공고 • Dec 30
Axsome Therapeutics, Inc. Announces Successful Completion and Results of Phase 3 Clinical Program of AXS-05 in Alzheimer’s Disease Agitation
Axsome Therapeutics, Inc. announced the successful completion of its Phase 3 clinical program evaluating AXS-05 (dextromethorphan-bupropion), a novel, oral, investigational NMDA receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor, in Alzheimer’s disease agitation, and results of the ACCORD-2, ADVANCE-2, and long-term safety trials in this indication. The ACCORD-2 Phase 3 trial achieved the primary endpoint with AXS-05 statistically significantly delaying the time to relapse of agitation, assessed by the Cohen-Mansfield Agitation Inventory (CMAI) total score, in patients with Alzheimer’s disease compared to placebo (hazard ratio for time to relapse of 0.276, p=0.001), demonstrating a 3.6-fold lower risk of relapse compared to placebo. AXS-05 also met the key secondary endpoint (relapse prevention, p=0.001). Further, AXS-05 reduced worsening for overall Alzheimer’s disease severity compared to placebo, as assessed by the Clinical Global Impression of Severity (CGI-S) for Alzheimer’s disease (p<0.001). The ADVANCE-2 Phase 3 trial did not demonstrate statistical significance for the primary endpoint, change in the CMAI total score from baseline to Week 5 (CMAI reductions of 13.8 and 12.6 points for AXS-05 and placebo, respectively). However, results for the primary and nearly all secondary endpoints numerically favored AXS-05 over placebo. AXS-05 was safe and well tolerated in both controlled studies. The long-term safety and tolerability of AXS-05 was also evaluated in more than 300 subjects treated for at least 6 months and more than 100 subjects treated for at least 12 months. In the controlled and long-term studies in subjects with Alzheimer’s disease, AXS-05 was not associated with increased risk of falls, cognitive decline, or sedation. In the clinical program for AXS-05 in Alzheimer’s disease agitation, there have been no deaths in subjects receiving AXS-05. AXS-05 has now demonstrated statistically significant efficacy compared to placebo in three completed pivotal Phase 3 trials (ADVANCE-1, ACCORD-1 and ACCORD-2), with supportive efficacy and controlled safety results in a fourth trial (ADVANCE-2). Axsome plans to submit an NDA for AXS-05 in Alzheimer’s disease agitation to the FDA in the second half of 2025, based on the efficacy and safety data from the above controlled and long-term studies. AXS-05 has been granted Breakthrough Therapy designation for the treatment of Alzheimer’s disease agitation. ACCORD-2 was a double-blind, placebo-controlled, randomized withdrawal trial of AXS-05 in Alzheimer’s disease patients with agitation, consisting of an open-label AXS-05 treatment period, and a randomized, double-blind treatment period. Patients who achieved a sustained clinical response with open-label AXS-05 were then randomized into the double-blind treatment period to either continue on AXS-05 or to switch to placebo. Open-Label AXS-05 Treatment Period A total of 295 patients were treated with open-label AXS-05 for up to 12 months and assessed for efficacy. The mean CMAI total score was 73.3 at baseline. Treatment with AXS-05 was associated with a mean reduction from baseline in the CMAI total score of 20.4 points at Week 6, representing a 46% reduction from the mean baseline score. Clinical response on the CMAI (defined as =30% reduction from baseline) after treatment with AXS-05 was achieved by 69% of patients at Week 6, after treatment with AXS-05. Improvement in Alzheimer's disease agitation, assessed using the clinician rated modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC), was achieved by 78% of patients at Week 6, after treatment with AXS-05. Improvement in Alzheimer's disease agitation, assessed using the caregiver rated Patient Global Impression of Change (PGI-C), was achieved by 71% of patients at Week 4, and 78% of patients at Week 8, after treatment with AXS-05. Of the patients treated for at least 8 weeks, 70% experienced a sustained clinical response and were randomized in the double-blind period. Double-Blind Randomized Period A total of 167 patients were randomized, 83 to continued treatment with AXS-05, and 84 switched to placebo. The mean CMAI total scores at randomization were 44.3 and 45.4 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 (hazard ratio for time to relapse of 0.276, p=0.001), demonstrating a 3.6-fold lower risk of relapse compared to placebo. AXS-05 met the key secondary endpoint by substantially and statistically significantly preventing relapse of Alzheimer's disease agitation as compared to placebo, with 8.4% of AXS-05 patients relapsing versus 28.6% of patients switched to placebo (p=0.001). AXS-05 substantially and statistically significantly prevented worsening of severity of Alzheimer's disease agitation as compared to placebo, with 20.5% of AXS-05 patients worsening on the CGI-S for agitation versus 41.7% of patients switched to placebo (p=0.004). AXS-05 substantially and statistically significantly prevented worsening of severity of Alzheimer's disease overall as compared to placebo, with 13.3% of AXS-05 patients worsening on the CGI-S for Alzheimer’s disease overall clinical status versus 39.3% of patients switched to placebo (p<0.001). The overall rates of adverse events in the double-blind period were 29.3% in the AXS-05 group and 32.1% in the placebo group, with no individual adverse events occurring in more than 3.7% of subjects. Two subjects (2.4%) in the AXS-05 group experienced falls, only one which was deemed related to study medication. There were two serious adverse events in the double-blind period (cellulitis and urinary retention) both of which occurred in the placebo group. Discontinuations in the double-blind period due to adverse events were low (0% for AXS-05 and 1.2% for placebo). There were no deaths in the ACCORD-2 trial, and AXS-05 was not associated with sedation or cognitive decline as assessed by the Mini-Mental State Examination (MMSE). The ADVANCE-2 trial was a double-blind, placebo-controlled, parallel group trial of AXS-05 in Alzheimer’s disease patients with agitation. A total of 408 patients were randomized in a 1:1 ratio to treatment with AXS-05 or placebo, for 5 weeks. The study did not demonstrate statistical significance for the primary endpoint, change in the CMAI total score from baseline to Week 5 (CMAI reductions of 13.8 and 12.6 points for AXS-05 and placebo, respectively). Results of the primary endpoint and almost all secondary endpoints numerically favored AXS-05 over the placebo group. The overall rates of adverse event in ADVANCE-2 were 26.0% in the AXS-05 group and 21.6% .