Now 4 years after the approvals of the first calcitonin gene-related peptide inhibitors, new therapies are being developed to address the lingering needs of patients with refractory migraine.
IN 2018, the FDA approved the first calcitonin gene-related peptide (CGRP) inhibitors specifically to prevent migraine. Designed to target CGRP, a protein known to be involved in migraine, these treatments represented a breakthrough for patients. Previously used preventive medications had been associated with numerous adverse events (AEs) that often limited their use, whereas this new class of therapies has demonstrated significantly improved tolerance and AE profiles.
In September 2022, Axsome Therapeutics announced it had enrolled the first patient in the phase 3, open-label, multicenter EMERGE trial (NCT05550207) assessing its investigational agent AXS-07 for the acute treatment of migraine (FIGURE).1 The unique trial will enroll 100 patients with an established diagnosis of migraine with or without aura and who have experienced an inadequate response to oral CGRP inhibitors. The study restricts those who are pregnant, breastfeeding, or planning to become pregnant, as well as those who have received any investigational drug or device within 30 days of screening.
AXS-07 is a novel, oral, rapidly absorbed medicine that consists of meloxicam and rizatriptan. Meloxicam is a new entity for migraine enabled by Axsome’s Molecular Solubility Enhanced Inclusion Complex (MoSEIC) technology, which results in rapid absorption of meloxicam while maintaining a long plasma half-life. Meloxicam is a COX-2 preferential nonsteroidal anti-inflammatory drug, whereas rizatriptan is a 5-HT1B/1D agonist.
In EMERGE, eligible individuals will receive open-label AXS-07 for 8 weeks for at-home treatment of their next 4 migraine attacks. Data from the study will be used to further elucidate the clinical profile of AXS-07 and is not a regulatory requirement. In May 2022, Axsome announced that it received a complete response letter from the FDA for its new drug application for AXS-07, citing reasons related to chemistry, manufacturing, and controls (CMC) considerations, specifically a requirement of further CMC data pertaining to the drug product and manufacturing process.2 In the announcement, Axsome noted it will be able to address these concerns and plans to provide timing for a resubmission following a meeting with the agency.
“It is our goal to work with the FDA to fully understand and adequately address their comments, so that we can make this important new medicine available to patients with migraine as quickly as possible,” Axsome CEO Herriot Tabuteau, MD, said in the announcement.2 “The approval of AXS-07 would offer a much-needed new multimechanistic treatment option for the millions of people living with this debilitating neurological condition.”
Accepted for review in September 2021, the new drug application of AXS-07 was supported by data from a pair of phase 3 randomized controlled clinical trials—MOMENTUM (NCT03896009) and INTERCEPT (NCT04163185). In both trials, the oral and dual-mechanism therapy showed statistically significant elimination of migraine pain relative to those on placebo and active controls.
MOMENTUM included 1594 patients randomly assigned in a 2:2:2:1 ratio to AXS-07, 10-mg rizatriptan, MoSEIC 20-mg meloxicam, or placebo, to manage a single migraine attack of moderate or severe intensity. All told, the agent met its primary end points, demonstrating significantly higher rates of achieving pain (19.9%) compared with placebo (6.7%; P < .001). Second, absence of the most bothersome symptom, assessed 2 hours after dosing, was reported in a higher proportion of patients on AXS-07 (36.9%) than placebo (24.4%; P = .002).3
In April 2020, Axsome announced the results of INTERCEPT, which displayed similar findings to the prior trial.4 The coprimary end points were also identical to MOMENTUM, with a statistically significantly greater percentage of patients achieving pain freedom compared with placebo (32.6% vs 16.3%, respectively; P = .002) at 2 hours post dose, as well as freedom from the most bothersome symptom (43.9% vs 26.7%, respectively; P = .003).4 AXS-07 also showed efficacy in preventing progression of migraine pain beyond mild intensity and significantly reducing the use of rescue medication, with freedom of pain progression occurring in 73.5% of AXS-07–treated patients compared with 47.4% of placebo patients between 2 and 24 hours post dose (P < .001).
In terms of safety, the agent was shown to be safe and well tolerated across both trials, with no reports of serious adverse events (AEs) throughout INTERCEPT and only 1 reported in MOMENTUM, though it was deemed unrelated to treatment. In INTERCEPT, somnolence, dizziness, and paresthesia, occurring in less than 5% of patients, were the most common reported AEs on AXS-07. In MOMENTUM, the most common AEs were nausea, dizziness, and somnolence, all occurring in less than 3% of patients.