On 30 April 2026, Axsome Therapeutics announced the FDA approval of Auvelity (dextromethorphan + bupropion) for the treatment of agitation associated with dementia due to Alzheimer’s disease, following a breakthrough therapy designation granted in 2020. Auvelity targets the N-methyl D-aspartate (NMDA) and sigma-1 receptors and is a first-in-class drug for treating agitation, providing the first non-antipsychotic treatment option for Alzheimer’s patients with agitation.
The approval of Auvelity was based on two Phase III trials: ADVANCE-1 (NCT03226522) and ACCORD-2 (NCT04797715). In ADVANCE-1, the short-term efficacy of Auvelity was demonstrated as the drug significantly improved agitation compared with placebo, as measured by reduction in Cohen-Mansfield Agitation Inventory (CMAI) total score at week 5. Auvelity was also superior to bupropion monotherapy. ACCORD-2 was a longer-term trial over 26 weeks, in which the primary endpoint was met as Auvelity treatment significantly delayed the time to relapse of Alzheimer’s agitation compared with placebo. Furthermore, 8.4% of patients in the Auvelity treatment arm experienced agitation relapse compared with 28.6% of patients in the placebo arm, showing that the drug was also significantly effective at preventing relapse.
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Caring for Alzheimer’s patients can be difficult, especially as patients advance into the more severe stages of the disease. A major unmet need in the Alzheimer’s market is for treatments for the many secondary symptoms associated with the disease that can negatively impact quality of life for both patients and caregivers. Key opinion leaders (KOLs) previously interviewed by GlobalData highlighted agitation as being a particularly distressing symptom, with a lack of good treatment options. When agitated, patients are often prescribed antipsychotic medications and sedatives off-label to alleviate behavioural issues; however, the FDA states that this practice can be dangerous in elderly patients. 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. Therefore, Auvelity’s approval as an alternative, novel treatment option for agitation associated with the disease is significant.
The unfavourable opinion about the use of atypical antipsychotics for Alzheimer’s agitation is largely related to their side-effect profiles. Indeed, the FDA label for Rexulti contains a boxed warning for increased mortality in elderly patients with dementia-related psychosis. Not having a boxed warning in elderly patients is a clear advantage for Auvelity in the Alzheimer’s patient population. In both ADVANCE-1 and ACCORD-2, Auvelity was well tolerated and was not associated with sedation or cognitive decline. Further, the overall safety profile is well established following its approval for major depressive disorder in the US in 2022.
Other novel products in late-stage development for Alzheimer’s agitation include Suven Life Sciences’ 5-hydroxytryptamine receptor 6 antagonist masupirdine and BioXcel Therapeutics’ alpha 2 adrenergic receptor agonist Igalmi (dexmedetomidine), which would provide competition for Auvelity in the future should they receive approval. Axsome Therapeutics is currently focused on development in the US only, so while Auvelity represents a significant breakthrough in the US Alzheimer’s market, significant unmet need and opportunity remain in other markets.
