Axsome Therapeutics: FDA Accepts NDA Resubmission for AXS-07 for Acute Treatment of Migraine

According to a company announcement, the FDA has accepted Axsome Therapeutics’ resubmitted new drug application (NDA) for its novel agent AXS-07 as am acute treatment for migraine. The agency has given the oral, rapidly absorbed, multi-mechanistic investigational medicine a Prescription Drug User Fee Act (PDUFA) action goal date of January 31, 2025.¹

AXS-07, a novel agent, is thought to act by inhibiting calcitonin gene-related peptide (CGRP) release, reversing CGRP-mediated vasodilation, and inhibiting neuroinflammation, pain signal transmission, and central sensitization. The agent, which consists of the COX-2 preferential NSAID meloxicam and 5-HT1 receptor agonist rizatriptan, is enabled by Axsome’s MoSEIC (Molecular Solubility Enhanced Inclusion Complex) technology, which results in faster absorption and longer plasma half-life.

In May 2022, the company received a complete response letter for its NDA submission of AXS-07, citing issues related to the chemistry, manufacturing, and controls considerations. At the time, the agency did not request any new clinical trials to be conducted^.2

The original NDA, accepted for review in September 2021, was supported by data from 2 phase 3 randomized controlled clinical trials—the MOMENTUM trial (NCT03896009) and the INTERCEPT trial (NCT04163185). Overall, the studies revealed a statistically significant elimination of migraine pain with AXS-07 compared with placebo and active controls. In MOMENTUM, AXS-07 met its 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) 2 hours after dosing. Second, the absence of the most bothersome symptom (36.9%) compared with placebo (24.4%) was significant (P = .002).³

In MOMENTUM, 1594 patients with migraine were randomly assigned 2:2:2:1 to AXS-07, 10-mg rizatriptan, MoSEIC 20-mg meloxicam, or placebo, to treat a single migraine attack of moderate or severe intensity. INTERCEPT included 302 patients with migraine who were randomly assigned to either AXS-07 (n = 152) or placebo (n = 150) at the earliest onset of migraine pain.

In April 2020, months after the initial readout of MOMENTUM, Axsome announced positive results from INTERCEPT. All told, 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). 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

Earlier this year, at the 2024 American Academy of Neurology Annual Meeting, investigators presented a pooled analysis of the MOMENTUM and INTERCEPT trials, with results showing that AXS-07 was effective at acutely treating migraine. In the pooled analysis, treatment with AXS-07 resulted in greater headache pain freedom (23% vs 11%; P <.001) and absence of the most bothersome symptom (39% vs 25%; P <.001) at 2 hours compared with placebo. Led by Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, 43% of AXS-07-treated patients had reduced rescue medication use through 24 hours vs 21% of those on placebo (P <.001). Notably, a higher rate of patients on the investigational agent returned to normal functioning in comparison with placebo starting at 1-hour post-dose.⁵

References
1. axsome therapeutics announces fda acceptance of nda resubmission for axs-07 for the acute treatment of migraine. News release. Axsome Therapeutics. September 4, 2024. Accessed September 4, 2024. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-fda-acceptance-nda-resubmission
2. axsome Therapeutics Receives FDA Complete Response Letter for New Drug Application for AXS-07 for the Acute Treatment of Migraine. News release. Axsome Therapeutics. May 2, 2022. Accessed September 4, 2024. https://www.prnewswire.com/news-releases/axsome-therapeutics-receives-fda-complete-response-letter-for-new-drug-application-for-axs-07-for-the-acute-treatment-of-migraine-301537093.html
3. Axsome Therapeutics Announces AXS-07 Achieves Co-Primary and Key Secondary Endpoints in MOMENTUM Phase 3 Migraine Trial in Patients with History of Inadequate Response. News release. Axsome Therapeutics. December 30, 2019. Accessed September 4, 2024. https://www.biospace.com/article/releases/axsome-therapeutics-announces-axs-07-achieves-co-primary-and-key-secondary-endpoints-in-momentum-phase-3-migraine-trial-in-patients-with-history-of-inadequate-response
4. axsome Therapeutics announces AXS-07 achieves both co-primary endpoints and prevents migraine pain progression in the INTERCEPT phase 3 trial in the early treatment of migraine. news release. Axsome Therapeutics. April 6, 2020. Accessed September 4, 2024. https://www.finance.yahoo.com/news/axsome-therapeutics-announces-axs-07-100010869.html
5. Tepper S. Lipton R, Chhabra A, Streicher C, Parks G, Tabuteau H. Combined efficacy and safety of AXS-07 (MOSEICTM meloxicam and rizatriptan) in two phase 3 clinical trials. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. Abstract 00519