Axsome’s approved depression drug clears Alzheimer’s agitation trial months after Lundbeck-Otsuka duo

After an August approval for treating major depressive disorder, Axsome Therapeutics’ tablet formulation of a cough suppressant and antidepressant has now cleared a Phase III in another indication.

The drug, known in MDD as Auvelity and under the investigational name AXS-05, was better than placebo at delaying the time for agitation relapse in patients with Alzheimer’s, the New York biotech said Monday morning. Topline data from the Phase III showed AXS-05 was statistically significant in delaying the time to relapse, with a p-value of 0.014.

Axsome claims that’s a 3.6-fold lower risk of relapse as compared to placebo. The so-called ACCORD trial treated 178 patients with the indication, which has no approved treatments. The primary endpoint was calculated based on the 108 patients who achieved a “sustained clinical response after open-label treatment” and were then randomized 1:1 to continue with the drug or switch to placebo.

The number of patients was lower than initially expected, with 260 originally expected to enroll in the trial, Cowen analysts noted.

It could be years before Axsome is at the FDA’s doorstep with an approval request, though, as the company started a second ADVANCE trial in September. That study won’t read out until 2025, the biotech guided during a quarterly update earlier this month. For now, CEO Herriot Tabuteau said Axsome looks to confab with the FDA about future clinical development plans for the indication.

Joseph Thome

“Given the strongly positive results of ACCORD, we look forward to the feedback from the FDA on whether ADVANCE and ACCORD could constitute a regulatory package, with ADVANCE-2 serving as more of a confirmatory trial,” Cowen analyst Joseph Thome wrote in a note shortly after the data drop. “This scenario would be upside to our late 2025 launch estimate.”

The data come months after Lundbeck and partner Otsuka reported their own Phase III success in the indication, with their depression and schizophrenia drug Rexulti. Meanwhile, days earlier, Acadia’s Alzheimer’s related psychosis drug was given a thumbs down by FDA’s advisors.

In Axsome’s study, relapse prevention was also observed. The rates of relapse in the double-blind portion were 7.5% for AXS-05-treated patients and 25.9% for those in the placebo arm, which equates to a p-value of 0.018, Axsome said.

The drug developer said agitation symptoms were hampered starting at week 1 on open-label treatment and through “all timepoints,” as observed by the Cohen Mansfield Agitation Inventory, or CMAI.

Study investigators also looked at the distress and burden on caregivers of the patients during the open-label portion. Those were both statistically significant compared to baseline at weeks 4 and 8, the biotech reported.

No discontinuations due to adverse events were reported for the AXS-05 group in the double-blind period, as compared to 1.9% for the placebo cohort. Adverse events were reported in 28.3% of drug-treated patients and 22.2% in the placebo arm. A serious adverse event, a fecal impaction, in the AXS-05 group was determined “to be not related to study medication,” per an investigator.

Two and a half years ago, the FDA tagged the drug with breakthrough therapy designation for Alzheimer’s disease agitation. Now, the company is planning to discuss the new data with the FDA “in the context of the ongoing clinical development of AXS-05 in this indication,” CEO Herriot Tabuteau said in a statement.

The breakthrough banner was granted after a Phase II/III ADVANCE-1 study showed CMAI total score decreased by 15.4 points on average from baseline at week 5. In the ACCORD study data released Monday, CMAI mean reductions were 6.7 points at week 1, 11.0 points at week 2 and 20.6 points at week 5, which all come out to a p-value below 0.001, Axsome said.

Axsome is also testing the drug in a mid-stage study for smoking cessation.

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breakthrough therapy designation
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