Introduction
Migraine, which affects about 12% of adults [
1], is associated with such overwhelming and disabling symptoms [
2] that it ranks as the leading cause of years lived with disability in patients aged 15–49 years and second only to low back pain in patients older than 49 years [
3]. People with migraine can experience impaired function across all domains of life, and these impairments are not limited to headache days but can both precede and follow a migraine attack. Migraine is classified as episodic (up to 14 migraine headache days/month) or chronic (15 or more headache days/month for more than 3 months, of which at least 8 of those days have features of migraine headache) [
2]. Such classifications are not static, and patients can move from one class to another over time.
Acute (abortive) therapy is appropriate and indicated for any number of migraine headache days/month [
4], whereas preventive treatment should be offered to patients with four or more migraine headache days/month with some degree of headache-related impairment [
5]. Unfortunately, only one in three patients who qualify for preventive therapy actually receive such treatment [
1]. The reasons for under-treatment with preventive therapy are multifactorial. Until recently, all preventive therapies were “borrowed” from other disease states such as mood disorders, hypertension, and epilepsy and are associated with low response rates and high rates of discontinuation [
6,
7]. In a retrospective analysis of migraine preventive prescriptions in a US claims database, among patients who initiated preventive therapy, a sharp decline in persistence was observed after the first 30 days [
6]. Another study evaluated cycling of preventive migraine medications from a claims database and found that in patients with episodic and chronic migraine, more than 75% of patients switched or discontinued their initial preventive treatment within 12 months, leading to increased healthcare resource utilization and cost [
7]. Lack of consistently effective preventive medications leads to patients with migraine suffering from stigmatization and loss of hope. The ideal preventive medication would have an early onset of effect and maintenance of effect, a good tolerability/safety profile supporting persistence, and improvement of overall quality of life [
8].
Recognition of the role of calcitonin gene-related peptide (CGRP), a neuropeptide released from the trigeminal nerve during a migraine attack, in precipitating the cascade of impairing symptoms, has been pivotal in the development of new target-specific migraine preventive treatment options. Although the pathophysiology of migraine is complex, it is thought that stimulation of the trigeminovascular system leads to a release of neuropeptides, including CGRP, which binds to CGRP receptors and leads to a cascade of activation of nociceptors, inflammation, and vasodilatation [
9].
Galcanezumab, a humanized monoclonal antibody, potently and selectively binds to the CGRP ligand and blocks its binding to the receptor [
10,
11]. Galcanezumab is approved for the preventive treatment of migraine in adults. Galcanezumab became available in the USA in September 2018 and is self-administered as a once-monthly subcutaneous injection using an auto-injector or prefilled syringe [
12]. The recommended and approved dosage of galcanezumab for migraine is an initial 240 mg loading dose (two consecutive subcutaneous injections of 120 mg each), followed by a monthly dose of 120 mg injected subcutaneously [
12]. The use of 240 mg as a monthly dose is not currently approved in the USA because it did not demonstrate superiority over the 120 mg monthly dose.
The efficacy, safety, and tolerability of galcanezumab for migraine prevention were established in three phase 3, randomized, double-blind, placebo-controlled studies in about 2800 patients with episodic migraine (EVOLVE-1/EVOLVE-2) and chronic migraine (REGAIN) [
13‐
15]. In all three pivotal studies, patients treated with monthly galcanezumab 120 mg (with a 240 mg loading dose) or 240 mg doses had a statistically significantly greater overall mean reduction from baseline in the number of monthly migraine headache days vs placebo-treated patients [
13‐
15]. Overall, there were about 4.5 fewer monthly migraine headache days among galcanezumab-treated patients who participated in these studies. Extrapolated out to 1 year of treatment, the reduction in migraine headache days would equate to about 8 weeks of fewer migraine headache days/year. Over half of patients in the episodic migraine trials and over a quarter of patients in the chronic migraine trial who received galcanezumab achieved a 50% response rate. Galcanezumab was well tolerated with low discontinuation rates, and the most common adverse event was injection site reactions [
13‐
15].
This paper describes the time course of effect of galcanezumab in patients with episodic and chronic migraine, including onset of effect following administration of the first dose, maintenance of effect over time, and gradual cessation of effect following discontinuation of treatment.
Discussion
The present analyses indicate that galcanezumab, a CGRP monoclonal antibody that is used for the preventive treatment of migraine, had an onset of effect beginning as early as the first day after injection for some patients with episodic or chronic migraine; maintenance of effect throughout the treatment period (6 months in episodic migraine and 3 months in chronic migraine); and gradual reduction of effect without signs of rebound headache throughout the 4-month post-treatment period in the majority of patients with episodic and chronic migraine. While results of the 120 mg/month (with a 240 mg loading dose) and 240 mg/month treatment arms are reported, the approved dose for migraine prevention is 120 mg monthly following a 240 mg loading dose. In all three clinical trials, the most common adverse reactions were injection site reactions [
12].
The time course of effect of galcanezumab has relevance to clinicians and patients. Patient persistence on oral migraine preventive medications is often low [
6,
7]. Speed of onset influences patient preference and may improve persistence [
25]. Galcanezumab showed an early onset of effect, which was replicated in three large phase 3 clinical trials in adult patients with episodic and chronic migraine. Both doses of galcanezumab (120 mg and 240 mg) achieved a statistically significant reduction in the number of monthly migraine headache days beginning at month 1. Additional weekly analyses within the first month showed separation from placebo at week 1. Daily analyses within the first week found that the estimated proportion of patients experiencing migraine headaches was significantly lower in the galcanezumab group beginning the first day after injection. Further, a numerically greater proportion of patients in the galcanezumab group achieved new-onset 50% response during the initial months of treatment compared to placebo. However, it is important to note that this early onset of effect is not necessary to achieve long-term efficacy as most guidelines recommend evaluating CGRP monoclonal antibodies for at least 3 months to determine if a patient is responsive [
8,
26].
Galcanezumab also demonstrated good maintenance of effect. Galcanezumab-treated patients were two times more likely than placebo-treated patients to achieve a sustained response of at least 50% for three consecutive months in both episodic and chronic migraine studies. There is some evidence that improvement with preventive treatment at 3 months may predict lasting remission [
27]. This maintenance of effect also has the potential to improve persistence.
Following cessation of galcanezumab, response rates declined over time but did not return to baseline for patients with episodic and chronic migraine [
20]. This persistence of effect is important for patients should they need to temporarily stop preventive treatment or switch medications. No new adverse events, including rebound headache, were observed during the post-treatment period [
20].
These findings of early onset, persistence of effect, and gradual decline in efficacy following cessation may be related to the pharmacokinetics of galcanezumab [
12]. Studies of the pharmacokinetic/pharmacodynamic properties of galcanezumab have found an average time to peak serum concentration of galcanezumab of 5 days and attainment of therapeutic steady-state concentrations following the loading dose [
12,
28]. The average half-life of 27 days allows for monthly administration of galcanezumab and may play a role in the persistence of effect even after discontinuation [
12]. This represents an advantage over some oral therapies, which require daily dosing and long titration schedules to reach a therapeutic dose. Patients may thus discontinue oral treatments before realizing their full potential.
These results were not without limitations. The study population was predominantly middle-aged, Caucasian women. Patients with unstable medical or psychiatric conditions, high body mass index (40 kg/m2 or more), high risk of serious cardiovascular events, and those who had failed three or more adequately dosed classes of migraine preventive treatments were excluded. Although these factors may limit generalizability, most patients with episodic and chronic migraine fall within the study spectrum. Several of these analyses are post hoc in nature and the parent studies were not specifically powered for these assessments. However, the results were replicated across three studies.
Acknowledgements
The authors thank the participants of the studies included in this review.