Axsome Therapeutics announces AXS 05 achieves primary endpoint in the ADVANCE-1 pivotal phase II/III Trial in Alzheimer’s disease agitation.

Axsome Therapeutics, Inc. announced that AXS 05, a novel, oral, investigational NMDA receptor antagonist with multimodal activity, met the primary endpoint in the ADVANCE-1 Phase II/III trial and rapidly, substantially, and significantly improved agitation in patients with Alzheimer’s disease as compared to placebo.

The ADVANCE-1 (Addressing Dementia via Agitation-Centered Evaluation) study was a randomized, double-blind, controlled, multicenter, U.S. trial, in which 366 Alzheimer’s disease patients were randomized to treatment with AXS 05 (dextromethorphan/bupropion modulated delivery tablet, dose escalated to 45 mg/105 mg twice daily), bupropion (dose escalated to 105 mg twice daily), or matching placebo, for 5 weeks. . Alzheimer’s disease is the most common form of dementia and is characterized by cognitive decline, and behavioral and psychological symptoms including agitation. Agitation is observed in up to 70% of patients with Alzheimer’s disease and is associated with accelerated cognitive decline, earlier nursing home placement, and increased mortality risk . AXS 05 has been granted FDA Fast Track designation for the treatment of Alzheimer’s disease agitation.

AXS 05 met the primary endpoint by demonstrating a statistically significant mean reduction in the Cohen Mansfield Agitation Inventory (CMAI) total score compared to placebo at Week 5, with mean reductions from baseline of 15.4
points for AXS 05 and 11.5 points for placebo (p=0.010). These results represent a mean percentage reduction from baseline of 48% for AXS 05 versus 38% for placebo. The CMAI is a 29-item caregiver-rated scale that assesses the frequency of agitation-related behaviors in patients with dementia, including excessive motor activity such as pacing and restlessness, verbal aggression such as screaming and shouting, and physical aggression such as grabbing, pushing, and hitting. AXS 05 was also superior to bupropion on the CMAI total score (p<0.001), establishing component contribution. AXS 05 rapidly improved agitation symptoms. Improvement on the CMAI total score with AXS 05 was numerically superior to placebo starting at Week 2, achieving statistical significance at Week 3 (p=0.007) only one week after full dosing with AXS 05.

A statistically significantly greater proportion of patients achieved a clinical response on the CMAI, defined as a 30% or greater improvement from baseline, with AXS 05 as compared to placebo (73% versus 57%, p=0.005). These results were consistent with clinicians’ global assessments of change measured using the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change for Agitation (mADCS-CGIC). AXS 05 demonstrated statistically significantly greater improvement in agitation as compared to placebo on this measure (p=0.036).

Comment:There are currently no FDA-approved treatments for Alzheimer’s disease agitation..