AXS-05, a Novel NMDA Receptor Antagonist, Shows Promise for Agitation in Alzheimer's Disease

Key Insights

• AXS-05, combining dextromethorphan and bupropion, is under development by Axsome Therapeutics for agitation in Alzheimer's disease, offering a novel approach by targeting glutamate and NMDA receptors.
• Clinical trials indicate AXS-05 demonstrates efficacy in reducing agitation with a more favorable side effect profile compared to traditional antipsychotics, avoiding significant sedation or motor impairment.
• Unlike acute treatments, AXS-05 requires approximately two weeks to show effects, positioning it as a maintenance therapy with the advantage of not carrying a boxed warning for increased mortality.

Axsome Therapeutics' AXS-05, a novel oral NMDA receptor antagonist, is showing promise as a targeted treatment for agitation in Alzheimer's disease (AD). The combination drug, containing dextromethorphan and bupropion, aims to address agitation through a unique mechanism of action, potentially offering a safer alternative to traditional antipsychotics.

Addressing Agitation in Alzheimer's Disease

Agitation affects up to 70% of individuals with Alzheimer's disease, posing significant challenges for patients, caregivers, and healthcare professionals. Current pharmacologic treatments often rely on off-label use of typical antipsychotics, which carry substantial risks, including somnolence, cerebrovascular events, extrapyramidal symptoms, increased hospitalization rates, and mortality.

AXS-05: A Novel Approach

AXS-05 combines dextromethorphan, the primary therapeutic component, with bupropion, which extends dextromethorphan's half-life. Dextromethorphan modulates the excitatory neurotransmitter glutamate by blocking glutamate, potentially mitigating agitation symptoms. According to George Grossberg, MD, Samuel W. Fordyce professor and director of Geriatric Psychiatry at Saint Louis University School of Medicine, bupropion is used in low doses to slow the metabolism of dextromethorphan, reducing the need for frequent administration.

Advantages Over Traditional Treatments

One key advantage of AXS-05 is that it is not an antipsychotic, thus avoiding the boxed warning about increased mortality associated with that drug class. Furthermore, AXS-05 appears to have a reasonable side effect profile, without causing excessive sedation or motor impairment. Clinical trials suggest that it takes about two weeks to see separation from placebo, indicating that it is not an acute medication for immediate calming but rather a maintenance therapy.

Clinical Trial Data and Future Prospects

Pivotal trial data for AXS-05 is anticipated, with ongoing studies expected to provide further evidence of its efficacy. If these trials yield positive results, AXS-05 could become an FDA-approved treatment for agitation in Alzheimer's dementia, filling a critical unmet need in managing this challenging symptom.