With less than two weeks to go until a decision was due, the FDA has found fault with Axome Therapeutics’ depression therapy—but the agency isn't ready to share their beef with the application.
The FDA has identified deficiencies in Axsome's submission for approval of AXS-05 in major depressive disorder (MDD). Axsome is yet to learn the nature of the deficiencies or their implications for the filing.
Axsome based its submission on phase 2 and phase 3 clinical trials that linked AXS-05, a combination of the active ingredient in GlaxoSmithKline’s Wellbutrin and a cough medicine, to improvements in depressive symptoms in patients with MDD.
The bupropion-dextromethorphan combination failed a phase 3 trial in treatment-resistant depression but looked well placed to win approval in MDD by the PDUFA date of Aug. 22. That timeline is now in doubt.
This is what we know. On July 30, Axsome received a letter from the FDA stating its reviewers had identified deficiencies that preclude discussion of labeling and postmarketing requirements. The FDA said it hadn’t reached a final decision and provided no details of the deficiencies.
Axsome has contacted the FDA to try to learn what the deficiencies are so that the biotech can resolve them if possible. However, the FDA is yet to share the information requested by Axsome.
The information void has created space for speculation. Analysts at Jefferies proposed three possible explanations. The identification of a chemistry, manufacturing and control issue topped the analysts’ list of most likely sources of the deficiency, although Axsome isn’t aware of any observations made by the FDA. The drug substance is made at a “bluechip” contract manufacturer, the company added.
Jefferies put resource constraints at the FDA as perhaps the next most likely explanation. The FDA has acknowledged the effect of COVID-19 on its operations, and Axsome admits the AXS-05 submission is large. However, Axsome has seen no changes to the FDA staff handling the submission or had interactions that indicate resource constraints are causing problems for the agency.
Finally, the analysts said the FDA could view the clinical package as inadequate, although they see that as a “nebulous concern” as the “only concrete suggestion is lack of abuse liability study.” The analysts pointed to the precedent set by Avanir Pharmaceuticals, which won FDA approval for a dextromethorphan combination in 2010, and real-world experience with both active ingredients as evidence that the lack of an abuse liability study is unlikely to be the cause of the problem.
The range of possible explanations for the FDA letter support different predictions about the impact on Axsome’s plans to bring AXS-05 to market. The Jefferies analysts expect at least a three-month delay but note that deficiency letters typically lead to rejections.
Investors responded by sending Axsome's shares off a cliff Monday morning. The stock was trading around $50 apiece when the market closed Friday, but plummeted to $26 on Tuesday morning.