Effect of Galcanezumab Following Treatment Cessation in Patients With Migraine

Results From 2 Randomized Phase 3 Trials

Virginia L. Stauffer, PharmD; Shufang Wang, PhD; Menelaos Voulgaropoulos, MD; Vladimir Skljarevski, MD; Amy Kovacik, PA-C; Sheena K. Aurora, MD

Disclosures

Headache. 2019;59(6):834-847. 

In This Article

Abstract and Introduction

Abstract

Objective: We examined the efficacy and safety of galcanezumab after treatment cessation in randomized double-blind, placebo-controlled, migraine prevention studies (EVOLVE-1; EVOLVE-2).

Background: Galcanezumab is indicated for migraine prevention in adults.

Methods: Adults with episodic migraine were enrolled into EVOLVE-1 and EVOLVE-2, which randomized 858 and 915 patients, respectively, to galcanezumab 120 mg (an initial 240-mg loading dose), galcanezumab 240 mg, or placebo, administered subcutaneously once monthly for 6 months. After treatment completion or discontinuation, patients entered a 4-month posttreatment period. Efficacy and safety from the posttreatment periods are reported.

Results: Overall, 740 patients (EVOLVE-1) and 830 (EVOLVE-2) patients entered the posttreatment periods, about 95% and 96% of patients, respectively, completed. In EVOLVE-1, change from pre-randomization baseline in monthly migraine headache days decreased over the posttreatment period from (mean [SE]) 5.2 (0.4) days (Month 6) to 4.1 (0.4) days (Month 10) for 120 mg and from 5.3 (0.4) days (Month 6) to 3.8 (0.4) days (Month 10) for 240 mg, and was stable for placebo (3.4 [0.3] days [Month 6] to 3.3 [0.3] days [Month 10]); differences between each galcanezumab dose group and placebo were statistically significant at each month, except for galcanezumab 240 mg at Month 10 (120 mg vs placebo: P < .001 Months 1–6, P = .007 Month 7, P = .044 Month 8, P = .016 Month 9, and P = .042 Month 10; 240 mg vs placebo: P < .001 Months 1–7, P = .015 Month 8, P = .021 Month 9, and P = .238 Month 10). EVOLVE-2 showed similar results. In both trials, there were no statistically significant differences between treatment groups and placebo for time-to-first loss of 50% response. During the posttreatment periods, 1.6% (EVOLVE-1) and 2.3% (EVOLVE-2) of patients initiated migraine preventive treatments. At Month 10, quality of life among galcanezumab-treated patients was similar to those taking placebo. The most common posttreatment emergent adverse event was upper respiratory tract infections. There were no discontinuations due to adverse events during the posttreatment periods.

Conclusions: Galcanezumab treatment effects were reduced during the posttreatment periods, but did not return to baseline. There were no unexpected adverse events after galcanezumab cessation.

Introduction

Migraine is a chronic disease causing debilitating headaches accompanied by sensory alterations.[1] In the United States (US), the prevalence of self-reported migraine and severe headache was 15.3% over a 3-month period.[2] Migraine disproportionately affects women of childbearing age and is among the top 5 reasons for emergency department visits. Globally, migraine is ranked second as a cause of disability expressed as years lived with disability.[3] According to researchers, preventive medication is indicated for a large proportion of patients (38.8%); however, many do not receive it.[4] Despite the personal and economic burden of migraine, only 12% of patients with migraine reported use of daily preventive migraine medication.[4] Oral preventive medications for migraine are available, but usage is frequently limited by adverse events (AE).[5] Thus, there is a medical need for new treatment options with improved tolerability.

The neuropeptide, calcitonin gene-related peptide (CGRP), is implicated in the pathophysiology of migraine and is hypothesized to be involved in the release of inflammatory mediators and transmission of nociceptive information from intracranial blood vessels to the nervous system.[6,7] CGRP or its receptor are targets for migraine preventive agents.[5,6] Small molecule receptor antagonists and monoclonal antibodies (ie, galcanezumab, erenumab, fremanezumab), directed against either CGRP or its receptor, are under development or approved by the US Food and Drug Administration (FDA) for migraine prevention.[8–10] Immunoglobulins of class G (IgG) have a half-life of approximately 3 weeks;[11] this can be exploited by drugs used as migraine preventive agents, which ideally should be administered infrequently and be long acting.

Galcanezumab is a humanized monoclonal antibody (IgG4) that binds to the CGRP ligand and blocks its binding to the receptor.[9,12] Galcanezumab was recently evaluated in 2 randomized double-blind, placebo-controlled phase 3 trials (EVOLVE-1; EVOLVE-2) examining the effect of monthly galcanezumab (120 mg or 240 mg) on the prevention of episodic migraine.[13,14] In both trials, both galcanezumab dose groups showed statistically and clinically relevant greater reductions from baseline in the number of monthly migraine headache days during the 6-month double-blind treatment periods relative to placebo. Subsequently, the 120-mg dose (following a 240-mg starting dose) was approved by the FDA for preventive treatment of migraine in adults.[9] Because galcanezumab has an elimination half-life of 27 days,[9] its effect can persist after the last injection. Persistence of therapeutic effects is of interest to both patients and clinicians since migraine is a life-long disease and preventive therapy may need to be stopped and started for various reasons (eg, surgery, comorbid conditions, and economics). While persistence of response is desirable, persistence of adverse events is not. The objective was to examine the efficacy and safety of galcanezumab after treatment cessation (posttreatment period) of 2 randomized phase 3 studies (EVOLVE-1, EVOLVE-2) in patients with migraine. We hypothesized that a washout of galcanezumab treatment of approximately 5 elimination half-lives would diminish the treatment effects.

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