FDA Approves Auvelity for Alzheimer's Disease Agitation, Marking Second Approved Treatment Option

The US Food and Drug Administration has approved dextromethorphanSearch drug hydrobromide and bupropionSearch drug hydrochloride extended-release tablets (AuvelitySearch drug) for the treatment of agitationSearch disease associated with dementiaSearch disease due to Alzheimer's diseaseSearch disease, according to Axsome TherapeuticsSearch company. This approval provides clinicians with a second FDA-approved treatment option for a challenging behavioral symptom that affects up to 76% of patients with Alzheimer's disease.

Clinical Trial Evidence Supporting Approval

The approval was supported by a comprehensive clinical development program that included randomized, double-blind phase 3 studies and long-term safety data. The pivotal ADVANCE-1 trial, a 5-week randomized, double-blind, controlled, multicenter US study, treated 366 participants with Alzheimer's diseaseSearch disease using AXS-05Search drug, bupropionSearch drug, or placebo.

In ADVANCE-1, dextromethorphan-bupropionSearch drug demonstrated statistically significant improvement compared with placebo in agitationSearch disease symptoms, measured by change in Cohen-Mansfield Agitation Inventory (CMAI) total score at week 5. The treatment resulted in mean reductions of 15.4 points for AXS-05Search drug compared to 11.5 points for placebo (P=0.010). The drug was also superior to bupropionSearch drug alone on the CMAI total score (P <0.001), establishing component contribution.

A statistically significantly greater proportion of treated patients were also rated by clinicians as at least minimally improved on the modified Alzheimer's DiseaseSearch disease Cooperative Study–Clinical Global Impression of Change.

Long-Term Efficacy Data

The ACCORD-2 trial provided additional evidence of sustained efficacy. This multicenter study included 167 participants with Alzheimer's diseaseSearch disease agitationSearch disease who completed an open-label treatment period followed by a 26-week, double-blind, placebo-controlled randomized withdrawal period.

In ACCORD-2, patients who had responded to dextromethorphan-bupropionSearch drug were randomly assigned to continue treatment or switch to placebo for up to 6 months. Patients who continued treatment had a statistically significantly longer time to relapse of agitationSearch disease symptoms than those who switched to placebo (hazard ratio for time to relapse of 0.276; P = .001). The drug also met its key secondary endpoint, with 8.4% of treated patients relapsing versus 28.6% of those on placebo (P = .001).

Mechanism of Action and Dosing

DextromethorphanSearch drug is thought to act on N-methyl-D-aspartate and sigma-1 receptors, while the bupropionSearch drug component inhibits cytochrome P450 2D6, increasing dextromethorphan exposure. However, the exact mechanism of action in agitationSearch disease associated with dementiaSearch disease due to Alzheimer's diseaseSearch disease remains unclear.

For agitationSearch disease associated with Alzheimer's diseaseSearch disease, the recommended dosing differs from the regimen used for major depressive disorderSearch disease. Dosing is initiated at 30 mg/105 mg (dextromethorphan/bupropion) once daily for 7 days, increased to twice daily on day 8, and then increased to 45 mg/105 mg twice daily from day 15 based on tolerability.

Safety Profile

The drug demonstrated a favorable safety profile in clinical trials. AXS-05Search drug was well tolerated and not associated with cognitive impairment or sedation. In the ADVANCE-1 trial, the most common adverse reactions occurring in at least 5% of treated patients and more than twice as often as placebo were dizziness and dyspepsia. The most commonly reported adverse events in the AXS-05 arm were somnolence (8.2% for AXS-05 vs 3.2% for placebo), dizziness (6.3% vs 3.2%), and diarrhea (4.4% vs 4.4%).

Discontinuation due to adverse events occurred in 1.3% of patients receiving dextromethorphan-bupropionSearch drug, the same rate reported with placebo.

Treatment Landscape Context

AuvelitySearch drug becomes the second medication approved for Alzheimer's diseaseSearch disease agitationSearch disease, following brexpiprazoleSearch drug (RexultiSearch drug), which received FDA approval in May 2023. Brexpiprazole's effectiveness was demonstrated through two 12-week studies, showing a mean difference in CMAI total scores of −22.6 from baseline compared to −17.3 for placebo (difference of −5.32; 95% CI, −8.77 to −1.87; P = .003).

Regulatory Pathway and Clinical Significance

The agitationSearch disease indication was developed with FDA Breakthrough Therapy designation, granted in 2020, and reviewed under Priority Review. This regulatory pathway reflects the significant unmet medical need for treating agitation in Alzheimer's diseaseSearch disease, which may include emotional distress, disruptive irritability, disinhibition, and verbal or physical aggression.

Alzheimer's diseaseSearch disease affects more than 7 million people in the US, making this approval particularly significant for addressing behavioral symptoms that pose challenges for patients, caregivers, and healthcare providers. The prescribing information includes important safety considerations, including a boxed warning for suicidal thoughts and behaviors associated with antidepressants, and the drug should not be used as an as-needed treatment for agitationSearch disease.