The FDA has approved Axsome Therapeutics’ Auvelity (dextromethorphan-bupropion, formerly known as AXS-05) for the treatment of agitation associated with Alzheimer’s disease.
The therapy is the first non-antipsychotic drug indicated for this condition, offering an alternative to existing treatments that carry serious safety concerns.
Until now, treatment options for agitation in Alzheimer’s disease have been extremely limited.
In 2023, the FDA approved Otsuka Pharmaceutical and Lundbeck’s antipsychotic drug Rexulti (brexpiprazole) as the first therapy specifically indicated for agitation linked to dementia, but it belongs to the antipsychotic class, which carries a boxed warning for increased risk of death in elderly patients with dementia-related psychosis.
Unlike antipsychotics, Auvelity targets neurotransmitter systems involved in mood and behavior regulation without being classified as an antipsychotic, potentially avoiding some of the risks associated with that class.
The drug targets the N-methyl D-aspartate (NMDA) and sigma-1 receptors. It contains a proprietary formulation and dose of dextromethorphan (DM) and bupropion.
Auvelity was first approved in 2022 to treat major depressive disorder in adults.
Alzheimer’s disease is the most common form of dementia and affects about 7 million people in the US.
Agitation is one of the most common and distressing symptoms of Alzheimer’s that affects up to 70% of Alzheimer’s patients.
It can manifest as restlessness, aggression, irritability and emotional distress, often placing a heavy burden on caregivers and accelerating the need for institutional care. It is associated with faster cognitive decline and an increased risk of death.
Despite its prevalence, treatment options have historically been limited, with many therapies used off-label and associated with safety concerns.
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In a press release from Axsome, CEO Herriot Tabuteau said: “The approval of our first-in-class medication for agitation associated with Alzheimer’s disease marks an important milestone for the millions of patients living with Alzheimer’s disease, their families and their caregivers. We are very pleased to deliver to clinicians and patients a new, effective, FDA-approved treatment option, with a distinct mechanism of action, for this debilitating and critically underserved condition.”
Auvelity’s expanded approval in dementia agitation is based on data from four late-stage clinical trials involving over 1,000 patients, which demonstrated that the drug significantly reduced agitation symptoms, delayed relapse time and reduced the worsening of other symptoms compared to placebo.
The studies included the randomized, placebo-controlled ACCORD-2 and ADVANCE-2 Phase III trials, which involved 167 and 408 participants, respectively.
In the ACCORD-2 trial, participants underwent an open-label treatment period followed by a 26-week, double-blind, placebo-controlled randomized withdrawal phase. AXS-05 met its primary endpoint, demonstrating a statistically significant delay in time to relapse of agitation compared with placebo, as measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score. The drug also achieved its key secondary endpoint, with relapse occurring in just 8.4% of AXS-05-treated participants versus 28.6% in the placebo group.
However, in ADVANCE-2, AXS-05 did not meet its primary endpoint of change in CMAI total score over a five-week period. While AXS-05 showed a greater numerical reduction in agitation (13.8-point decrease versus 12.6 with placebo), the difference was not statistically significant. Notably, ADVANCE-2 was the only trial out of the four pivotal studies (ADVANCE-1, ADVANCE-2, ACCORD-1 and ACCORD-2) that failed to meet its primary endpoint.
Axsome submitted a supplemental NDA to the FDA on November 4, 2025, seeking approval of AXS-05 for the treatment of agitation associated with Alzheimer’s disease.
AXS-05 was granted FDA Breakthrough Therapy designation in Alzheimer’s disease in 2020 and Priority Review for its Alzheimer’s agitation application.
Auvelity is Axsome’s top-selling product and brought in $507.1 million in revenue in 2025.
According to Reuters, UBS analyst Ashwani Verma estimated about $2 billion in additional sales for the new indication. He also noted that although Auvelity is not an antipsychotic, Auvelity will likely receive a black box warning typically associated with antipsychotics.
Auvelity’s list price is $1,248 for a 30‑day supply with the same pricing across indications.
Axsome anticipates launching the Alzheimer’s disease agitation indication in June.
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