Smith, Jeff

Objective To determine the onset of preventive efficacy with eptinezumab in patients with migraine. Background Eptinezumab is a monoclonal antibody inhibiting calcitonin gene‐related peptide approved as an intravenously administered treatment for the prevention of migraine. Methods Patients who received eptinezumab 100 mg, eptinezumab 300 mg, or placebo in PROMISE7‐1 (episodic migraine; 100 mg, n = 221; 300 mg, n = 222; placebo, n = 222) or PROMISE7‐2 (chronic migraine; 100 mg, n = 356; 300 mg, n = 350; placebo, n = 366) were included. Testing of the percentage of patients with a migraine on day 1 after dosing was prespecified and alpha‐controlled. In further exploration of this prespecified endpoint, a post hoc closed testing procedure, which controlled the false‐positive (type 1) error rate, provided a statistically rigorous evaluation of migraine prevention onset. The procedure involved up to 84 tests of significance, all of which were performed in sequence until the first nonsignificant result. Results For both studies, all tests for significance for eptinezumab 100 and 300 mg, from days 1‐84 through day 1 alone, achieved nominal significance ( P < .05), indicating that eptinezumab was fully effective beginning on day 1. Over each interval, the treatment effect was comparable to the effect over weeks 1‐12. Mean changes from baseline in monthly migraine days for the primary endpoint period ranged from −3.9 to −4.9, −4.1 to −4.9, and −2.2 to −3.2 for eptinezumab 100, 300 mg, and placebo, respectively, in PROMISE7‐1 and from −7.2 to −8.0, −7.9 to −8.2, and −4.3 to −5.6, respectively, in PROMISE7‐2. The difference from placebo (95% confidence interval) in day 1 treatment effect was −2.2 (−4.1, −0.3) and −2.5 (−4.4, −0.6) days/month for eptinezumab 100 and 300 mg, respectively, in PROMISE7‐1, and was −3.8 (−5.6, −2.0) and −4.0 (−5.8, −2.1) days/month for 100 and 300 mg, respectively, in PROMISE7‐2. Conclusions The migraine preventive effect of eptinezumab is rapid and sustained in patients with episodic or chronic migraine, with onset of optimal preventive efficacy observed on the day following the initial dose.

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. Methods This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Results The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo ( p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. Conclusions The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. Trial Registration ClinicalTrials.gov identifier: NCT02275117.