FDA Rejects Axsome's Fibromyalgia Drug Application Due to Trial Design Issues
Key Insights
The FDA issued a Refusal to File letter for Axsome Therapeutics' AXS-14 (esreboxetine) fibromyalgia (search) application, citing inadequate trial design in one of two submitted studies.
The agency found the second placebo-controlled trial insufficient due to its 8-week endpoint and flexible-dose paradigm, while accepting the first trial with a 12-week fixed-dose design.
Axsome plans to conduct an additional controlled trial incorporating FDA feedback, with initiation expected in Q4 2025 to address the unmet need for 17 million U.S. fibromyalgia (search) patients.
Axsome Therapeutics received a setback in its fibromyalgia (search) drug development program when the FDA issued a Refusal to File letter for its New Drug Application for AXS-14 (esreboxetine), citing inadequate trial design in one of the two submitted studies.
The FDA determined that the NDA was not sufficiently complete to permit substantive review, specifically finding the second placebo-controlled trial inadequate due to its 8-week primary endpoint and flexible-dose paradigm. In contrast, the agency considered the first trial, which utilized a 12-week endpoint and fixed-dose paradigm, to be adequate and well-controlled.
Regulatory Pathway Forward
To address the FDA's feedback from its Division of Anesthesiology, Addiction Medicine, and Pain Medicine, Axsome will conduct an additional controlled trial incorporating the requested design elements. The new study will employ a fixed-dose paradigm with a 12-week primary endpoint, with initiation anticipated 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 (search)," said Herriot Tabuteau, MD, Chief Executive Officer of Axsome.
Clinical Efficacy Maintained
Importantly, the FDA did not raise questions regarding the positive results of either study, both of which met their primary endpoints. The completed trials demonstrated consistent efficacy across a broad range of fibromyalgia (search) symptoms, including significant improvements in pain, function, and fatigue.
Addressing Unmet Medical Need
Fibromyalgia (search) affects approximately 17 million Americans, with 90% being women, according to population-based studies. The chronic debilitating disorder is characterized by widespread pain, fatigue, disturbed sleep, depression, and cognitive impairment, with considerable detrimental effects on physical, emotional, social, and day-to-day functioning.
Treatment options remain limited, with only three pharmacologic treatments currently approved by the FDA for fibromyalgia (search) management. As highlighted in the FDA's Patient-Focused Drug Development Initiative report "The Voice of the Patient: Fibromyalgia," patients experience debilitating symptoms and report living with constant stigmatization, anxiety, depression, and fear of ongoing or worsening symptoms.
Drug Profile
AXS-14 (esreboxetine) is a highly selective and potent norepinephrine reuptake inhibitor (search) being developed for fibromyalgia (search) management. Esreboxetine, the SS-enantiomer of reboxetine, demonstrates greater potency and selectivity compared to racemic reboxetine. The compound is considered to target fibromyalgia's central nervous system-mediated pathophysiology.
Axsome Therapeutics maintains an industry-leading neuroscience portfolio that includes FDA-approved treatments for major depressive disorder (search), excessive daytime sleepiness associated with narcolepsy (search) and obstructive sleep apnea (search), and migraine (search), alongside multiple late-stage development programs addressing neurological and psychiatric conditions affecting over 150 million people in the United States.