The FDA has approved a new indication for Auvelity (dextromethorphan hydrobromide and bupropion hydrochloride) for the treatment of agitation associated with dementia due to Alzheimer’s disease (AD).

Auvelity, a first-in-class oral non-antipsychotic treatment for AD agitation, is the second FDA-cleared drug for this indication. The antipsychotic brexpiprazole was approved in 2023.

Agitation is one of the most common and challenging neuropsychiatric symptoms in AD and may include restlessness, pacing, emotional distress, irritability, and verbal or physical aggression. These symptoms are associated with increased caregiver burden, earlier institutionalization, and accelerated functional decline. 

“Auvelity was found to be efficacious for treating agitation in Alzheimer’s disease in two randomized trials and now represents an additional option to address one of the most difficult sequelae of the disease, especially as it progresses,” Tracy Beth Hoeg, MD, PhD, acting director of the FDA’s Center for Drug Evaluation and Research said in a statement. 

“We hope this approval will provide meaningful benefit to patients, their families, and caregivers,” Hoeg added.

Novel Mechanism of Action 

Manufacturer Axsome Therapeutics had received breakthrough designation and priority review status for the fixed-dose combination drug due to its novel mechanism of action. 

Dextromethorphan targets N-methyl D-aspartate and sigma-1 receptors, while bupropion acts as a CYP2D inhibitor to sustain therapeutic levels of dextromethorphan to modulate pathways involved in agitation and behavioral symptoms in neurodegenerative disease. It was originally approved in 2022 for major depressive disorder. 

FDA approval for AD agitation was based on the performance of Auvelity — previously known as AXS-05 — in the phase 3 ADVANCE-1 and ACCORD-2 studies. 

ACCORD-2 became the most clinically meaningful dataset in this program due to its randomized withdrawal design and strong signal for relapse prevention. As previously reported by Medscape Medical News, the 26-week trial enrolled 167 patients with AD agitation who first stabilized on open-label AXS-05 before being randomly assigned to continue therapy or switch to placebo.

Compared to placebo, treatment with AXS-05 delayed time to relapse (hazard ratio [HR], 0.276; P = .001) and reduced relapse incidence (8.4% vs 28.6%; P = .001). 

“In the clinic, we want to know if a drug works, but also whether a drug maintains its efficacy over the long haul during the maintenance phase,” ACCORD-2 principal investigator George Grossberg, MD, professor and director of the Division of Geriatric Psychiatry at the Saint Louis University School of Medicine in St. Louis, Missouri, told Medscape Medical News.

Findings from ACCORD-2 showed that durable benefit in maintaining behavioral stability once patients respond to treatment, he added. 

ACCORD-1 similarly showed a significant reduction in relapse risk, with a 3.6-fold lower risk compared with placebo (HR, 0.275; P = .014). Relapse occurred in 7.5% of patients receiving AXS-05 vs 25.9% receiving placebo. Together with the results of ACCORD-2, these findings provide a consistent relapse-prevention signal across randomized withdrawal designs, Grossberg noted. 

Mixed Results in ADVANCE  

In contrast to relapse-prevention data, acute treatment studies show greater variability. In the ADVANCE-1 phase 2/3 trial, 366 patients with AD received the experimental drug, placebo, or bupropion monotherapy. 

AXS-05 demonstrated a statistically significant reduction in agitation severity at week 5, with a 15.4-point reduction in Cohen-Mansfield Agitation Inventory (CMAI) scores for AXS-05 vs 11.5 points for placebo (P = .010), and superiority over bupropion monotherapy (P < .001). 

However, the phase 3 ADVANCE-2 trial did not meet its primary endpoint for change in CMAI score at the prespecified time point, with no statistically significant difference vs placebo despite numerical improvement with AXS-05, the company reported in a statement.

ADVANCE-2 was “the only negative study in the AXS-05 portfolio,” Grossberg said. “I attribute the negative outcome to a robust placebo effect and that in a short study, the placebo effect may not wear off.”

Taken together, the data suggest a more consistent signal for relapse prevention than for acute symptom reduction, he added.

Dosing and Safety 

Auvelity must be titrated in AD agitation, with an initial dosing of 30 mg/105 mg once daily in the morning, increasing on day 8 to 30 mg/105 mg twice daily, separated by at least 8 hours, based on tolerability. The maximum dosage of 45 mg/105 mg twice daily, separated by at least 8 hours, begins on day 15. Patients should not exceed two doses within the same day.

The most common adverse reactions (≥ 5%, and occurring more than twice as frequently as with placebo) included dizziness, somnolence, gastrointestinal symptoms, sexual dysfunction, and uncontrolled sweating, the FDA noted in a statement. 

Auvelity also includes a boxed warning for elevated risk for suicidal ideation in adolescents and young adults taking antidepressants. The FDA advised regular monitoring for clinical worsening and suicidal ideation, especially during initial treatment. 

The medicine can cause seizures, with risk increasing with dose. It can also cause elevated blood pressure and hypertension, and may activate mania or hypomania (irritable mood) in susceptible patients.

Before starting AXS-05, the FDA recommends clinicians evaluate blood pressure, screen for a personal or family history of bipolar disorder, and review concomitant medications for other agents containing bupropion or dextromethorphan.

Additional prescribing information is available online.

Grossberg has provided consultation to Acadia, Alkahest, Avanir, Axovant, Axsome Therapeutics, Biogen,BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda. He has provided research support for Lilly, Roche, and the National Institute on Aging. He has served on a speaker's bureau for Acadia, Biogen, and Eisai and has served on safety monitoring committees for Anavex, EryDel, IntracellularTherapies, Merck, Newron, and Oligomerix.