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.

Conflict of interest statement

Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MA is a consultant, speaker or scientific advisor for Alder, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis and Teva; and a primary investigator for Alder, Allergan, Amgen, Eli Lilly, Novartis and Teva. He has no ownership interest and does not own stocks in any pharmaceutical company. He serves as associate editor of Cephalalgia, associate editor of Headache, and associate editor of the Journal of Headache and Pain; and is the President of the International Headache Society.

DD is a speaker, consultant or scientific advisor for Allergan, Amgen, Eli Lilly, Novartis, and Teva, as well as a primary investigator for Alder, Allergan, Amgen, Eli Lilly, Novartis, and Teva.

JHB reports no conflicts. JK is an employee of Novartis and owns Novartis stock. LZ, HP and DDM are employees of Amgen Inc., and own Amgen stock/stock options.

Figures

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.