Eptinezumab Demonstrated Efficacy in Sustained Prevention of Episodic and Chronic Migraine Beginning on Day 1 After Dosing

David W. Dodick, MD; Christopher Gottschalk, MD; Roger Cady, MD; Joe Hirman, PhD; Jeff Smith, MD, FRCP; Steve Snapinn, PhD

Disclosures

Headache. 2020;60(10):2220-2231. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Patients with migraine consider speed of onset as one of the most important attributes of preventive treatment, second to efficacy.[1] Patients' decisions to discontinue or switch preventive medication can be made as early as 30 days after beginning treatment;[2,3] thus, there is a need for preventive treatments with a rapid onset of sustained effect to ensure patient adherence, management of acute medications, and beneficial long-term outcomes. Unfortunately, commonly prescribed preventive migraine therapies can take 2–6 months to achieve maximal effects.[4–6] Although data from most newer agents suggest that they may have earlier onset, the time to clinically meaningful and optimal benefit remains undefined[7–13] and a statistically robust methodology to determine onset of full efficacy of a preventive agents has, to date, not been determined.

Eptinezumab, a humanized calcitonin gene-related peptide (CGRP)-targeted monoclonal antibody (mAb), was recently approved by US Food and Drug Administration for the preventive treatment of migraine in adults. Eptinezumab was developed to provide an early onset of preventive action that is sustained throughout a 12-week dosing interval. By intravenous (IV) administration over 30 minutes, eptinezumab has 100% bioavailability and achieves maximum plasma concentration at the end of IV administration.[14] Pharmacokinetic results coupled with data from phase 2 studies[15,16] suggested that migraine preventive efficacy of eptinezumab may begin immediately, leading to the inclusion of the percentage of patients reporting a migraine headache on day 1 as a prespecified and alpha-controlled endpoint in pivotal phase 3 trials conducted in patients with episodic (PROMISE7-1) and chronic (PROMISE7-2) migraine. In both pivotal trials, the percentage of patients reporting a migraine on day 1 was reduced by more than 50% compared to baseline in eptinezumab-treated patients and by approximately 25% in placebo patients.[17,18] However, questions remained if the results on this specific day (day 1) represented onset of benefit or a transient benefit; we hypothesized that day 1 represented the onset of treatment. The objective of this post hoc closed testing analysis was to determine whether this day 1 observation represents the point at which the preventive benefit of eptinezumab was established and whether that effect was sustained without interruption for 12 weeks in this broad spectrum of patients with episodic and chronic migraine. This methodology has the potential to better align patient expectations and the capabilities of drug development.

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