Dextromethorphan-bupropion (known as AXS-05) delayed time to relapse in patients with Alzheimer's-related agitation, according to a phase III trial presented here.
Compared with placebo, AXS-05 increased the time to relapse for agitation symptoms (HR 0.275, 95 % CI 0.091-0.836, P=0.014), with a 3.6-fold lower risk of relapse in patients with probable Alzheimer's and clinically significant agitation, according to Anton Porsteinsson, MD, of the University of Rochester School of Medicine and Dentistry in New York, and colleagues.
In addition, a smaller proportion of patients on AXS-05 had relapsed by 26 weeks compared with placebo (7.5% vs 25.9%, P=0.018), Porsteinsson told attendees at the American Academy of Neurology annual meeting here.
In an initial open-label period, nearly 80% of participants had a clinical response by week 6, defined by a ≥30% reduction in their Cohen-Mansfield Agitation Inventory (CMAI) score, where lower scores indicate less agitation.
"The positive efficacy and favorable safety results with AXS-05 support its potential to fulfill a high unmet need for the treatment of AD [Alzheimer's disease] agitation," Porsteinsson said during a plenary session.
Alzheimer's disease-related agitation is reported in up to 70% of those with the disease, characterized by emotional distress, disruptive irritability, reduced inhibitions, and aggressive behaviors, according to Porsteinsson's presentation. It can also negatively affect caregivers, accelerate cognitive decline, lead to earlier placement in nursing homes, and is associated with increased mortality.
Nonpharmacological therapies haven't always proven effective for agitation, the researchers noted, and the sometimes-controversial use of psychotropic medications for neuropsychiatric symptoms of dementia has been linked to adverse effects like death, stroke, and cognitive decline.
The double-blind, randomized withdrawal study included adults ages 65 to 90 with probable Alzheimer's disease according to 2011 National Institute of Aging-Alzheimer's Association (NIA-AA) criteria, clinically significant agitation according to the International Psychogeriatric Association (IPA) provisional definition, and a Mini-Mental State Examination (MMSE) score of 10-24.
Patients were excluded if they had predominantly non-Alzheimer's dementia, agitation symptoms not secondary to the disease, other medical conditions that could interfere with the study, or if AXS-05 was deemed inappropriate by an investigator.
A total of 178 participants were enrolled in the open-label phase, during which they received 45 mg dextromethorphan and 105 mg bupropion twice daily. Sustained clinical response was defined as a ≥30% improvement from baseline in CMAI score and a Patient Global Impression of Change (PGI-C) score improvement (3 or less, at least "minimally improved"), both maintained for 4 or more consecutive weeks.
After the open-label period of up to 9 weeks, 108 patients began a double-blind second phase randomized to either AXS-05 or placebo. The AXS-05 group received the same doses, and the period continued until agitation relapse. Relapse was defined as a ≥10-point worsening in CMAI score from randomization, or a score greater than at study entry (higher scores mean worsening agitation symptoms); or institutionalization, including hospitalization, due to Alzheimer's.
The treatment was well-tolerated, safety data suggested, with 0% discontinuation due to adverse events with AXS-05 versus 1.9% for the placebo group. Three serious adverse events (fecaloma in the study group, cardiac arrest and femur fracture in the placebo group) were reported; there was one death in the placebo group.
Notably, there was no evidence of cognitive decline, and no association with sedation for patients on AXS-05 -- both of which are concerns with the use of psychotropic medications for symptoms of dementia.
Raya Elfadel Kheirbek, MD, MPH, of the University of Maryland School of Medicine in Baltimore, who was not involved in the current study, said it "makes AXS-05 a preferable option for older adults, aiming to preserve cognitive function."
The delayed relapse time "suggests an advantage over traditional antipsychotics, which may require dose adjustments to maintain efficacy," Kheirbek wrote in an email to MedPage Today.
"AXS-05's dual mechanism as an NMDA [N-methyl D-aspartate] receptor antagonist and sigma-1 receptor agonist offers a unique approach to modulating brain activity," she added, "potentially benefiting patients through multiple pathways, unlike traditional treatments that mainly target dopamine receptors."
The FDA approved AXS-05 under the name Auvelity in 2022 for adults with major depressive disorder.
When considering AXS-05 as a treatment alternative in Alzheimer's populations, Kheirbek noted, healthcare professionals "should also note the study's short duration, its focus on initial responders, and the lack of direct comparisons with other antipsychotics."
"These factors should guide clinical decisions regarding the broader application of AXS-05 in diverse Alzheimer's populations," she wrote.
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