Zavegepant (ZAVZPRET): First Intranasal CGRP Receptor Antagonist Approved by FDA for Acute Migraine Treatment with Onset of Relief in 15 Minutes

On March 10, Pfizer announced that the FDA had approved zavegepant (brand name: ZAVZPRET) for marketing, indicated for the acute treatment of migraine with or without aura in adults. ZAVZPRET is the first and only calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray to be approved for marketing.

Zavegepant is a highly selective, high-affinity, structurally unique third-generation small molecule calcitonin gene-related peptide (CGRP) receptor antagonist. It is currently being developed in two formulations: nasal spray and oral dosage form. The formulation approved this time is the nasal spray.

The approval for marketing was based on positive data from two pivotal clinical studies. Among them, the results of the Phase II/III clinical trial (NCT03872453) showed that 22.5% and 23.1% of patients receiving 10mg and 20mg zavegepant, respectively, experienced headache relief after 2 hours, compared to 15.5% in the placebo group, reaching the primary efficacy endpoint.

The Phase III clinical trial (NCT04571060) also met the co-primary endpoints, showing that 2 hours after treatment, the proportion of patients achieving pain relief in the zavegepant group and placebo group was 24% vs 15% (p<0.0001), and the proportion without the most bothersome symptom was 40% vs 31% (p=0.0012). Additionally, as early as 15 minutes post-treatment, the zavegepant group demonstrated superior pain relief compared to the placebo group. Zavegepant showed good safety and tolerability, with the most common adverse event being dysgeusia (21% vs 5%).

Migraine is a chronic neurovascular disease characterized by recurrent moderate to severe unilateral and/or pulsating headaches, often accompanied by symptoms such as nausea, sensitivity to light and/or sound. Individual episodes can last 4-72 hours, significantly impacting patients' daily lives. It is estimated that there are approximately 1.3 billion migraine sufferers globally, with the prevalence in women being 2-3 times higher than in men, indicating a substantial market demand.

CGRP is a potent vasodilatory neuropeptide that has the effects of lowering blood pressure, reducing peripheral resistance, dilating renal arteries, and increasing renal blood flow. Since the release level of CGRP significantly increases during migraine attacks and is positively correlated with the severity of headache, it is believed that headache relief and migraine prevention can be achieved by inhibiting the activity of CGRP and its receptor (CGRPR).

As of now, eight CGRP/CGRPR drugs have entered the global market, including four injectables, three oral medications, and the nasal spray that was just approved today. In China, three CGRP/CGRPR drugs are in the application stage for marketing approval: Amgen/Novartis' Aimovig, Eli Lilly's Emgality, and Pfizer's Nurtex.

Globally Approved CGRP-Based Migraine Drugs

Note: Zavegepant is not listed in the table above.

From the perspective of global sales in 2022, the overall growth rate of CGRP/CGRPR antagonists slowed compared to 2021 but still steadily increased by 26% to reach $3.171 billion. Analysts previously predicted that the migraine market size could exceed $11 billion by 2027; CGRP/CGRPR-targeted drugs alone may reach $6.5 billion. With the expansion of indications for related drugs and the entry of new products, their sales are expected to surpass the forecast.

Based on the vast market potential, Pfizer first acquired the rights to rimegepant outside the United States and the U.S. rights to zavegepant from Biohaven for $1.24 billion in November 2021; in May 2022, Pfizer announced an approximately $11.6 billion all-cash acquisition of Biohaven, gaining multiple CGRP programs including rimegepant and zavegepant.

Rimegepant is an oral CGRP receptor antagonist that was first approved by the FDA in February 2020 for the treatment of acute migraine in adults. In May 2021, it was granted a new indication for the prevention of episodic migraine in adults. In its second year on the market, the drug’s sales skyrocketed from $64 million to $463 million, showing strong growth. Pfizer predicts that rimegepant’s annual sales could reach up to $6 billion.

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