Zavegepant Tolerable, Safe When Used in Combination With Other CGRP Monoclonal Antibodies

Gary Berman, MD

Findings from a subgroup analysis of a phase 2/3 trial (NCT04408794) showed that zavegepant (Zavzpret; Pfizer), a recently approved therapy for acute migraine, was safe and tolerable when used concomitantly with other calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb).

Presented at the 2023 American Headache Society (AHS) Annual Meeting, held June 15-18, in Austin, Texas, findings showed that the incidence of adverse events (AEs) while on zavegepant 10 mg nasal spray was comparable in individuals using and not using a CGRP mAb (76.9% vs 76.2%). Additionally, the rate of discontinuation because of AEs was similar among those concomitantly using a CGRP mAb and those who did not (7.7% vs 6.7%).

Led by Gary Berman, MD, an assistant professor of medicine at the University of Minnesota, the analysis featured 603 individuals treated with zavegapant 10 mg, 39 (6.5%) of which reported current or concomitant use of a CGRP mAb. The study, open-label in design, featured adults aged at least 18 years with a history of 2 to 8 moderate to severe monthly migraine attacks. Erenumab was the most used concomitant CGRP (n = 22), followed by galcanezumab (n = 11), and fremanezumab (n = 7).

Results showed that the most common AEs found in individuals on a CGRP mAb were dysgeusia (28.2%), nasal discomfort (15.4%), back pain (15.4%), throat irritation (12.8%), and arthralgia (12.8%). No serious AEs were reported among those using a CGRP mAb, as well as no new safety signals were identified.

Zavegepant, a third generation, high affinity, selective and structurally unique agent, received FDA approval earlier this year, becoming the first and only CGRP nasal spray available for patients with migraine. It had it’s new drug application backed by 2 pivotal double-blind, placebo controlled studies in which it showed statistically significant differences relative to placebo on the coprimary end points of superiority at 2 hours for pain freedom and freedom from the most bothersome symptom (MBS).

READ MORE: Migraine Related Stigma and its Impact on Patients in Healthcare

The first trial (NCT03872453) assessed the agent in forms of 5-, 10-, and 20-mg doses vs placebo in a cohort of 1673 patients with migraine. 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 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]).²

Announced in December 2021, the second pivotal trial (NCT04571060) 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.³

Earlier this year, at the 2023 American Academy of Neurology Annual Meeting, post-hoc findings from a pooled analysis of these 2 trials showed that zavegepant was effective regardless of the presence or absence of aura. Above all, zavegepant outperformed placebo on the coprimary end point of 2h pain freedom for patients with (23.1% vs 16.6%; P = .0323) and without (23.2% vs 14.3; P <.001) predose aura. As for achieving freedom 2h from MBS, the CGRP medication continued to be beneficial regardless of aura status (with predose aura: 37.5% vs 29.6%; P = .0292; without predose aura: 41.9% vs 33.4%; P <.0001).⁴

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REFERENCES
1. Berman G, Mullin K, Pavlovic J, et al. Long-term safety and tolerability of zavegepant 10 mg nasal spray during concomitant use of CGRP monoclonal antibodies: results from a 1-year open-label safety trial. Presented at: 2023 AHS Annual Meeting; June 15-18; Austin, TX. IO-13.
2. Biohaven achieves positive topline results in pivotal phase 2/3 study of vazegepant, the first and only intranasal CGRP receptor antagonist in clinical development for the acute treatment of migraine. News release. December 17, 2019. Accessed June 17, 2023. https://www.prnewswire.com/news-releases/biohaven-achieves-positive-topline-results-in-pivotal-phase-23-study-of-vazegepant-the-first-and-only-intranasal-cgrp-receptor-antagonist-in-clinical-development-for-the-acute-treatment-of-migraine-300976000.html
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, randomized, placebo-controlled multicentre trial. Lancet Neurol. 2023;22(3):209-217. doi:10.1016/S1474-4422(22)00517-8
4. Smith T, Pavlovic J, Mullin K, et al. Zavegepant nasal spray for the acute treatment of migraine with aura and without aura: pooled results from 2 randomized, placebo-controlled clinical trials. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. 004348.