With two earlier trials meeting their primary endpoints, Axsome claimed it has the data to support a filing for FDA approval in the second half of 2025.
Axsome Therapeutics said Monday it plans to seek FDA approval in Alzheimer’s disease agitation despite seeing mixed results in late-phase studies.
The biotech reported data from two trials of AXS-05, a combination of dextromethorphan and bupropion that is already used to treat major depressive disorder. One study hit its primary endpoint, but AXS-05 failed to beat placebo in the other trial. However, two earlier trials met their primary endpoints, and Axsome said it has the data to support a filing for FDA approval in the second half of 2025.
Axsome reported the latest Phase III win in the ACCORD-2 trial. Investigators treated 295 people with AXS-05 in the open-label portion of the trial. The 167 patients who had a sustained clinical response to the treatment were randomized to either continue taking AXS-05 or switch to placebo.
The risk of relapse was 3.6-fold lower in people taking AXS-05, achieving the trial’s primary endpoint. The study also met secondary goals regarding the severity of Alzheimer’s and agitation associated with the disease. An earlier, similar trial, ACCORD-1, met its primary endpoint in 2022.
However, AXS-05 was statistically no better than placebo in the other Phase III trial, ADVANCE-2. The study randomized 408 people to receive AXS-05 or placebo. After five weeks, scores on a measure of agitation fell 13.8 on AXS-05 and 12.6 points on placebo, causing the study to miss its primary endpoint. The trial also missed secondary endpoints, although AXS-05 was numerically better on most measures.
A similar study, ADVANCE-1, met its primary endpoint in 2020. Agitation scores in the earlier trial fell 15.4 points and 11.5 points, respectively, in the AXS-05 and placebo groups. The patient populations in the failed and successful studies were similar.
The readouts leave Axsome with three Phase III trials that met their primary endpoints, one study that failed but favored AXS-05 and enough 6- and 12-month follow-up results to meet the filing requirements. Axsome CEO Herriot Tabuteau told investors on a conference call Monday that the biotech needs to prepare the filing and complete manufacturing work related to a titration dose before seeking approval.
“Overall . . . we believe it is clear that AXS-05 is active and efficacious in AD-A and the relapse-prevention data is impressively consistent,” William Blair analysts wrote in a Monday note to investors, adding that “There are several examples of neuropsychiatry drugs being approved on total data packages despite a pivotal trial failure . . . .”
If approved, AXS-05 will compete with Ostuka Pharmaceutical and Lundbeck’s Rexulti. The FDA approved Rexulti for agitation associated with dementia due to Alzheimer’s in 2023. Lundbeck cited penetration of the U.S. Alzheimer’s market as a driver of growth of Rexulti over the first nine months of the year. The drug is also approved in depression.
Axsome’s expectation that AXS-05 can win market share from Rexulti is partly built on the belief that the drug candidate has a differentiated safety profile. Rexulti has a boxed warning because of an increased risk of death. There were no deaths in the AXS-05 trials. Jeffrey Cummings, a research professor at the University of Nevada, Las Vegas, discussed what may happen if AXS-05 avoids a boxed warning.
“The black box will weigh heavily on the thinking of the prescriber and of the prescribing system. So, I think AXS-05 will be well positioned to compete with Rexulti, but I think there will continue to be robust Rexulti use because docs are familiar with it,” Cummings said on the Axsome conference call.
