Phase III ACCORD trial of AXS 05 meets primary endpoint in Alzheimer’s Disease Agitation
Axsome Therapeutics announced that AXS 05 (bupropion + dextromethorphan), 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 III 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 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 an at least 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).
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).
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