Efficacy and safety of 2 dose regimens of subcutaneous administration of fremanezumab (TEV-48125) versus placebo for the preventive treatment of chronic migraine

Background: Migraine is a prevalent disease which may progress to greater severity, frequency, duration and disability over time. The International Headache Society defines Chronic Migraine (CM) as 15 or more headache (HA) days per month over a 3-month period of which more than 8 are migrainous, in the absence of medication overuse. Patients with 4 or more headaches days per month are at risk for progression to chronic migraine. Migraine prevention is intended to reduce the frequency, severity, and disability associated with migraine attacks. Although an estimated 38% of migraine patients would benefit from preventive treatment, only 13% are on preventive therapy. Recommendations from the U.S. Headache Consortium include initiating preventive treatment in those with 4 HA days per month with some impairment. There is a need for safe and effective preventive therapy that treats the cause of migraine and reduces the associated treatment burden. Fremanezumab, a fully humanized monoclonal antibody targeting the calcitonin gene related peptide (CGRP) ligand, is a preventive treatment designed to specifically target the underlying pathophysiology of migraine, with proven efficacy in the treatment of migraine. Objective: To evaluate the efficacy and safety of two subcutaneous (SQ) doses of fremanezumab in the preventive treatment of CM. Methods: This is a 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to compare the safety, tolerability, and efficacy of 2 SQ dose regimens of fremanezumab and placebo (PBO) in adults with CM. Patients had history of migraine for at least 12 months and CM prospectively documented during a 28-day run-in period. Patients were assigned randomly to 1:1:1 ratio to 1 of 3 treatment groups: (1) monthly dosing: an initial dose of 675 mg fremanuzemab followed by 225 mg of fremanezumab at months 2 and 3 (2) quarterly dosing: a single dose of 675 mg of fremanuzemab at month 1, followed by placebo injections at months 2 and 3 and (3) monthly administration of matching placebo. The primary efficacy endpoint, the mean change from baseline (28-day run-in period) in the monthly average number of HA days of at least moderate severity during the 12-week period after the 1st dose of fremanezumab, was analyzed using an analysis of covariance method. Results: Patients treated with fremanezumab experienced statistically significant reduction in the number of monthly headache days of at least moderate severity vs. placebo (22.5 days) during the 12-week period after 1st dose, for both monthly (24.6 days p<0.0001) and quarterly (24.3 days p<0.0001) dosing regimens. The most commonly-reported adverse event in the study was injection site pain, with similar rates in the placebo and active groups. Conclusion: These results confirm the efficacy and favorable benefit/risk profile of fremanezumab for the preventive treatment for migraine.