Axsome Therapeutics Provides Update on the New Drug Application (NDA) for AXS-14 for the Management of Fibromyalgia

Rhea-AI Summary

Axsome Therapeutics (NASDAQ: AXSM) received a Refusal to File (RTF) letter from the FDA regarding their New Drug Application for AXS-14 (esreboxetine) for fibromyalgia management. The FDA found the application incomplete, specifically citing issues with the second placebo-controlled trial's 8-week primary endpoint and flexible-dose paradigm. The first trial, using a 12-week endpoint and fixed-dose paradigm, was deemed adequate. Notably, both trials met their primary endpoints, and the FDA didn't question the positive results. In response, Axsome will conduct an additional controlled trial with a fixed-dose paradigm and 12-week primary endpoint, planned to start in Q4 2025. The drug aims to address approximately 17 million U.S. fibromyalgia patients' needs, having shown promising results in improving pain, function, and fatigue symptoms.

Positive

• Both clinical trials met their primary endpoints with positive results
• First placebo-controlled trial was deemed adequate and well-controlled by FDA
• Clear regulatory pathway provided by FDA for moving forward
• Large market opportunity with 17 million U.S. patients with fibromyalgia
• Previous trials showed consistent efficacy across broad range of fibromyalgia symptoms

Negative

• FDA issued Refusal to File letter for the NDA
• Second trial deemed inadequate due to 8-week endpoint and flexible-dose paradigm
• Additional clinical trial required, causing significant delay in potential approval
• New trial won't begin until Q4 2025, further extending timeline to market

Insights

Pharmaceutical Regulatory Analyst

FDA rejects Axsome's fibromyalgia drug application, requiring additional trial that will delay potential approval by at least 12-18 months.

The FDA's Refusal to File (RTF) for AXS-14 represents a significant setback in Axsome's regulatory strategy for its fibromyalgia candidate. The agency specifically rejected one of the two pivotal studies based on methodological concerns - the 8-week endpoint and flexible-dose design - rather than efficacy results. This technical rejection highlights the FDA's increasingly stringent requirements for CNS drug applications, particularly for conditions like fibromyalgia that have historically faced regulatory challenges.

The company must now conduct an entirely new controlled trial with a fixed-dose paradigm and 12-week primary endpoint. This additional study will likely require 15-25 million in unplanned R&D expenditure and delay potential market entry by at least 12-18 months. With trial initiation planned for Q4 2025, followed by enrollment, treatment period, data analysis, and resubmission, AXS-14 approval could now be pushed into 2027-2028.

The silver lining is that both previous studies actually met their primary endpoints, suggesting the drug's efficacy profile remains promising. The FDA's feedback also provides clear direction for addressing the deficiencies, reducing regulatory uncertainty. The fibromyalgia market remains substantially underserved with approximately 17 million patients in the US alone, maintaining the commercial opportunity despite this timeline extension.

For investors, this development necessitates resetting near-term expectations for AXS-14 while refocusing on Axsome's other CNS assets in its pipeline that may reach market sooner. The company appears adequately positioned to absorb this setback, but the additional clinical trial represents an unexpected burden on resources that could impact other development programs.

NEW YORK, June 09, 2025 (GLOBE NEWSWIRE) -- Axsome Therapeutics, Inc. (NASDAQ: AXSM), a biopharmaceutical company leading a new era in the treatment of central nervous system (CNS) disorders, today announced it has received a Refusal to File (RTF) letter from the U.S. Food and Drug Administration (FDA) for its New Drug Application (NDA) for AXS-14 (esreboxetine) for the management of fibromyalgia.

The FDA states that upon preliminary review, it found that the NDA was not sufficiently complete to permit a substantive review. Specifically, the FDA does not consider the second of the two 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 two placebo-controlled trials in the submission, which utilized a 12-week endpoint and a fixed-dose paradigm, is adequate and well-controlled. The FDA did not raise any questions relating to the positive results of the studies, both of which met their primary endpoints.

To address the FDA’s feedback, Axsome will conduct an additional controlled trial, which will use a fixed-dose paradigm and a 12-week primary endpoint as requested by the FDA. Axsome anticipates initiating this trial in the fourth quarter of 2025.

“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 U.S. 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, 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.”

About AXS-14

AXS-14 (esreboxetine) is a highly selective and potent norepinephrine reuptake inhibitor for the management of fibromyalgia and other conditions. Esreboxetine, the SS-enantiomer of reboxetine, is more potent and selective than racemic reboxetine. AXS-14 is an investigational drug product not approved by the FDA.

About Fibromyalgia

Fibromyalgia is a chronic debilitating disorder characterized by widespread pain, fatigue, disturbed sleep, depression, and cognitive impairment.¹ Other symptoms of this disorder can include tingling in the hands and feet and headaches.¹ Fibromyalgia has considerable detrimental effects on physical, emotional, social, and day-to-day functioning.¹ Fibromyalgia is considered to be mediated mainly in the central nervous system. Approximately 17 million Americans, 90% of whom are women, are estimated to suffer from fibromyalgia.² Treatment options for fibromyalgia are limited with only three pharmacologic treatments currently approved by the FDA.

About Axsome Therapeutics

Axsome Therapeutics is a biopharmaceutical company leading a new era in the treatment of central nervous system (CNS) conditions. We deliver scientific breakthroughs by identifying critical gaps in care and develop differentiated products with a focus on novel mechanisms of action that enable meaningful advancements in patient outcomes. Our industry-leading neuroscience portfolio includes FDA-approved treatments for major depressive disorder, excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea, and migraine, and multiple late-stage development programs addressing a broad range of serious neurological and psychiatric conditions that impact over 150 million people in the United States. Together, we are on a mission to solve some of the brain’s biggest problems so patients and their loved ones can flourish. For more information, please visit us at www.axsome.com and follow us on LinkedIn and X.

Forward Looking Statements

Certain matters discussed in this press release are “forward-looking statements”. The Company may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. In particular, the Company’s statements regarding trends and potential future results are examples of such forward-looking statements. The forward-looking statements include risks and uncertainties, including, but not limited to, the commercial success of the Company’s SUNOSI^®, AUVELITY^®, and SYMBRAVO^® products and the success of the Company’s efforts to obtain any additional indication(s) with respect to solriamfetol and/or AXS-05; the Company’s ability to maintain and expand payer coverage; the success, timing and cost of the Company’s ongoing clinical trials and anticipated clinical trials for the Company’s current product candidates, including statements regarding the timing of initiation, pace of enrollment and completion of the trials (including the Company’s ability to fully fund the Company’s disclosed clinical trials, which assumes no material changes to the Company’s currently projected revenues or expenses), futility analyses and receipt of interim results, which are not necessarily indicative of the final results of the Company’s ongoing clinical trials, and/or data readouts, and the number or type of studies or nature of results necessary to support the filing of a new drug application (“NDA”) for any of the Company’s current product candidates; the Company’s ability to fund additional clinical trials to continue the advancement of the Company’s product candidates; the timing of and the Company’s ability to obtain and maintain U.S. Food and Drug Administration (“FDA”) or other regulatory authority approval of, or other action with respect to, the Company’s product candidates, including statements regarding the timing of any NDA submission; the Company’s ability to successfully defend its intellectual property or obtain the necessary licenses at a cost acceptable to the Company, if at all; the Company’s ability to successfully resolve any intellectual property litigation, and even if such disputes are settled, whether the applicable federal agencies will approve of such settlements; the successful implementation of the Company’s research and development programs and collaborations; the success of the Company’s license agreements; the acceptance by the market of the Company’s products and product candidates, if approved; the Company’s anticipated capital requirements, including the amount of capital required for the commercialization of SUNOSI, AUVELITY, and SYMBRAVO and for the Company’s commercial launch of its other product candidates, if approved, and the potential impact on the Company’s anticipated cash runway; the Company’s ability to convert sales to recognized revenue and maintain a favorable gross to net sales; unforeseen circumstances or other disruptions to normal business operations arising from or related to domestic political climate, geo-political conflicts or a global pandemic and other factors, including general economic conditions and regulatory developments, not within the Company’s control. The factors discussed herein could cause actual results and developments to be materially different from those expressed in or implied by such statements. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

Investors:
Mark Jacobson
Chief Operating Officer
(212) 332-3243
mjacobson@axsome.com

Media:
Darren Opland
Director, Corporate Communications
(929) 837-1065
dopland@axsome.com

References:

1. Matthew J. Bair, Erin E. Krebs. Fibromyalgia. Ann Intern Med. 2020;172:ITC33-ITC48. doi:10.7326/AITC202003030
2. Vincent A, et al. Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project. Arthritis Care Res (Hoboken). 2013 May;65(5):786-92. doi: 10.1002/acr.21896.

FAQ

Why did the FDA reject Axsome's AXS-14 NDA for fibromyalgia?

The FDA issued a Refusal to File letter because the second placebo-controlled trial was deemed inadequate due to its 8-week endpoint and flexible-dose paradigm, making the NDA incomplete for substantive review.

What is AXSM's plan to address the FDA's concerns about AXS-14?

Axsome plans to conduct an additional controlled trial with a fixed-dose paradigm and 12-week primary endpoint, scheduled to begin in Q4 2025.

How many fibromyalgia patients could potentially benefit from AXS-14?

According to Axsome, approximately 17 million patients in the United States are living with fibromyalgia who could potentially benefit from AXS-14.

What results did AXSM's previous trials show for AXS-14 in fibromyalgia?

The previous trials demonstrated consistent efficacy across fibromyalgia symptoms, showing significant improvements in pain, function, and fatigue.

What was the FDA's assessment of Axsome's first trial for AXS-14?

The FDA considered the first placebo-controlled trial, which used a 12-week endpoint and fixed-dose paradigm, to be adequate and well-controlled.