First Patient Dose in Phase 3 Trial of AXS-14 for Treatment of Fibromyalgia

Axsome Therapeutics today announced the first patient has been dosed in the FORWARD phase 3 trial of esreboxetine (AXS-14) for the management of fibromyalgia.

The FORWARD (Fibromyalgia Response with Esreboxetine Evaluated Using a Randomized Withdrawal Research Design) study is a phase 3, double-blind, placebo-controlled, multicenter, randomized withdrawal trial in participants with fibromyalgia consisting of an open-label AXS-14 treatment period and a randomized, double-blind treatment period. Participants who achieve a treatment response during the 12-week open-label period will be randomly assigned in a 1:1 ratio to continue AXS-14 (8 mg) once daily or to switch to matching placebo for up to 12 weeks or until a loss of therapeutic response occurs. The primary endpoint will be the time from randomization to loss of therapeutic response.

AXS-14 is a highly selective and potent norepinephrine reuptake inhibitor, as well as the SS-enantiomer of racemic reboxetine.

Back in June 2025, the US Food and Drug Administration (FDA) issued a Refusal to File letter to Axsome concerning its New Drug Application for AXS-14. The FDA stated that upon preliminary review, it found that the NDA was not sufficiently complete to permit a substantive review, and specifically did not consider the second of the 2 placebo-controlled trials in the submission to be adequate and well-controlled because its primary endpoint was at 8 weeks and it used a flexible-dose paradigm. The FDA indicated that the first of the 2 placebo-controlled trials in the submission, which utilized a 12-week endpoint and a fixed-dose paradigm, was adequate and well-controlled. Notably, the FDA did not raise any questions relating to the positive results of the studies, both of which met their primary endpoints.²

“The clear feedback provided by the FDA’s Division of Anesthesiology, Addiction Medicine, and Pain Medicine allows us to move expeditiously with the continued development of this important investigational medicine for the approximately 17 million patients in the US living with fibromyalgia. We are well positioned to initiate a new controlled trial that will incorporate the FDA’s feedback by the end of 2025,” said Herriot Tabuteau, MD, the chief executive officer of Axsome. “As highlighted in the FDA’s Patient-Focused Drug Development Initiative report The Voice of the Patient: Fibromyalgia, patients with fibromyalgia experience debilitating widespread pain, fatigue, and functional impairment, and report living with constant stigmatization, anxiety, depression, and fear of ongoing or worsening symptoms. We are excited and motivated by the potential for AXS-14 to address this high unmet medical need for patients, as evidenced by the consistent efficacy demonstrated to date across a broad range of fibromyalgia symptoms, including significant improvements in pain, function, and fatigue, in the completed trials.”²

Fibromyalgia, which is mediated primarily in the central nervous system, affects approximately 17 million Americans, 90% of whom are women.³ Fibromyalgia has considerable detrimental effects on physical, emotional, social, and day-to-day functioning and is associated with significantly reduced quality of life.⁴ Despite its prevalence and impact, current treatment options remain limited.

References

1. Axsome Therapeutics initiates FORWARD phase 3 trial of AXS-14 for the management of fibromyalgia. News release. January 15, 2026. Accessed January 15, 2026. https://finance.yahoo.com/news/axsome-therapeutics-initiates-forward-phase-120000095.html

2. Axsome Therapeutics provides update on the New Drug Application (NDA) for AXS-14 for the management of fibromyalgia. News release. June 19, 2025. Accessed January 15, 2026. https://www.biospace.com/press-releases/axsome-therapeutics-provides-update-on-the-new-drug-application-nda-for-axs-14-for-the-management-of-fibromyalgia

3. Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311(15):1547-1555.

4. Bair MJ, Krebs EE. Fibromyalgia. Ann Intern Med. 2020;172:ITC33-ITC48.