On 7 April 2025 at the American Academy of Neurology (AAN) 2025 annual meeting held in San Diego, California, Axsome Therapeutics presented efficacy and safety data from the Phase III ACCORD-2 (NCT04797715) study evaluating AXS-05 (bupropion + dextromethorphan) for the treatment of agitation associated with Alzheimer’s disease. The US Food and Drug Administration (FDA) granted AXS-05 fast track designation then breakthrough therapy designation for Alzheimer’s agitation in May 2017 and June 2020. During the presentation, Axsome Therapeutics announced plans to file for FDA approval in the spring/summer of 2025. If approved, AXS-05 would become the second drug available for the treatment of Alzheimer’s agitation in the US following years of off-label antipsychotic use, intensifying competition in the space.
The primary endpoint in ACCORD-2 was met, as AXS-05 treatment significantly delayed the time to relapse of Alzheimer’s agitation compared with placebo, with the risk of relapse with AXS-05 3.6 times less than with placebo. 8.4% of patients in the AXS-05 treatment arm experienced agitation relapse compared with 28.6% of patients in the placebo arm, showing that the drug was also significantly effective in prevention. AXS-05 treatment also significantly reduced the worsening of agitation compared with placebo.
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A major unmet need in the market is for treatments for the many secondary symptoms that can negatively impact patients’ and caregivers’ quality of life. Key opinion leaders (KOLs) previously interviewed by GlobalData highlighted agitation as a particularly distressing symptom with a lack of good treatment options. At the AD/PD 2025 International Conference on Alzheimer’s and Parkinson’s Diseases held in Vienna, Austria, in early April 2025, during a symposium sponsored by Bristol Myers Squibb that focused on the neuropsychiatric dimensions of Alzheimer’s, the unmet need for the management of agitation was further highlighted. Up to 75% of patients can present with this issue and it is associated with a more rapid decline in cognition and function, resulting in increased risk of earlier patient institutionalisation and increased risk of mortality.
Agitated patients are often prescribed antipsychotic medications and sedatives off-label to alleviate behavioural issues. The FDA states that this practice can be dangerous for the elderly. In 2023, Otsuka Pharmaceuticals’ Rexulti (brexpiprazole) became the first FDA-approved treatment for agitation associated with Alzheimer’s in the US, but KOLs felt that Rexulti’s efficacy was only comparable to other atypical antipsychotics and thus did not provide a significant breakthrough for Alzheimer’s agitation treatment. AXS-05’s positive efficacy is therefore particularly significant, as it would provide a novel, non-antipsychotic treatment option if approved. AXS-05’s novel mechanism of action was highlighted as promising for Alzheimer’s agitation during the BMS AD/PD 2025 symposium, particularly when compared to Rexulti.
Unfavourable opinion about the use of atypical antipsychotics for Alzheimer’s agitation is chiefly due to their side-effect profiles. In ACCORD-2, AXS-05 was well tolerated, with no serious treatment-emergent adverse events (TEAEs) and no-one discontinuing the drug due to TEAEs. AXS-05 was also not associated with sedation or cognitive decline, and the overall safety profile is well established following its approval under the brand name Auvelity for major depressive disorder (MDD) in the US in 2022. Physician experience with Auvelity in MDD and its safety profile should give it a further competitive edge in the AD market.
Other products in late-stage development for AD agitation are Suven Life Sciences’s 5-hydroxytryptamine receptor 6 antagonist masupirdine and BioXcel Therapeutics’ alpha 2 adrenergic receptor agonist Igalmi (dexmedetomidine). BMS’s M1–M4 muscarinic agonist Cobenfy (trospium chloride + xanomeline tartrate), which is currently marketed for schizophrenia, is in the late-stage pipeline for psychosis associated with Alzheimer’s, for which there are no approved drugs. While these products will begin to help meet the present need, both Axsome Therapeutics and BioXcel Therapeutics are currently focusing on development in the US only, so opportunity will remain outside the US.
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