Axsome expects to address the concerns in the letter and plans to resubmit AXS-07. The MoSEIC meloxicam-rizatriptan combination significantly reduced migraine symptoms and pain compared with placebo and both active agents in a pair of phase 3 trials.
Axsome Therapeutics has been issued a complete response letter (CRL) for its new drug application (NDA) for its investigational acute migraine treatment AXS-07. The company noted in an announcement that it neither identified nor raised any concerns regarding the efficacy or safety data in the application.1
The FDA additionally did not request any new clinical trials to be conducted. The principal reasons for the CRL were related to chemistry, manufacturing, and controls (CMC) considerations, specifically a requirement of further CMC data pertaining to the drug product and manufacturing process. Axsome noted that 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," Herriot Tabuteau, MD, chief executive officer, Axsome, said in a statement.1 "The approval of AXS-07 would offer a much-needed new multi-mechanistic treatment option for the millions of people living with this debilitating neurological condition."
The NDA was supported by data from 2 phase 3 randomized controlled clinical trials—the MOMENTUM trial (NCT03896009) and the INTERCEPT trial (NCT04163185)—included in the new drug application, which was accepted for review in September 2021. The data demonstrate a statistically significant elimination of migraine pain with AXS-07 compared with placebo and active controls. The oral and dual-mechanism therapy consists of a combination of the company’s molecular solubility enhanced inclusion complex (MoSEIC) 20-mg meloxicam, a COX-2 preferential nonsteroidal anti-inflammatory drug, and 10-mg rizatriptan, a 5-HT1B/1D agonist.
Data from the MOMENTUM trial were originally announced in January 2020.2 The trial included 1594 patients randomized in a 2:2:2:1 ratio to AXS-07, 10-mg rizatriptan, MoSEIC 20-mg meloxicam, or placebo, to treat a single migraine attack of moderate or severe intensity. AXS-07 met the coprimary end points with statistical significance, first showing a greater percentage of patients achieving pain freedom (19.9%) compared with placebo (6.7%; P <.001). Second, the absence of the most bothersome symptom (36.9%) compared with placebo (24.4%) was significant (P = .002). Both were assessed 2 hours after dosing.3
On the secondary end point, AXS-07 showed significant numbers of patients achieving pain-freedom (16.1%) compared with the rizatriptan, MoSEIC meloxicam, and placebo groups (11.2%, 8.8%, and 5.3%, respectively), with all comparisons being significant (P = .038, P = .001, and P <.001, respectively).
Additionally, the newly approved therapy displayed a higher percentage of patients achieving relief from pain at every time point measured, starting at 15 minutes post dose. This difference was statistically significant at 60 minutes (P = .04). At 90 minutes post dose, 60.5% of those in the AXS-07 group had pain relief compared with 52.5% for both rizatriptan (P = .019) and placebo (P = .004). The combination agent’s effects were also statistically significant compared with rizatriptan on several other secondary end points, such as the Patient Global Impression of Change (P = .022), and return to normal functioning at 24 hours (P = .027).3
A few short months later, in April 2020, Axsome announced the results of INTERCEPT, which displayed similar findings to the prior trial. 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).4
In both trials, the drug was generally safe and well-tolerated with no reports of serious adverse events (AEs) throughout INTERCEPT, and only 1 reported in MOMENTUM, though it was deemed unrelated to treatment.3,4 In INTERCEPT, the most commonly reported AEs were somnolence, dizziness, and paresthesia, occurring in less than 5% of patients.4 In MOMENTUM, they were nausea, dizziness, and somnolence, all occurring in less than 3% of patients.3