Axsome to Submit NDA for AXS-05 in Alzheimer Agitation Following Positive Phase 3 Trials

Jeffrey Cummings, MD, ScD

Axsome Therapeutics recently released positive topline data from several phase 3 studies, including ACCORD-2 and ADVANCE-2, along with supportive evidence from its clinical development program, that demonstrated the benefits of investigational AXS-05 in treating Alzheimer disease (AD) agitation. Based on these data, the company plans to submit a new drug application (NDA) to the FDA for the therapy in the second half of 2025.¹

ACCORD-2 was a multicenter trial that featured 167 patients with AD agitation who completed an open-label treatment period followed by a 26-week, double-blind, placebo-controlled randomized withdrawal period. In the study, AXS-05 met its primary end point, with treated patients demonstrating a statistically significant delay in the time to relapse of agitation relative to placebo, assessed by the Cohen-Mansfield Agitation Inventory (CMAI) total score (hazard ratio for time to relapse of 0.276; P = .001). The investigational agent also met its key secondary end point of AD agitation relapse, with 8.4% of treated patients relapsing vs 28.6% of those on placebo (P = .001).

In ADVANCE-2, another double-blind, placebo-controlled trial, 408 patients were randomly assigned to AXS-05 or placebo, for 5 weeks. While the study did not demonstrate statistical significance on the primary end point of change in CMAI total score (AXS-05 reductions: 13.8 points; placebo: 12.6), results of the primary end point and secondary end points numerically favored AXS-05 over the placebo group. Among the 4 clinical trials for AXS-05 (ADVANCE-1, ADVANCE-2, ACCORD-1, and ACCORD-2), ADVANCE-2 was the only that did not demonstrate statistical significance on the primary end point.

"Agitation is one of the most troubling and consequential aspects of Alzheimer’s disease, poses significant challenges to both the patient and their family, and represents a high unmet need. The robust, clinically meaningful efficacy results of the ACCORD-2 trial are consistent with the statistically significant results of the previously completed ADVANCE-1 and ACCORD-1 Phase 3 trials of AXS-05,” Jeffrey Cummings, MD, ScD, vice chair of research at the UNLV Department of Brain Health, said in a statement.¹

He added, "The improvement in overall Alzheimer’s disease severity with AXS-05 in the ACCORD-2 trial is noteworthy. Importantly, short and long-term treatment with AXS-05 was well tolerated and not associated with increased mortality, risk of falls, sedation, or cognitive decline. Taken together, results from this comprehensive Phase 3 program encompassing distinct clinical trial designs strongly support the potential for AXS-05 to become an important treatment for patients living with Alzheimer’s disease agitation."

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AXS-05, a novel, oral, NMDA receptor antagonist, sigma-1 agonist, and aminoketone CYP2D6 inhibitor, prevented AD agitation worsening than placebo in ACCORD-2. Overall, 20.5% of AXS-05-treated patients worsened on Clinical Global Impression-Severity (CGI-S) for agitation vs 41.7% of those who switched to placebo (P = .004). In addition, 13.3% of those on the investigational agent had worsening on the CGI-S AD overall clinical status domain vs 39.3% of those who switched to placebo (P <.001).

In the ACCORD-2 open-label period, the phase that preceded the double-blind phase, 295 patients received AXS-05 for up to 12 months. At Week 6, the mean CMAI total score decreased by 20.4 points (46% reduction from baseline), with 69% of patients achieving a clinical response (≥30% reduction). Improvements in agitation were reported by 78% of patients on the mADCS-CGIC scale and 71–78% on the PGI-C scale between Weeks 4 and 8. Among those treated for at least 8 weeks, 70% experienced sustained clinical responses and entered the double-blind period.

Herriot Tabuteau, MD

"We are very pleased with the successful completion of the planned Phase 3 clinical trial program of AXS-05 in the treatment of Alzheimer’s disease agitation. With the strong results of the ACCORD-2 trial, AXS-05 has now demonstrated substantial and statistically significant improvements in Alzheimer’s disease agitation across three pivotal, Phase 3, placebo-controlled trials, underscoring its potential to provide meaningful benefit to patients living with this condition and their families," Herriot Tabuteau, MD, chief executive officer at Axsome, said in a statement.¹ "The improvements in the AXS-05 arm relative to placebo in ADVANCE-2 did not reach statistical significance. However, we are pleased with the very positive controlled safety data from this trial which will be an essential part of our planned NDA submission of AXS-05 in Alzheimer’s disease agitation, which is targeted for the second half of 2025."

Between the AXS-05 and placebo groups, the rate of adverse events (AEs) was similar across both ACCORD-2 (AXS-05: 29.3%; placebo: 32.1%) and ADVANCE-2 (AXS-05: 26.0%; placebo: 21.6%). In both studies, there were no deaths and AXS-05 was not associated with sedation or cognitive decline as assessed by Mini Mental State Exam. Discontinuations due to AEs during the double-blind period of ACCORD-2 (AXS-05: 0%; placebo: 1.2%) and ADVANCE-2 (AXS-05: 1.5%; placebo: 0%) were low. In ACCORD-2, 2 patients (2.4%) in the AXS-05 group experienced falls, only 1 which was deemed related to study medication. One subject (0.5%) each in the AXS-05 and placebo groups of ADVANCE-2 experienced falls, which was deemed not related to study medication for the subject in the AXS-05 group.

In 2022, Axsome announced positive data from ACCORD (NCT04797715), the first of the phase 3 studies, with results showing that AXS-05 met its primary end point of delay in time to relapse and preventing relapse of agitation. In the double-blind portion, investigators observed a 3.6-fold lower risk of relapse of agitation symptoms when treated with AXS-05 relative to placebo (HR, 0.275; P = .014). Preventing relapse of AD agitation, a secondary end point, was also met, as 7.5% of AXS-05-treated patients relapsed vs 25.9% of those who switched to placebo (P = .018).²

REFERENCES
1. Axsome Therapeutics Announces Successful Completion and Results of Phase 3 Clinical Program of AXS-05 in Alzheimer’s Disease Agitation. News release. Axsome Therapeutics. December 30, 2024. Accessed January 6, 2025. https://www.biospace.com/press-releases/axsome-therapeutics-announces-successful-completion-and-results-of-phase-3-clinical-program-of-axs-05-in-alzheimers-disease-agitation
2. Axsome Therapeutics announces AXS-05 achieves primary end point in the ACCORD phase 3 trial in Alzheimer’s disease agitation. News release. November 28, 2022. Accessed January 6, 2025. https://www.biospace.com/article/releases/axsome-therapeutics-announces-axs-05-achieves-primary-endpoint-in-the-accord-phase-3-trial-in-alzheimer-s-disease-agitation/