Migraine is a leading cause of disability worldwide, affecting more than 1 billion of the world’s population (nearly 1 in 8 people) worldwide1.
Current treatment strategies in general follow the guidelines developed by the American Headache Society (AHS)2, with commonly involved medication including NSAID, acetaminophen, triptans, and ergotamine. On March 10th 2023, FDA approved the use of a newly developed intranasal spray – zavegepant (Pfizer’s ZEVZPRETTM) to treat migraine with or without aura in adults3.
The mechanism of action of zavegepant is based on the positive relationship4 between serum concentration of calcitonin gene-related peptide (CGRP) and acute migraine attacks. During migraine attacks, as well as episodes of other neurovascular headache types such as cluster headaches, serum concentrations of CGRP are found to be elevated. In addition, relief of migraine pain by triptans seem to reduce4 the CGRP concentrations in blood. Zavegepant is a third-generation, high-affinity, selective small molecule CGRP receptor antagonist and the only CGRP receptor antagonist in clinical development with both intranasal and oral formulations3.
The recent approval of zavegepant used for migraine treatment in adults is based on phase 3 double-blind, randomised, placebo-controlled trial5 conducted at 90 academic medical centres, headache clinics, and independent research facilities in the US, recruited adults (aged ≥18 years) with a history of two to eight moderate or severe migraine attacks per month. 2 h after the treatment dose, more participants in the zavegepant group than in the placebo group had pain freedom (147 [24%] of 623 participants vs 96 [15%] of 646 participants) and freedom from their most bothersome symptom (247 [40%] vs 201 [31%]). The following figure is a Forest plot of coprimary and secondary efficacy endpoints in order of hierarchical testing5.
Significant differences were identified between zavegepant and placebo for 14 secondary endpoints. Meanwhile, a greater proportion of patients in the zavegepant group had pain relief and pain freedom at each measured time point between 0-2 hours, and 2-48 hours post-treatment.
The most frequently reported adverse events5 were dysgeusia, nasal discomfort, nausea, vomiting, throat irritation, and increased concentrations of blood creatine phosphokinase. No severe adverse events were recorded. Overall it has been well-tolerated in its phase 3 trials.
The approval of zavegepant marks a milestone as the first parenteral medication approved to treat migraine in community settings. It would be extremely helpful for migraine patients who cannot tolerate oral pain medications, or who have developed severe side effects on triptans or ergotamine.
In conclusion, zavegepant 10 mg nasal spray was effective in the acute treatment of migraine in adults, with favourable tolerability and safety profiles, based on its phase 3 trial. Additional trials are needed to establish the long-term safety and consistency of effect across attacks.
References
1.Amiri P, Kazeminasab S, Nejadghaderi SA, Mohammadinasab R, Pourfathi H, Araj-Khodaei M, et al. Migraine: A Review on Its History, Global Epidemiology, Risk Factors, and Comorbidities. Frontiers in Neurology. 2022 Feb 23;12.
2.Ailani J, Burch RC, Robbins MS. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache: The Journal of Head and Face Pain. 2021 Jun 23;61(7):1021–39.
3.Pfizer’s ZAVZPRETTM (zavegepant) Migraine Nasal Spray Receives FDA Approval | Pfizer [Internet]. www.pfizer.com. Available from: https://www.pfizer.com/news/press-release/press-release-detail/pfizers-zavzprettm-zavegepant-migraine-nasal-spray
4.Durham PL. Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache [Internet]. 2006 Jun 1;46(Suppl 1):S3–8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134175/
5.Croop R, Madonia J, Stock DA, Thiry A, Forshaw M, Murphy A, et al. Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial. Headache [Internet]. 2022 Oct 1 [cited 2023 Mar 26];62(9):1153–63. Available from: https://pubmed.ncbi.nlm.nih.gov/36239038/
