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Evidence of therapeutic benefit for zavegepant was observed on multiple secondary end points, including return to normal function at 30 min postdose, sustained pain relief, and sustained pain freedom.
Richard B. Lipton, MD
Recently, positive findings from the phase 2/3 trial (BHV3500-201; NCT03872453) of zavegepant nasal spray (Biohaven), a calcitonin gene-related peptide (CGRP) receptor antagonist currently under review for the acute treatment of migraine, were published in Headache.
All told, zavegepant 10 and 20 mg were more effective than placebo on the coprimary end points of pain freedom at 2 hours postdose (placebo: 15.5% [98.3% CI, 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; P = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; P = 0.0055]) and freedom from the most bothersome symptom (MBS) at 2 hours postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; P = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; P = 0.0094]). With a PDUFA date set for Q1 2023, zavegepant aims to become the first FDA-approved mediation to target CGRP in an intranasal formulation, giving patients a new treatment option that provides ultra-rapid pain relief.
"These results suggest that zavegepant may have a therapeutic role in the acute treatment of migraine as an effective alternative to oral and parenteral agents,” Senior investigator Richard B. Lipton, MD, director, Montefiore Headache Center, and colleagues, wrote. "Patients most likely to benefit from the use of zavegepant will be adults seeking a rapid onset of action (e.g., people regularly awakened by attacks) and those whose attacks typically involve marked gastrointestinal distress. The nasal spray formulation may be a particularly advantageous nonoral, needle-free approach to avoid exacerbations of nausea or vomiting, facilitate drug administration, and eliminate the effects of gastroparesis on drug absorption."
Lipton et al assessed 1673 patients aged 18 to 79 years, who were treated with either zavegepant 5 mg, 10 mg, 20 mg, or placebo. Pain freedom, one of the coprimary end points, was assessed using ratings of pain intensity on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Freedom from the MBS was assessed using the presence or absence of the symptom identified by participants as the MBS (selected from among photophobia, phonophobia, or nausea) for the treated attack.
Of the 1573 participants randomized, 1588 were in the safety population, and 1581 were in the efficacy population. Most of the cohort were female (85.5%) and White (78.3%), with a mean body mass index of 27.4 kg/m2. At randomization, 13.6% of the participants used preventive migraine medications. For the 22.3% of patients who discontinued the study before randomization, screening failures (20.6%) were the main reason. After randomization, 2 participants discontinued the study because of a clavicle fracture and clostridium difficile colitis in 1 participant each.
Although the 10 and 20 mg doses of zavegepant proved significance for the coprimary end points, the findings for the 5 mg dose were not significant. In terms of secondary efficacy end points, 53.6% of those on placebo had pain relief at 2 hours postdose vs 60.6% and 61.2% for the zavegepant 10- and 20-mg groups, respectively. In the absence of a significance difference between the active treatments and placebo on this end point, P-values reported for all the secondary end points were nominal. Despite this, zavegepant was greater than placebo on multiple secondary end points, including return to normal function at 30 min post dose with zavegepant 20 mg and sustained pain freedom from 2 to 48 hours postdose with zavegepant 5, 10, and 20 mg.
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The most common treatment-emergent adverse events (AEs) in zavegepant-treated patients were dysgeusia (zavegepant: 13.5% to 16.1%; placebo: 3.5%), nausea (zavegepant: 2.6% to 4.1%; placebo: 0.5%) and nasal discomfort (zavegepant: 1.3% to 5.2%; placebo, 0.2%). Five participants experienced a serious AE, although none were considered related to the active treatment. The only serious AE in any zavegepant group was thrombosis, which was reported for 1 patient in the 10 mg group, and was attributed to trauma from a motor vehicle accident.
This study, along with another second pivotal trial (NCT04571060) currently serve as the basis for zavegepant’s new drug application. The second study 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.
