Thursday, June 7, 2018

Galcanezumab for the prevention of migraine

Injections of the calcitonin-gene-related peptide (CGRP) monoclonal antibody galcanezumab reduce monthly headache days in patients with episodic migraine, according to results from the EVOLVE-1 phase 3 study.

Galcanezumab prevents the biological activity of CGRP, which has been implicated in the pathophysiology of migraine, without blocking the CGRP receptor. Eli Lilly and Company, which funded the new work, submitted a Biologics License Application for galcanezumab to the U.S. Food and Drug Administration in December 2017.

Dr. David W. Dodick from Male Clinic in Phoenix, Arizona, and colleagues from 90 sites in North America investigated the efficacy of two doses of galcanezumab, given monthly by subcutaneous injection (120 mg and 240 mg), versus placebo in 858 patients with episodic migraine with or without aura.

At baseline, mean monthly migraine headache days (MHDs) were 9.1, mean monthly migraine attacks were 5.7, mean monthly headache hours were 60.6 and mean baseline Migraine Disability Assessment (MIDAS) scores were 33.2. 

Mean monthly MHDs, the primary endpoint, decreased to a significantly greater extent with galcanezumab 120 mg (by 4.7 days) and galcanezumab 240 mg (by 4.6 days) than with placebo (by 2.8 days).

A significant benefit of galcanezumab versus placebo was seen as early as the first month, the researchers report in JAMA Neurology, online May 29.

Both doses of galcanezumab were superior to placebo in the proportion of patients who maintained at least 50% response for six consecutive months of treatment (20.5% of those treated with galcanezumab 120 mg; 19.2% of those treated with galcanezumab 240 mg; and 8.9% of those treated with placebo).

Mean monthly headache hours decreased by 29.7 hours with galcanezumab 120 mg, by 29.3 hours with galcanezumab 240 mg and by 15.7 hours with placebo (P<0.001).

Both galcanezumab doses showed improvements superior to those with placebo for Migraine-Specific Quality of Life Questionnaire (MSQ), Patient Global Impression of Severity (PGI-S) and MIDAS scores.

The percentage of patients who reported at least one treatment-emergent adverse event was non-significantly greater in the galcanezumab groups than in the placebo group.

"These data provided consistent, clinically meaningful evidence that treatment with galcanezumab reduced migraine frequency and migraine-related disability and improved patient functioning," the researchers conclude.

Dr. Philip R. Holland from King's College London, who recently reviewed the CGRP pathway and its role in migraine, told Reuters Health by email, "The 'Umabs' have arrived, and your patients are going to be contacting you looking to get them now."

"Cost implications will make galcanezumab unlikely to be a general first-level preventative; however, in those who have failed other preventatives (and there are many), this is an important option," said Dr. Holland, who was not involved in the new work. "The early effect (seen with other Umabs also) will also open the door for a short-term commitment (3 months) and revaluation when efficacy can be better predicted in individual patients."

Dr. Uwe Reuter from Charite-Universitaetsmedizin Berlin, who also was not involved in the new work, recently reviewed monoclonal antibody therapies and other preventive treatments for migraine. "For now it is too early to recommend a monoclonal antibody as first-line preventive therapy," he told Reuters Health by email, adding that monoclonal antibodies might be appropriate for "subjects who have failed other first-line preventatives or cannot tolerate these due to adverse effects."

Virginia L. Stauffer, PharmD1; David W. Dodick, MD2; Qi Zhang, PhD1; et al Jeffrey N. Carter, PhD1; Jessica Ailani, MD3; Robert R. Conley, MD1,4. Evaluation of Galcanezumab for the Prevention of Episodic Migraine. The EVOLVE-1 Randomized Clinical Trial.  JAMA Neurol. Published online May 29, 2018. doi:10.1001/jamaneurol.2018.1212

Key Points
Question  Is galcanezumab effective for prevention of migraine in patients who experience 4 to 14 migraine headache days per month?

Findings  In this randomized clinical trial, both galcanezumab doses (120 mg and 240 mg) achieved statistically significant overall mean reductions in the number of monthly migraine headache days during treatment compared with placebo. Galcanezumab was associated with low discontinuation rates owing to adverse events, and adverse events were transient and predominantly mild or moderate in severity.

Meaning  Galcanezumab demonstrated clinically and statistically significant benefits across several migraine-relevant outcomes in this study, with a favorable tolerability profile.

Importance  Migraine is a disabling neurological disease characterized by severe headache attacks. Treatment options reduce migraine frequency for many patients, but adverse effects lead to discontinuation in many patients.

Objective  To demonstrate that galcanezumab is superior to placebo in the prevention of episodic migraine with or without aura.

Design, Setting, and Participants  The EVOLVE-1 (Evaluation of LY2951742 in the Prevention of Episodic Migraine 1) trial was a double-blind, randomized, placebo-controlled (January 11, 2016, to March 22, 2017) trial comparing galcanezumab (120 mg and 240 mg) vs placebo. Patients received treatments once monthly for 6 months (subcutaneous injection via prefilled syringe) and were followed up for 5 months after their last injection. It was a multicenter, clinic-based study involving 90 sites in North America. Participants in the study were adults (aged 18 to 65 years) with at least a 1-year history of migraine, 4 to 14 migraine headache days per month and a mean of at least 2 migraine attacks per month within the past 3 months, and were diagnosed prior to age 50 years. During the study, no other preventive medications were allowed. A total of 1671 patients were assessed; 809 did not meet study entry or baseline criteria, and 858 were included in the intent-to-treat population.

Interventions  Patients were randomized (2:1:1) to monthly placebo, galcanezumab, 120 mg, and galcanezumab, 240 mg.

Main Outcomes and Measures  The primary outcome was overall mean change from baseline in the number of monthly migraine headache days during the treatment period. Secondary measures included at least 50%, at least 75%, and 100% reduction in monthly migraine headache days, migraine headache days with acute medication use, and scores from the Migraine-Specific Quality of Life questionnaire, Patient Global Impression of Severity, and Migraine Disability Assessment. Treatment-emergent adverse events and serious adverse events were reported.

Results  Of the 1671 patients assessed, 858 (mean age, 40.7 years; 718 women [83.7%]) met study entry criteria and received at least 1 dose of investigational product. The primary objective was met for both galcanezumab doses; treatment with galcanezumab significantly reduced monthly migraine headache days (both P < .001) by 4.7 days (120 mg) and 4.6 days (240 mg) compared with placebo (2.8 days). All key secondary objectives were also significant after multiplicity adjustment. There were no meaningful differences between 120-mg and 240-mg doses of galcanezumab on measures of efficacy. Completion rate during treatment was high (81.9%; n = 718), and the incidence of discontinuation owing to adverse events was less than 5% across all treatment groups.

Conclusions and Relevance  Galcanezumab 120-mg and 240-mg monthly injections provided clinical benefits and improved functioning. The incidence rate of adverse events was low, demonstrating the favorable tolerability profile of galcanezumab.

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