A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention

Abstract

Objective: To assess the safety and efficacy of AMG 301, an inhibitor of the pituitary adenylate cyclase-activating polypeptide (PACAP)-1 (PAC1) receptor, for prevention of migraine.

Methods: In a double-blind trial, patients were randomized 4:3:3 to placebo, AMG 301 210 mg every 4 weeks, or AMG 301 420 mg every 2 weeks for 12 weeks. Effect on monthly migraine days and other secondary measures were assessed over weeks 9-12. Safety and tolerability were assessed.

Results: Of 343 randomized patients (mean age, 41.8-42.5 years), the majority were women (85.4-90.4%), white (94.1-96.2%), and had episodic migraine (62.5-67.9%). A total of 305 patients completed treatment (placebo, n = 124; AMG 301 210 mg, n = 94; AMG 301 420 mg, n = 87). Least squares mean reduction at week 12 in monthly migraine days from baseline was -2.5 (0.4) days for placebo and -2.2 (0.5) days for both AMG 301 treatment groups. No difference between AMG 301 and placebo on any measure of efficacy was observed; mean (95% confidence interval) treatment difference versus placebo for monthly migraine days for AMG 301 210 mg, 0.3 (-0.9 to 1.4); AMG 301 420 mg, 0.3 (-0.9 to 1.4). The incidence of adverse events was similar across groups.

Conclusion: AMG 301 offered no benefit over placebo for migraine prevention; further studies may be necessary to fully understand the role of PACAP isoforms and its receptors in migraine pathophysiology.

Study registration: ClinicalTrials.gov: NCT03238781.

Keywords: AMG 301; chronic migraine; episodic migraine; pituitary adenylate cyclase-activating polypeptide; preventive treatment.

Figure 1.

Trial design. Q2W: every 2 weeks; Q4W: every 4 weeks; SC: subcutaneous. *18 weeks after last dose of investigational product.

Figure 2.

Patient disposition. Q2W: every 2 weeks; Q4W: every 4 weeks; TEAE: treatment-emergent adverse event.

Figure 3.

Effect of AMG 301 and placebo on (a) change from baseline of MMD, (b) proportion of patients achieving a ≥ 50% reduction in MMD, and (c) change from baseline of monthly acute migraine-specific medication use as assessed in the last 4 weeks of a 12-week double-blind treatment period. LS: least squares; MMD: monthly migraine days; MSMD: migraine-specific medication days; N: number of patients in the primary analysis dataset (i.e. received ≥ 1 dose of investigational product and completed ≥ 1 post-baseline monthly electronic diary measurement); N1: number of patients with observed data; OR: odds ratio; Q2W: every 2 weeks; Q4W: every 4 weeks. *Odds ratio versus placebo.

Figure 4.

Effect of AMG 301 and placebo on change from baseline for (a) MPFID impact on everyday activities sub-score, and (b) MPFID on physical impairment sub-score as assessed in the last 4 weeks of a 12-week double-blind treatment period. LS: least squares; MPFID: Migraine Physical Function Impact Diary; N: number of patients in the primary analysis dataset (i.e. received ≥ 1 dose of investigational product and completed ≥ 1 post-baseline monthly electronic diary measurement); Q2W: every 2 weeks; Q4W: every 4 weeks.