FDA approves Auvelity to treat Alzheimer’s-related agitation
First-in-class therapy works by different mechanism than antipsychotic meds
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The U.S. Food and Drug Administration (FDA) has approved a new first-in-class treatment, Auvelity (dextromethorphan-bupropion), for the treatment of agitation associated with Alzheimer’s disease.
Auvelity is now the only FDA-approved treatment for Alzheimer’s-related agitation that is not classified as an antipsychotic, according to the Alzheimer’s Association.
“For too long, people living with Alzheimer’s disease agitation and their families have had limited options, and the options that existed came with significant risks,” Joanne Pike, the association’s president and CEO, said in a press release. “This approval gives patients, caregivers and clinicians an important new tool — one that works through a different mechanism than antipsychotic medications and that can help address a symptom that profoundly affects quality of life for people living with Alzheimer’s and those who care for them.”
Previously known as AXS-05, Auvelity was developed by Axsome Therapeutics. The company said that when it commercially launches the new medication, it will also launch a patient support program called Auvelity OnMySide, which will provide resources, including financial aid and insurance assistance, for eligible patients.
“The approval of our first-in-class medication for agitation associated with Alzheimer’s disease marks an important milestone for the millions of patients living with Alzheimer’s disease, their families, and their caregivers. We are very pleased to deliver to clinicians and patients a new, effective, FDA-approved treatment option, with a distinct mechanism of action, for this debilitating and critically underserved condition,” Herriot Tabuteau, MD, Axsome’s CEO, said in a company press release.
Auvelity eases agitation by modulating activity of 2 brain cell receptors
Alzheimer’s is marked by difficulty thinking and problems regulating emotions. Agitation — which can include everything from restless pacing to physically or verbally lashing out at other people — is a common Alzheimer’s symptom, reported in roughly three-quarters of people with the disease. Auvelity is designed to ease agitation by modulating the activity of two brain cell receptors called the NMDA and sigma-1 receptors. The therapy was already FDA-approved to treat adults with major depressive disorder.
“Agitation is highly prevalent in patients with Alzheimer’s disease and among the most burdensome aspects of the disease for patients and families,” Jeffrey Cummings, MD, a professor in the Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas, said in the Axsome press release.
Cummings noted that agitation in Alzheimer’s “is associated with accelerated cognitive decline, placement in assisted living and long-term care facilities, and increased mortality risk,” adding that treatment for agitation “has been a critical unmet medical need.” He said the approval of Auvelity “has the potential to play an important role in patient care for this challenging and impactful symptom of Alzheimer’s disease.”
Application to FDA based on data from a battery of clinical trials
Axsome’s application seeking FDA approval of Auvelity for Alzheimer’s-related agitation was based on data from a battery of clinical trials. These included four Phase 3 studies called ACCORD (NCT04797715), ACCORD-2 (NCT04947553), ADVANCE-1 (NCT03226522), and ADVANCE-2 (NCT05557409), as well as an extension study (NCT06736509) that monitored long-term outcomes.
In the ACCORD and ACCORD-2 studies, all participants were initially treated with Auvelity. Those who experienced a substantial reduction in agitation — as measured with a standardized test called the Cohen-Mansfield Agitation Inventory (CMAI) — were then randomly assigned to continue the therapy or switch to a placebo. In both studies, patients who switched to a placebo were more likely to experience recurring agitation than those who kept taking the active therapy.
“Auvelity is the only FDA-approved product to result in a statistically significantly longer time to relapse of agitation symptoms, compared to placebo, in a long-term study,” George Grossberg, MD, a professor at the Saint Louis University School of Medicine, noted in the Axsome press release.
The ADVANCE-1 and ADVANCE-2 studies, meanwhile, tested Auvelity directly against a placebo in patients with Alzheimer’s-related agitation. In the smaller ADVANCE-1 study, Auvelity significantly outperformed a placebo at reducing agitation as measured by CMAI scores. In the larger ADVANCE-2 study, patients given Auvelity also tended to report reductions in agitation compared with those given a placebo, but the difference did not reach statistical significance, meaning the probability that this difference is due to random chance is non-negligible.
Importantly, Auvelity showed a compelling safety and tolerability profile, with rates of discontinuation due to adverse events that were low and matched those of placebo.
According to the newly approved therapy’s prescribing information, the most common side effects of Auvelity in Alzheimer’s patients are dyspepsia (indigestion) and dizziness. As with many medications approved to treat depression, the prescribing information also includes a black box warning — the FDA’s most stringent safety warning — noting that use of antidepressants can increase the risk of suicidal behaviors in young people.
“Importantly, Auvelity showed a compelling safety and tolerability profile, with rates of discontinuation due to adverse events that were low and matched those of placebo. The approval of Auvelity is a significant advancement that provides patients and their caregivers with a much-needed treatment option for this debilitating condition,” Grossberg said.
In an email sent to Alzheimer’s News Today, Frank Longo, MD, PhD, a professor of neurology at Stanford University, said that the FDA’s approval of Auvelity for Alzheimer’s agitation “highlights the advances being made in addressing the day-to-day realities of the disease.”
“For patients and caregivers, any progress in Alzheimer’s treatment is meaningful. This milestone … reflects the growing momentum in innovative treatments for neurodegenerative diseases and further underscores the continued need for disease-modifying therapies,” added Longo, who is co-founder of Pharmatrophix, a company working to develop new Alzheimer’s treatments.
