Efficacy and Safety of Erenumab in Patients with Chronic Migraine Who Have Experienced Preventive Treatment Failure

Background

There are limited data from randomized placebo-controlled trials that demonstrate the efficacy of therapies used for the prevention of chronic migraines. Currently, the only agents approved for the prevention of chronic migraine are topiramate and onabotulinumtoxinA. Other commonly used agents (eg, antidepressants, antihypertensives, and valproic acid) are used off label for prevention of migraine. Adherence to oral agents for migraine prevention is a common challenge, often resulting in frequent switching, re-initiation, or discontinuation of therapy. Higher rates of discontinuation have been observed with an increasing number of failed preventive therapies. Thus, there is an unmet need for effective and tolerable preventive migraine therapies.¹

Erenumab (AMG334) is a fully human monoclonal antibody that selectively inhibits the canonical calcitonin gene-related peptide receptor.¹ The efficacy and safety of monthly subcutaneous injections of erenumab for the prevention of migraines were evaluated in a phase 2 clinical trial.² The study results showed that patients with chronic migraines receiving erenumab had fewer monthly migraine days (MMDs), a greater rate of achieving at least a 50% reduction from baseline in MMDs, and fewer monthly acute migraine-specific medication days (MSMDs) than patients receiving placebo.² Seeking to provide further data to assist clinical decision making, a subgroup analysis of these data was conducted to evaluate whether the efficacy of erenumab varied based on prior migraine preventive treatment failure.¹

Methods

The clinical trial was a 12-week, multicenter, double-blind, randomized, placebo-controlled study of a monthly subcutaneous injection of erenumab 70 or 140 mg in adult patients with chronic migraine, defined as at least 15 headache days per month or at least 8 migraine days per month. Although the study excluded patients who did not respond to more than 3 preventive treatment categories, patients who had a partial response to prior treatment or discontinued treatment before a therapeutic response due to adverse events (AEs) were included. Patients with prior overuse of medications for migraines (eg, triptans, ergots, and analgesics) were also included.¹

The study consisted of 2 phases: a 1-month baseline phase and a 3-month double-blind treatment phase. During both phases, patients entered information about their migraine and nonmigraine headaches and use of acute migraine-specific medications and other analgesic agents into an electronic diary. The primary efficacy end point was the change in MMD from baseline to month 3 of the treatment phase. Key secondary efficacy end points included the proportions of patients who achieved at least a 50% and at least a 75% reduction from baseline in MMDs and change in monthly acute MSMDs from baseline.¹

For this subgroup analysis, efficacy was evaluated for each of the following subgroups: at least 1 preventive treatment failure, at least 2 preventive treatment failures, and never failed preventive treatment (treatment naïve or received prior treatment but did not fail due to lack of efficacy or intolerability). Post hoc analyses included efficacy in patients with at least 3 preventative treatment failures and safety for all 4 subgroups.¹

Results

At baseline, 73.8% of the overall patient population previously received 1 or more preventive treatments. The most commonly reported reasons for treatment failure were lack of efficacy (73.2%) and intolerability (66%). Across all subgroups, the mean age ranged from 40.7 to 44.2 years and the majority of patients were female (73.5%-90.8%). Baseline MMDs ranged from 17.1 to 19.0. MSMDs use at baseline was higher in patients with prior treatment failure (10.0-12.5 days) compared with those who never failed treatment (6-7 days). The investigators opined that patients with prior treatment failure may be a more severely affected, difficult-to-treat population.¹

Efficacy

There were 214 patients evaluated in the never-failed-treatment subgroup, 453 patients in the subgroup with at least 1 treatment failure, 327 patients in the subgroup with at least 2 treatment failures, and 232 patients in the subgroup with at least 3 treatment failures. With regard to the primary efficacy end point, patients receiving erenumab (70 and 140 mg) in all 3 treatment-failure subgroups (≥1, ≥2, ≥3 treatment failures) had larger decreases in MMDs from baseline to month 3 than those receiving placebo. When comparing subgroups, greater reductions from baseline in MMD between erenumab and placebo were seen in patients who previously failed treatment (≥1, ≥2, and ≥3 treatment failure groups) compared with those who never failed treatment (Table).¹ However, the investigators noted that the larger difference may be due to the lower response in patients given placebo with prior treatment failure. For patients who previously failed treatment who received erenumab, reductions in MMDs were greater with erenumab 140 mg than 70 mg. Conversely, there was greater efficacy at month 3 with erenumab 70 mg than 140 mg in patients who never failed treatment.¹

Across all subgroups, greater proportions of patients who received erenumab (70 and 140 mg) had at least a 50% reduction in MMDs from baseline and at least a 75% reduction in MMDs from baseline compared with those given placebo (Table). Similar to the primary end point, there was a greater difference between erenumab and placebo in patients who previously failed preventive treatment (≥1, ≥2, and ≥3 treatment failure groups) than in those who never failed, for both secondary end points; however, the treatment difference was influenced by a lower response in those given placebo who previously failed treatment (Table). Also similar to the primary end point, greater efficacy in achieving at least a 50% and a 75% reduction in MMDs was seen with erenumab 140 mg compared with 70 mg, respectively, in the patients who failed prior treatment. In the never-failed-prior-treatment group, there was a numerically higher percentage of patients receiving erenumab 70 mg who achieved at least a 50% reduction in MMDs and at least a 75% reduction in MMDs (50.0% and 23.4%, respectively) than those who received erenumab 140 mg (41.9% and 22.6%, respectively). Compared with placebo, erenumab 70 mg and 140 mg reduced monthly acute MSMDs (Table).¹

Safety

The incidence of AEs was comparable between erenumab 70 mg, erenumab 140 mg, and placebo within each subgroup. AEs were reported by 30.6% to 37.5% of patients who never failed treatment and 42.4% to 60.0% of those who previously failed treatment. There was a low incidence of serious AEs and AEs resulting in treatment discontinuation.¹

Discussion

The investigators concluded that this analysis showed the 70- and 140-mg erenumab doses were effective in reducing MMDs and MSMDs in patients who previously failed preventive treatment compared with placebo, particularly the 140-mg dose. Greater proportions of patients achieved at least a 50% and at least a 75% reduction in MMDs from baseline in all subgroups that previously failed treatment (≥1, ≥2, and ≥3 treatment failures). Given the efficacy and tolerability results, the investigators opined there may be clinical utility of erenumab in prevention of migraine in patients with chronic migraine who have failed other preventive therapies. However, further studies are required to determine the efficacy of erenumab in patients who have not responded to more than 3 classes of preventive therapy. It was noted that the LIBERTY trial (NCT03096834), which evaluated the efficacy of erenumab in episodic migraine in patients who previously failed 2 to 4 preventive treatments, may provide more high-quality data in this population.¹

References

1. Ashina M, Tepper S, Brandes JL, et al. Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: a subgroup analysis of a randomized, double-blind, placebo-controlled study [published online January 1, 2018]. Cephalalgia. doi: 10.1177/0333102418788347.

2. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434. doi: 10.1016/S1474-4422(17)30083-2.