Axsome Therapeutics says AXS-05 achieves primary endpoint in ACCORD trial

Axsome Therapeutics announced that AXS-05, a novel, oral, investigational NMDA receptor antagonist with multimodal activity, met the primary and key secondary endpoints in the ACCORD 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 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 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, 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. Relapse was defined as a greater than or equal to10-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 was seen with open-label AXS-05 treatment at all timepoints starting at Week 1, with mean reductions from baseline of 11.0 points at Week 2, and 20.6 points at Week 5. Improvements were also significant with open-label AXS-05 treatment on all CMAI subscales including the Physically Aggressive subscale at all timepoints. 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. 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 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. Caregiver burden was assessed using the Zarit Burden Interview. Patient quality of life was assessed using the caregiver rated Quality of Life Alzheimer’s Disease scale. Depressive symptoms were assessed using the Cornell Scale for Depression in Dementia. 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. One serious adverse event was reported in the AXS-05 group, which was determined by the investigator to be not related to study medication, and 2 serious adverse events were reported in the placebo group. 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, a widely utilized measure of general cognitive function. Treatment with AXS-05 was not associated with sedation. AXS-05 was granted Breakthrough Therapy designation for the treatment of Alzheimer’s disease agitation by the FDA in June 2020. The FDA Breakthrough Therapy designation was supported by the positive results of the ADVANCE-1 trial. A Breakthrough Therapy designation is granted to potentially expedite development and review timelines for a promising investigational medicine when preliminary clinical evidence indicates it may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies for a serious or life-threatening condition. A total of 178 patients were treated with open-label AXS-05 for up to 9 weeks and assessed for efficacy. The primary timepoint for open-label efficacy assessments was 5 weeks, and the key secondary timepoint was 2 weeks. P-values were calculated versus baseline. The mean CMAI total score was 70.9 at baseline. Treatment with AXS-05 was associated with a mean reduction from baseline in the CMAI total score of 6.7 points at Week 1, 11.0 points at Week 2, and 20.6 points at Week 5. Clinical response on the CMAI after treatment with AXS-05 was achieved by 21.8% of patients at Week 1, 40.4% of patients at Week 2, and 70.0% of patients at Week 5. Treatment with AXS-05 was also associated with improvements on all CMAI subscales including the Physically Aggressive subscale at all timepoints. Improvement in Alzheimer’s disease agitation, assessed using the clinician rated mADCS-CGIC, was achieved by 47.1% of patients at Week 1, 66.3% of patients at Week 2, and 86.3% of patients at Week 5, after treatment with AXS-05. Improvement in Alzheimer’s disease agitation, assessed using the caregiver rated PGI-C, was achieved by 51.2% of patients at Week 1, 67.5% of patients at Week 2, and 89.3% of patients at Week 5, after treatment with AXS-05. Caregiver distress, assessed using the NPI Agitation and Aggression Caregiver Distress score, was significantly reduced after treatment with AXS-05. Caregiver burden, assessed using the ZBI, was significantly reduced after treatment with AXS-05. Patient quality of life, assessed using the caregiver rated QoL-AD scale, was significantly improved after treatment with AXS-05. Depressive symptoms, assessed using the CSDD, were significantly reduced after treatment with AXS-05. A total of 108 patients were randomized, 53 to continued treatment with AXS-05, and 55 switched to placebo. The mean CMAI total scores at randomization were 43.7 and 44.9 for the AXS-05 and placebo groups respectively. AXS-05 met the primary endpoint by substantially and statistically significantly delaying the time to relapse of Alzheimer’s disease agitation as compared to placebo, demonstrating a 3.6-fold lower risk of relapse compared to placebo. AXS-05 met the key secondary endpoint by preventing relapse of Alzheimer’s disease agitation as compared to placebo, with 7.5% of AXS-05 patients relapsing versus 25.9% of patients switched to placebo. The rates of adverse events 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.