Axsome Therapeutics is moving forward with plans to seek FDA approval for AXS-05, a novel oral drug for treating agitation in Alzheimer's disease, despite mixed results from its Phase 3 clinical program. The company anticipates submitting a New Drug Application (NDA) in the second half of 2025, based on data from four pivotal Phase 3 trials and a long-term safety study.
ACCORD-2 Trial Demonstrates Significant Delay in Agitation Relapse
The ACCORD-2 trial, a double-blind, placebo-controlled, randomized withdrawal study, evaluated AXS-05 in Alzheimer's disease patients experiencing agitation. The trial met its primary endpoint, demonstrating a statistically significant delay in the time to relapse of agitation compared to placebo (p=0.001). The results indicated a 3.6-fold lower risk of relapse in patients treated with AXS-05, as assessed by the Cohen-Mansfield Agitation Inventory (CMAI) total score.
In addition to the primary endpoint, AXS-05 also met a key secondary endpoint, showing a statistically significant prevention of relapse of Alzheimer's disease agitation compared to placebo (p=0.001). Furthermore, AXS-05 reduced the worsening of overall Alzheimer's disease severity compared to placebo, as measured by the Clinical Global Impression of Severity (CGI-S) for Alzheimer's disease (p<0.001).
ADVANCE-2 Trial Shows Numerical Improvement but Lacks Statistical Significance
While the ACCORD-2 trial yielded positive results, the ADVANCE-2 trial, a double-blind, placebo-controlled, parallel-group study, did not demonstrate statistical significance for its primary endpoint. The trial assessed the change in the CMAI total score from baseline to Week 5. Although the primary endpoint was not met, results for the primary and nearly all secondary endpoints numerically favored AXS-05 over placebo.
Safety and Tolerability Profile
Across both controlled studies, AXS-05 was shown to be safe and well-tolerated. The long-term safety and tolerability of AXS-05 were evaluated in over 300 subjects treated for at least 6 months and over 100 subjects treated for at least 12 months. The controlled and long-term studies indicated that AXS-05 was not associated with an increased risk of falls, cognitive decline, or sedation. Notably, there were no deaths reported in subjects receiving AXS-05 throughout the clinical program.
Regulatory Pathway and Unmet Need
Based on the comprehensive data from the Phase 3 clinical program, Axsome plans to submit an NDA for AXS-05 in Alzheimer's disease agitation to the FDA in the second half of 2025. The FDA has granted AXS-05 Breakthrough Therapy designation for this indication, which could expedite the development and review process.
Agitation affects up to 70% of individuals with Alzheimer's disease and is characterized by emotional distress, verbal and physical aggressiveness, disruptive irritability, and disinhibition. This condition is associated with accelerated cognitive decline, increased caregiver burden, earlier nursing home placement, and increased mortality, highlighting the urgent need for effective treatment options.
AXS-05: A Novel Mechanism of Action
AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational drug with a multimodal mechanism of action. It functions as an N-methyl-D-aspartate (NMDA) receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor. The dextromethorphan component modulates glutamate receptor activity and acts as a sigma-1 receptor agonist, while the bupropion component increases the bioavailability of dextromethorphan and acts as a norepinephrine and dopamine reuptake inhibitor.
"Agitation is one of the most troubling and consequential aspects of Alzheimer's disease, poses significant challenges to both the patient and their family, and represents a high unmet need," said Jeffrey Cummings, MD, ScD, Vice Chair of Research, UNLV Department of Brain Health. He added that the results from the ACCORD-2 trial, along with the previously completed ADVANCE-1 and ACCORD-1 Phase 3 trials, strongly support the potential for AXS-05 to become an important treatment for patients living with Alzheimer's disease agitation.
