Axsome breaks new ground in Alzheimer's with Auvelity OK

Axsome Therapeutics' Auvelity has become the first non-antipsychotic therapy for agitation in patients with Alzheimer's disease to be approved by the FDA, which called the drug a "significant advancement" in care.

Auvelity (dextromethorphan/bupropion) – a first-in-class oral NMDA receptor antagonist and sigma-1 receptor agonist – is already approved to treat major depressive disorder (MDD) and made more than $500 million in sales last year.

The new indication is expected to lead to an acceleration in growth, as more than 7 million people are living with Alzheimer's in the US, and agitation – which can include verbal and physical aggression – is a very common symptom that affects an estimated 50% to 70% of all patients.

Antipsychotic medications are currently the main therapy for Alzheimer's agitation, but carry serious risks, including an increased risk of death, due to side effects. They also offer only modest, short-term benefits and may also accelerate cognitive decline, so are typically used as a last resort, for example when there is a risk of harm to the patient or those around them.

While many antipsychotics are used off-label, the only FDA-approved option is Otsuka/Lundbeck's dopamine- and serotonin-targeting Rexulti (brexpiprazole), which got a green light for this use in 2023.

Auvelity is thought to target pathways involved in mood regulation and stress responses in the brain. In the ADVANCE-1 trial, it outperformed placebo in improving agitation scores over five weeks' follow-up, while in ACCORD-2, patients who switched from Auvelity to placebo had a shorter time to relapse than those who continued treatment with the drug.

According to geriatric psychiatry expert George Grossberg of Saint Louis School of Medicine in the US, Auvelity is the only FDA-approved product to show a statistically significant increase in time to relapse of agitation symptoms, compared to placebo, in a long-term study.

"Agitation in patients with dementia due to Alzheimer's disease is distressful, consequential, and challenging for patients, their caregivers and healthcare providers," he said, adding that Auvelity also showed "a compelling safety and tolerability profile, with rates of discontinuation due to adverse events that were low and matched those of placebo."

That profile should give Auvelity an immediate edge over Rexulti, which carries a boxed warning that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

Analysts have said that Alzheimer's agitation could be a $1.5 billion market for Auvelity, on top of its potential in MDD, which has been estimated at between $1 billion and $3 billion at peak. Axsome, meanwhile, is hoping to extend the label for Auvelity even further, with a phase 2/3 clinical trial already running in smoking cessation.

Shares in the company rose nearly 13% on the news, driving its market cap to almost $10.7 billion.

Photo by razi pouri on Unsplash