The above studies were recently pooled in a meta-analysis that arrived at the same conclusion that the studies repeatedly found, that regardless of dose, galcanezumab statistically decreases the number of migraine headache days (MHDs) in patients with episodic migraines [
37]. The REGAIN and EVOLVE-1/2 studies were also pooled by a separate study group to look at initial non-responders who continued to receive galcanezumab, to determine whether a certain population had a delayed response to the medication. This group examined patients who, after 1 month, did and did not have a protocol-defined response in migraine reduction (> 50% reduction in MHDs). They further separated the non-responders into four groups of modest responders (30–50% reduction), limited responders (10–30% reduction), minimal/non-responders (10% reduction to 10% increase in MHDs), and worsening (> 10% increase in MHDs). In the cohort of 450 non-responders after 1 month (51.3% of total subjects), the moderate responders were more likely than the limited responders to eventually achieve a protocol-defined reduction, and likewise the limited responders were more likely than the minimal responders. Of the modest responders, 61.9% crossed the 50% threshold during the study and were therefore deemed responders. This number declined to 42.6% for the limited responders, and only 34.1% and 19.6% of the minimal and worsening categories exceeded the threshold, respectively. These numbers were rerun after 2 months, and 290 subjects were still non-responders (33%). At this point, only 50% of the modest, 40.8% of the limited, 17.9% of the minimal, and 9.3% of the worsening categories would reach > 50% reduction by the end of the 6-month study duration. Therefore, in general, a more immediate response provides a more positive outcome; however, even if galcanezumab provides initial worsening of symptoms in the first month, there is still evidence showing a 20% chance that symptoms can be reduced by more than 50% through 6 months of treatment [
38].
Adverse Effects
Migraine is associated with significant headache-related disability and impairment of daily living and functioning, often calculated using a scoring system for disability-adjusted life-years (DALY) [
39]. Traditionally, treatments for migraine have been evaluated using monthly migraine headache days as a primary endpoint, but this simple quantitative approach disregards the effects of migraine on physical, emotional, and social aspects of life [
39]. Thus, more recently, existing and potential treatments for migraine have started to be evaluated based on their ability to improve health-related quality of life (HRQoL) scores [
39]. Given that most oral migraine medications must be up-titrated to an efficacious dose over the course of weeks, many patients experience reductions in HRQoL scores and increased disability secondary to premature discontinuation [
39]. In order to assess the effects of galcanezumab not only on physical health but also on daily living and functioning, Ford and colleagues compared the MSQv2.1 and Migraine Disability Assessment (MIDAS) scores of patients with episodic migraine taking the drug versus placebo [
39]. Data were reported from two randomized, double-blind, placebo-controlled phase 3 studies (EVOLVE-1 and EVOLVE-2) [
39]. Patients were evaluated for 6 months according to MSQv2.1 and MIDAS assessments conducted at baseline and then either monthly (MSQv2.1) or at months 3 and 6 (MIDAS) [
39]. Patients had baseline MSQv2.1 scores of less than 60%, indicating considerable functional impairment due to migraine [
39].
It is known that high measures of disability correlate with low measures of HRQoL [
39]. Consequently, treatments that improve disability are associated with higher HRQoL scores [
39]. Analysis by Ford and colleagues demonstrated that a 6-month trial of galcanezumab in patients with episodic migraine was associated with significant improvements in HRQoL measured by MSQv2.1 and significant reductions in disability measured by MIDAS [
39]. With treatment, patients exceeded approximately 80% of the total possible score for the MSQv2.1, suggesting substantially improved functional capacity in daily life [
39]. This improvement indicates significantly increased capabilities in work and daily activity, productivity, personal relationships, leisure, and emotional well-being [
39]. More than 70% of the patients in the treatment group experienced a reduction of at least 50% in MIDAS total score [
39]. Patient improvement was similar across the two dose regimens (120 mg in EVOLVE-1 and 240 mg in EVOLVE-2), and differences between galcanezumab and placebo were seen starting in the first month of treatment [
39]. These results corroborated the findings of prior studies supporting an association between galcanezumab and reductions in migraine headache days, low discontinuation rates, and high safety and tolerability [
39].
As mentioned earlier, safety and tolerability play an important role in determining patient adherence to treatment regimens. The adverse effect profile of galcanezumab was investigated in a subset of patients diagnosed with episodic or chronic migraine not previously exposed to the drug [
40]. Patients were administered galcanezumab 120 mg or 240 mg subcutaneously once a month for a year [
40]. Safety and tolerability were assessed by calculating the frequency of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to discontinuation of treatment [
40].
It was determined that approximately 78% of patients completed the trial, with 4% of patients experiencing an SAE and 5% discontinuing the study as a result of AEs [
40]. Treatment compliance exceeded 95% in patients who finished the trial [
40]. The rate of discontinuation due to AEs was lower than the adverse-event-related rate of discontinuation with topiramate [
40]. The TEAEs experienced most frequently were injection site discomfort, nasopharyngitis, upper respiratory tract infections, sinusitis, and back pain [
40]. Although migraines are commonly thought to be associated with increased risk of suicidal ideation, no treatment-emergent suicidal behavior was reported in this study [
40]. While one-third of patients experienced injection site AEs such as injection site pain or reaction, only five patients discontinued for this reason [
40]. Injection site discomfort was mild to moderate in severity and occurred most often on the day of injection, with resolution on the following day [
40]. None of the TEAEs, including injection site discomfort, were dose-dependent, with the exception of upper respiratory tract infections [
40]. However, data from the phase 3 double-blind, placebo-controlled study showed that incidence of upper respiratory tract infections was similar across the 120 mg, 240 mg, and placebo groups [
40].
When the safety of galcanezumab was assessed by considering changes from baseline in vital signs, laboratory values, EKG parameters, and weight, there were no clinically meaningful differences between the two dose regimens and placebo [
40]. Further, the study group, characterized by a mean of 10.6 migraine headache days per month at baseline, experienced reductions in migraine headache days of 5.6 (120 mg) and 6.5 days (240 mg) [
40]. This safety and effectiveness profile was consistent with those of two previous phase 2 and two phase 3 studies in patients with episodic migraines and one phase 3 study in patients with chronic migraines [
40].
Guidelines for Use
Galcanezumab and other monoclonal antibodies acting on CGRP or its receptors (eptinezumab and fremanezumab) are new therapies for the prevention of episodic and chronic migraine [
41]. The development of evidence- and expert-based guidelines for their use is still in progress [
41]. The European Headache Federation (EHF) performed a systematic literature review to assess the quality of available evidence and to establish recommendations to guide clinicians in the use of the CGRP monoclonal antibodies [
41]. EHF considered evidence from inception to November 2018, with 28 studies identified as eligible for consideration [
41].
Analysis of the available data indicated that galcanezumab is effective for the prevention of migraine in patients with both episodic and chronic disease [
41]. Phase 2 and 3 randomized controlled studies demonstrated that galcanezumab use decreased the number of migraine headache days, decreased the number of days of acute medication use, and improved disability [
41]. Of note, galcanezumab was shown to be effective in chronic migraine patients with a long history of disease who had failed two or more preventive treatment regimens [
41]. The effectiveness of galcanezumab in patients with severe episodic migraine and history of preventive treatment failure is not as well established and requires further investigation [
41]. The aforementioned rapid onset of action of galcanezumab and its ease of use via subcutaneous injection with monthly or quarterly dosing increases convenience and patient adherence [
41]. For this reason, the long-term efficacy, safety, and tolerability of the drug is also currently being evaluated in patients with episodic and chronic cluster headache (ClinicalTrials.gov Identifier NCT02797951) [
42].
Data on the management of other oral prophylactic migraine treatments in association with galcanezumab are scarce. It is not believed that CGRP monoclonal antibodies interact with other migraine regimens to a large degree, and it is likely that these drugs can be used in combination [
41]. The development of binding and/or neutralizing antibodies with galcanezumab use is infrequent and has not been shown to affect treatment [
41]. Thus, it is fair to consider adding galcanezumab in patients with insufficient response to other therapies [
41]. Likewise, it is reasonable to allow the use of additional preventive drugs when galcanezumab produces incomplete symptom relief [
41]. At present, no information on the concurrent use of galcanezumab and onabotulinumtoxinA is available [
41].
Given the demonstrated effectiveness and high patient adherence to galcanezumab, and the significant negative impact on quality of life associated with migraine, the EHF has concluded that it is reasonable to treat patients with galcanezumab and other CGRP monoclonal antibodies [
41]. As stated, while drug–drug interaction with galcanezumab is unlikely, CGRP is the most potent known vasodilator peptide and is considered dangerous in patients with known disease of the vascular system [
41]. While no evidence of increased cardiovascular events has been recorded to date, patients with cardiovascular and cerebrovascular disease have been excluded from existing clinical trials [
41]. Thus, long-term safety studies with galcanezumab are needed to justify offering the drug to this subset of patients [
41].
With respect to duration of treatment, the EHF found that it is reasonable not to stop treatment even in the absence of clinical response [
41]. Given limited data on the sustainability of the effects of galcanezumab following withdrawal of treatment, it is also reasonable to continue the drug for at least 6–12 months in patients with positive response [
41]. It is essential to recognize that the costs of galcanezumab are not yet entirely known, but are expected to be higher than other migraine drugs [
41]. For this reason, while galcanezumab appears to be a suitable option for patients with contraindications to other prophylactic medications, comorbidities, or poor compliance, it is unlikely that this therapy will be accessible to all patients [
41].