A phase 3, long-term, open-label safety study of Galcanezumab in patients with migraine

DOI: https://doi.org/10.1186/s12883-018-1193-2

Abstract-Summary Galcanezumab, a humanized monoclonal antibody that selectively binds to the cal- citonin gene-related peptide, has demonstrated in previous Phase 2 and Phase 3 clinical studies (≤6-month of treatment) a reduction in the number of migraine headache days and improved patients’ functioning.

This study evaluated the safety and tolerability, as well as the effectiveness of

galcanezumab for up to 12 months of treatment in patients with migraine.

Patients diagnosed with episodic or chronic migraine, 18–65 years old, that were not exposed previously to galcanezumab, were randomized to receive galcanezumab 120 mg or 240 mg, administered subcutaneously once monthly for a year.

Overall change from baseline in the number of monthly migraine headache days,

functioning, and disability were assessed.

One hundred thirty five patients were randomized to each galcanezumab

dose group.

The majority of patients were female (>80%) and on average were 42 years old

with 10.6 migraine headache days per month at baseline.

Laboratory values, vital signs, or electrocardiograms did not show anyclinically meaningful differences between galcanezumab dosesOverall mean reduction in monthly migraine headache days over 12 months for the galcanezumab dose groups were 5.6 (120 mg) and 6.5 (240 mg).

Level of functioning was improved and headache-related disability was reduced

in both dose groups.

Twelve months of treatment with self-administered injections of galcanezumab was safe and associated with a reduction in the number of monthly migraine head- ache days.

Extended: In this study, the majority of the patients met criteria for episodic migraine and further assessment of the patients with episodic compared to chronic migraine will be explored in a future publication.

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4 Treatment

Background For patients with frequent migraine attacks, and for whom abortive treatments are inadequately effective, preventive therapies are recommended [134, 272, 273].

It is estimated that approximately 39% of migraine patients would benefit from preventive pharmacotherapy to reduce the frequency of migraine attacks [213], which includes the ability to function at work and school, and interferes with family and social interactions [274].

For patients with chronic migraine, there are two preventive treatments consid- ered as standard of care, onabotulinumtoxinA and topiramate, which are the most frequently prescribed medications for chronic migraine [124, 275].

Although all of these medications are considered preventive treatment for epi- sodic or chronic migraine, none of them were developed specifically to treat migraine, and some are not well tolerated [276].

The purpose of this study was to investigate the long-term safety, tolerability, and

effectiveness of galcanezumab treatment in patients with migraine.

Methods Key exclusion criteria were: prior exposure to galcanezumab (or any other CGRP antibody); use of any therapeutic antibody in the past 12 months; current treatment with preventive migraine medication; history of failure to respond to three or more classes of migraine preventive treatments (as defined by the American Academy of Neurology treatment guidelines Level A or Level B evidence [152]); presence of a medical condition that would preclude study participation, including pregnancy, presence of suicidal ideation within the past month, history of substance abuse or dependence in the past year, or recent history of acute cardiovascular events and/or serious cardiovascular risk based on history or ECG findings.

The evaluation included overall change from baseline in the number of monthly MHD, headache days, responder analysis of ≥30%, ≥50%, ≥75, and 100% reduc- tion in MHD, the percentage of patients who maintained a monthly MHD response, and change from baseline in the number of days acute treatment is taken for migraine or headache.

Study Period 3 was a 4-month post-treatment period (washout phase), during which patients no longer received study medication, but continued to track head- ache information and received safety assessments.

Results Of the patients who discontinued the treatment period early, significantly more patients in the galcanezumab 120  mg dose group discontinued compared to the galcanezumab 240 mg dose group (P = 0.028).

There were four patients who missed an injection at a home dosing visit, but they did complete the treatment phase, and the mean treatment compliance in this study was 95.8 and 96.9% in the galcanezumab 120  mg and 240  mg dose groups, respectively.

In the galcanezumab 120 mg dose group, two patients discontinued due to injec- tion site reaction, and one patient each discontinued due to injection site erythema, lethargy, migraine, and suicidal ideation.

4.3 Results

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In the galcanezumab 240 mg dose group, two patients discontinued due to injec- tion site reaction, and one patient each discontinued due to non-cardiac chest pain, paranoia, rash, tongue discomfort, and vertigo.

Discussion In this 12-month open-label study of once monthly subcutaneous injections of gal- canezumab 120 mg and 240 mg as a preventive treatment for migraine, the safety and effectiveness profile observed was consistent with previous studies: two Phase 2 studies [270, 277], and two Phase 3 studies in patients with episodic migraine [278], and one Phase 3 study in patients with chronic migraine [279].

Where patients or caregivers administered subcutaneous injections of galcane-

zumab, AEs of particular interest were those associated with the injection site.

Safety data from the Phase 3, double-blind, placebo-controlled studies for all three treatment groups (galcanezumab 120 mg, galcanezumab 240 mg, and placebo) showed a similar incidence of the AE of the upper respiratory tract infection [280].

Nearly 17% of the patients had comorbid depression, but treatment-emergent

suicidal behavior was not reported.

Three of these patients did not have a history of depression, but had a one-time incidence of treatment-emergent suicidal ideation as assessed by the C-SSRS, and all 3 patients continued in the study.

Conclusion There were no meaningful differences between galcanezumab doses with respect to measures of safety and tolerability.

Acknowledgement A machine generated summary based on the work of Camporeale, Angelo; Kudrow, David; Sides, Ryan; Wang, Shufang; Van Dycke, Annelies; Selzler, Katherine J.; Stauffer, Virginia L. 2018 in BMC Neurology.

Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2)