Axsome headed to FDA after Phase III Alzheimer’s agitation win

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Axsome headed to FDA after Phase III Alzheimer’s agitation win

Published: Nov 28, 2022

By Alex Keown


A Phase III trial of Axsome Therapeutics’ oral N-methyl D-aspartate (NMDA) receptor antagonist hit both primary and secondary endpoints in patients with Alzheimer’s disease agitation, a condition for which there is currently no approved treatment.

In the ACCORD study, AXS-05 showed “substantially and statistically significantly” delayed time to relapse and prevented relapse of agitation in patients with Alzheimer’s disease, Axsome announced Monday.

Following treatment with AXS-05, 66% of patients achieved control after two weeks, with 86% seeing improvements by week five in disease agitation, according to the modified Alzheimer’s Disease Cooperative Study-CGIC scale. In all, the data showed a 3.6-fold lower risk of relapse compared to placebo, Axsome reported.

Caregivers reported improvement in agitation in 67.5% of patients at week two and 89.3% at week five after treatment with AXS-05. This was assessed with the Patient Global Impression of Change (PGI-C) rated by the caregiver, Axsome noted.

AXS-05 met the key secondary endpoint of relapse prevention, based on rates of relapse during the double-blind treatment period. The data showed 7.5% of AXS-05 patients had a relapse prevention effect compared to 25.9% of placebo patients.

Relapse was defined as a worsening greater than or equal to 10 points in CMAI total score from randomization or hospitalization or other institutionalization due to agitation associated with Alzheimer’s.

The double-blind, placebo-controlled ACCORD study included 178 patients with Alzheimer’s disease agitation. Patients who achieved a sustained clinical response after open-label treatment with AXS-05 were then randomized to either continue treatment with the drug or switch to placebo. With open-label treatment, patients experienced rapid, substantial and statistically significant improvement compared to baseline in agitation symptoms, the company announced.

Nearly three-fourths of Alzheimer’s patients experience some form of agitation, which is characterized by emotional distress, aggressive behaviors, disruptive irritability and disinhibition.

“Agitation is one of the most troubling and consequential aspects of Alzheimer’s disease for patients and their caregivers as it is associated with early nursing home placement, accelerated cognitive decline and increased mortality,” said Jeffrey Cummings, M.D., ScD, director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health, in a statement. 

Cummings, who is also a professor of brain science at the University of Nevada Las Vegas, said the ACCORD data offer “convincing clinical activity” for AXS-05 in this indication based on both the significant delay in symptom relapse as well as the reduction of relapse compared to placebo.

Treatment with AXS-05 during the open-label period resulted in “rapid and clinically meaningful improvements” in Alzheimer’s disease agitation, he added. 

Based on the data, Axsome intends to meet with the FDA to discuss the future development of AXS-05 and ways to bring this medication to Alzheimer’s patients experiencing agitation, said Chief Executive Officer Herriot Tabuteau, M.D. The ACCORD data complement previous clinical data seen in the Phase II/III ADVANCE-1 study in Alzheimer’s disease agitation, Tabuteau added.

The FDA granted Breakthrough Therapy designation to AXS-05 for Alzheimer’s disease agitation in 2020.

The data builds on other successes Axsome has seen with its NMDA drugs. In August, the company won approval for AXS-05, now marketed as Auvelity (dextromethorphan HBr -bupropion HCl), an extended-release tablet for the treatment of major depressive disorder. The approval marked the first NMDA greenlit for that indication.

Shares of Axsome climbed in premarket trading. The stock was up nearly 19% to $67.50 ahead of the opening bell.

Source: BioSpace