Axsome Therapeutics, Inc. announced that AXS-05, a novel, oral, investigational NMDA receptor antagonist with multimodal activity, met the primary and key secondary endpoints in the ACCORD (Assessing Clinical Outcomes in Alzheimer's Disease Agitation) Phase 3 trial, by substantially and statistically significantly delaying the time to relapse and preventing relapse of agitation in patients with Alzheimer's disease, as compared to placebo. The ACCORD study was a double-blind, placebo-controlled, multi-center, randomized withdrawal, U.S. trial which treated 178 patients with Alzheimer's disease agitation. Patients achieving a sustained clinical response after open-label treatment with AXS-05 were randomized (n=108) in a 1:1 ratio to continue treatment with AXS-05 or to discontinue AXS-05 and switch to placebo.

AXS-05 has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease agitation. There are currently no FDA-approved treatments for Alzheimer's disease agitation. AXS-05 met the primary endpoint by substantially and statistically significantly delaying the time to relapse of agitation symptoms as compared to placebo, with a hazard ratio for time to relapse of 0.275 (p=0.014), representing a 3.6-fold lower risk of relapse compared to placebo.

AXS-05 also met the key secondary endpoint of relapse prevention, based on the rates of relapse during the double-blind treatment period (7.5% of AXS-05 patients vs. 25.9% of placebo patients, p=0.018). Relapse was defined as a =10-point worsening in the CMAI total score from randomization or a CMAI total score greater than that at study entry; or hospitalization or other institutionalization due to agitation associated with Alzheimer's disease.

With open-label treatment with AXS-05, patients experienced rapid, substantial, and statistically significant improvement compared to baseline in agitation symptoms. Statistically significant improvement on the Cohen Mansfield Agitation Inventory (CMAI) was seen with open-label AXS-05 treatment at all timepoints starting at Week 1 (p<0.001), with mean reductions from baseline of 11.0 points at Week 2 (p<0.001), and 20.6 points at Week 5 (p<0.001). Improvements were also significant with open-label AXS-05 treatment on all CMAI subscales including the Physically Aggressive subscale at all timepoints (p<0.001). Rapid and substantial improvement in Alzheimer's disease agitation was reported by both clinicians and caregivers on global measures.

Clinicians reported improvement in agitation in 66.3% of patients at Week 2 and 86.3% at Week 5 after treatment with AXS-05, as assessed using the modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change for Agitation (mADCS-CGIC). Caregivers reported improvement in agitation in 67.5% of patients at Week 2 and 89.3% at Week 5 after treatment with AXS-05, as assessed using the Patient Global Impression of Change (PGI-C) rated by the caregiver. Caregiver distress and burden, patient quality of life, and depressive symptoms were all statistically significantly improved compared to baseline after patients were treated with open-label AXS-05.

Caregiver distress was assessed using the NPI Agitation and Aggression Caregiver Distress score (p<0.001, at Weeks 4 and 8). Caregiver burden was assessed using the Zarit Burden Interview (ZBI) (p=0.006 at Week 4, p=0.003 at Week 8). Patient quality of life was assessed using the caregiver rated Quality of Life Alzheimer's Disease (QoL-AD) scale (p<0.001 at Week 4, p=0.013 at Week 8).

Depressive symptoms were assessed using the Cornell Scale for Depression in Dementia (CSDD) (p<0.001, at Weeks 4 and 8). The rates of adverse events observed in the double-blind period were 28.3% in the AXS-05 group and 22.2% in the placebo group. Discontinuations in the double-blind period due to adverse events were low (0% for AXS-05 and 1.9% for placebo).

One serious adverse event was reported in the AXS-05 group (faecaloma), which was determined by the investigator to be not related to study medication, and 2 serious adverse events were reported in the placebo group (cardiac arrest, femur fracture). Falls were reported in 4 patients in the AXS-05 group, none of which were associated with serious adverse events and all of which were determined by the investigators to be not related to study medication, and in 2 patients in the placebo group, one of which was associated with a femur fracture. One death was reported in the placebo group.

There was no evidence of cognitive decline for patients treated with AXS-05 as shown by the Mini-Mental State Examination (MMSE), a widely utilized measure of general cognitive function. Treatment with AXS-05 was not associated with sedation.