AXS-05 Shows Reduction in Relapse Risk in Phase 3 ACCORD Trial for Alzheimer Disease Agitation

George Grossberg, MD

New data from the phase 3 ACCORD trial (NCT04797715) assessing AXS-05 (Axsome Therapeutics), a novel, investigational n-methyl-D-aspartate receptor antagonist, showed that the therapy met its primary end point of statistically significant delay the time to relapse of agitation symptoms compared with placebo, and was generally well-tolerated in patients with Alzheimer disease (AD) agitation during the open-label treatment period.¹ These findings suggest that the therapy can significantly reduce the risk of relapse and demonstrate safety, supporting the continued development of AXS-05 for agitation in patients with AD.²

In the open-label treatment period with AXS-05, investigators observed statistically significant improvement on the Cohen Mansfield Agitation Inventory (CMAI) at all time points starting at week 1 (P <.001) with mean reductions from baseline of 6.7 points at week 1 and 20.6 points at week 5 (P <.001). The therapy delayed the time to relapse of agitation symptoms, representing a 3.6-fold lower risk of relapse compared with placebo (HR, 0.275; P = .014). AXS-05 also met the key secondary end point of relapse prevention with a 7.5% relapse incidence rate for AXS-05-treated patients and 25.9% for placebo (P = .018).

“I think it's important for all of us to keep in mind that AD is not just a cognitive disorder. Many patients—in fact, the majority of patients—during the course of the disease will exhibit some type of behavioral or neuropsychiatric disturbance. This can happen more likely toward the moderate and more advanced stages, but it can occur throughout the disease,” coauthor George Grossberg, MD, professor and director of the division of geriatric psychiatry at the Saint Louis University School of Medicine said in a recent interview with NeurologyLive®. “Of these neuropsychiatric or behavioral disturbances, agitation is one of the most common. In fact, it's estimated that maybe 50% or more of patients with AD will have clinically significant agitated behaviors throughout the mild, moderate, or more advanced stages of the disease.”

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Presented at the 2023 Clinical Trials on Alzheimer Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, 178 individuals with a diagnosis of probable AD and clinically meaningful agitation were enrolled into the open-label period and treated with AXS-05 (mean CMAI total score at baseline, 70.9) for 9 weeks. In the randomized discontinuation phase of the trial, 108 participants were randomized to continue AXS-05 (n = 53) or switched to placebo (n = 55). The participants who achieved a sustained clinical response during the open-label period were randomly assigned 1:1 to continue treatment with AXS-05 or placebo in a double-blind fashion for up to 26 weeks. The primary end point in the study was time from randomization to relapse of agitation and the secondary end point was the percentage of participants who relapsed.

In the double-blind period of this trial, investigators observed that 28.3% of patients AXS-05-treated experienced adverse events and 22.2% reported them in the placebo group. In the AXS-05-treated group, none of the patients discontinued the treatment because of adverse events but 1.9% in the placebo group did discontinue. The authors noted that there was no evidence of cognitive decline in those treated with AXS-05 and that the treatment was not associated with sedation.

“Agitation, which is seen in up to 70% of people with AD, is among the most complex, challenging and costly aspects of care and is associated with multiple negative outcomes such as increased caregiver burden, morbidity, mortality, earlier nursing home placement, and overall functional impairment,” Cecilia Brain, MD, PhD, vice president of medical affairs at Axsome, said in a statement.¹ “The detailed efficacy and safety results of the ACCORD trial support the potential of AXS-05 in this area of significant unmet medical need.”

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REFERENCES
1. Axsome Therapeutics Presents Results of the ACCORD trial of AXS-05 in Alzheimer’s Disease Agitation at the Clinical Trials on Alzheimer’s Disease (CTAD) 2023 Conference. News Release. Axsome Therapeutics. Published October 24, 2023. Accessed October 25, 2023. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-presents-results-accord-trial-axs-05
2. Cummings J, Grossberg G, Andersson C, et al. Efficacy and Safety Of AXS-05 in Agitation Associated With Alzheimer’s Disease: Results From ACCORD, a Phase 3, Double-Blind, Placebo-Controlled, Relapse Prevention Trial. Presented at: CTAD Conference 2023; October 24-27; Boston, MA. LP093.