable unit. Each carton includes 6 units designed to treat 6 migraine attacks as needed. The maximum cumulative dose allowed within a 24-hour period is 10 mg (one spray). The safety of treating more than 8 migraines in a 30-day period has not been established.⁵

Zavegepant's emergence in the migraine treatment landscape raises questions about its future implications and potential role in broader therapeutic strategies. While its acute treatment focus addresses the immediate needs of individuals experiencing migraines, ongoing research may explore its effectiveness in specific patient populations, such as those with comorbidities or varying levels of migraine severity.

Furthermore, considerations regarding the long-term impact of zavegepant, its compatibility with other migraine treatments, and potential adverse effects necessitate continued investigation. Comprehensive studies and real-world evidence will contribute to a more nuanced understanding of zavegepant's role in the comprehensive management of migraines.

Zavegepant stands as a significant breakthrough in migraine treatment, offering a targeted and effective approach to alleviate symptoms during acute episodes. Its mechanism of action as a CGRP receptor antagonist, coupled with its potential for non-oral administration, makes it a unique and valuable option for individuals seeking relief from migraines. As ongoing research unfolds, zavegepant may contribute to a paradigm shift in the way migraines are approached and treated, providing newfound hope for those in need of freedom from pain.

References

1. Noor N, Angelette A, Lawson A, Patel A, et al. A Comprehensive Review of Zavegepant as Abortive Treatment for Migraine. Health Psychol Res. 2022;10(3):35506. doi:10.52965/001c.35506

2. Goadsby PJ. Migraine and Other Primary Headache Disorders. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw-Hill Education; 2022.

3. Lipton RB, Croop R, Stock DA, et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol. 2023;22(13):209-217. doi:10.1016/S1474-4422(22)00517-8

4. Tallian KB, Heinrich NT. Headache Disorders. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023.

5. Zavzpret (zavegepant) [prescribing information]. New York, NY: Pfizer Labs; March 2023.