Intranasal CGRP Antagonist Is Approved for the Treatment of Acute Migraines

In March 2023, the FDA approved zavegepant (Zavzpret) nasal spray for the acute treatment of migraine with and with-out aura in adults.¹ Zavegepant belongs to a class of medications that antagonize the calcitonin gene-related pep-tide (CGRP).² It is a first-in-class intranasal spray.

Zavegepant is a high-affinity, third-generation molecule that exerts antimigraine effects in 3 distinct ways. First, it blocks neurogenic inflammation by binding to receptors on mast cells. These mast cells promote inflammatory signaling via the trigeminal nerve within the meninges of the brain. Second, CGRP antagonists inhibit dilation of cerebral arteries induced by the trigeminal nerve by blocking CGRP receptors on smooth muscle cells within vessel walls. Third, CGRP antagonists inhibit pain transmission by binding CGRP receptors located on postjunctional cells, suppressing CGRP-induced enhancement of trigeminal nerve pain signals coming from the periphery to the brain. These 3 mechanisms of action serve to relieve migraine headaches.

Efficacy

Zavegepant efficacy was demonstrated in a double-blind, placebo-controlled, multicenter phase 3 trial (NCT04571060).³ Coprimary end points were freedom from pain and from the most bothersome symptom 2 hours after receiving the dose. Study participants were 18 years or older with at least a 1-year history of migraine with or without aura, had migraine onset before aged 50 years, had 2 to 8 migraine attacks of moderate or severe intensity per month, and had fewer than 15 days per month with migraine or a nonmigraine headache within 3 months of screening. Exclusion criteria included the presence of any medical condition that might interfere with safety or efficacy assessments or expose patients to undue risks, receipt of treatment for alcohol or drug use in the 12 months prior, pregnancy, history of allergies, an ECG or lab result that raised safety concerns, or the use of other CGRP antagonists.

Participants were randomly assigned to receive zavegepant (n = 703) or placebo (n = 702), along with an electronic clinical outcome assessment device. The assessment device was used to determine whether the patient had a headache of appropriate severity (moderate to severe). After the patients took the assessment and noted their most bothersome symptom, they administered a single spray from the device. Use of rescue medication, such as acetaminophen, nonsteroidal anti-inflammatory drugs, and/or antiemetics, was permissible 2 hours after treatment with study drug if needed. Two hours after treatment, more participants in the zavegepant group had freedom from pain vs placebo (24% vs 15%, respectively; 95% CI, 4.5-13.1; P < .0001). More participants in the zavegepant also experienced freedom from the most bothersome symptom (40% vs 31%, respectively; 95%CI, 3.4-13.9, P = .0012). Secondary end point data provided supporting evidence of early onset (15 minutes) and prolonged effect (48 hours) of migraine pain relief with intranasal zavegepant.

Safety

Zavegepant is contraindicated in patients with a history of hypersensitivity reactions to the medication or to any component of the product. Avoid using this medication in patients with severe hepatic impairment or with creatinine clearance less than 30 mL/min; no additional dosage adjustments are recommended for hepatic or renal impairment. Common adverse events include dysgeusia/ageusia (18%), nausea (4%), nasal discomfort (3%), and vomiting (2%). There are no adequate data regarding the developmental risks associated with use during pregnancy, and safety has yet to be established in pediatric or geriatric patients. Coadministration of zavegepant with medications that induce or inhibit OATP1B3 or NTCP should be avoided.

Dosing and Administration

Zavegepant is available as a unit dose package that delivers 10 mg into 1 nostril once daily. This device does not need to be primed before use. The safety of treating more than 8 migraines in 30 days with zavegepant has not been established, and patients should not exceed 10 mg in 24 hours. It is recommended that patients avoid taking intranasal decongestants because these can decrease the absorption of zavegepant. Blister packs should be stored at controlled room temperature.¹