Alzheimer’s disease (AD) agitation occurs in up to 70% of AD patients and is characterized by emotional distress, aggressive behaviors, disruptive irritability and disinhibition.¹ AD agitation is not only associated with decreased functioning and accelerated cognitive decline, but also with increased caregiver burden, earlier nursing home placement, and increased mortality.¹ Although non-pharmacological therapies are recommended as first-line therapy for AD agitation, they are not always effective.¹

AXS-05 is a novel pharmacological oral treatment that combines dextromethorphan and bupropion, and has been approved by the US Food and Drug Administration to treat major depressive disorder.¹ Dextromethorphan (DM) acts as a N-methyl-D-aspartate (NMDA) receptor antagonist and a sigma-1 receptor agonist, which may further modulate glutamate and monoamine signaling, whereas bupropion (BUP) is a CYP2D6 inhibitor that can increase and prolong plasma concentrations of dextromethorphan.¹ In the earlier ADVANCE-1 phase 2/3 study, AXS-05 was shown to rapidly and substantially improve agitation in AD patients compared to placebo as measured by the Cohen-Mansfield Agitation Inventory (CMAI) total score.¹ The results of the ACCORD study (Assessing Clinical Outcomes in Alzheimer’s Disease Agitation), which aims to evaluate the efficacy and safety of AXS-05 in the treatment of AD agitation, were presented during the AAN 2024 Annual Meeting by Dr. Anton Porsteinsson from the University of Rochester School of Medicine and Dentistry, New York, United States.¹

The ACCORD study was a phase 3, randomized withdrawal study consisting of an open-label period, followed by a double-blind, placebo-controlled period.¹ Older adults aged 65-90 years with probable AD (according to the 2011 National Institute on Aging and Alzheimer’s Association criteria) and clinically significant agitation (according to the International Psychogeriatric provisional definition) were enrolled.¹ Participants must have a Mini-Mental State Examination (MMSE) score of 10-24 and caregiver participation, and were excluded if they had predominantly non-AD dementia, agitation symptoms not secondary to AD, or concurrent medical conditions that may interfere with the study.¹

In total, 178 participants were enrolled in the study with a mean age of 74.9 years and a mean baseline CMAI total score of 70.9 (SD=22.3).¹ During the open-label phase of the trial, all patients received AXS-05 (45mg DM/105mg BUP) twice daily for up to 9 weeks or until sustained clinical response, defined as a ≥30% improvement in CMAI total score from baseline and improvement on the Patient's Global Impression of Change (PGI-C, score ≤3) which were both maintained for ≥4 consecutive weeks.¹ Sustained clinical responders (n=108) were then randomized 1:1 to receive AXS-05 (n=53) or placebo (n=55) for up to 26 weeks or until agitation relapse, defined as ≥10 point worsening in the CMAI total score from randomization or a score greater than that at study entry, or hospitalization or other institutionalization due to AD agitation.¹ The primary endpoint was the time from randomization to relapse of agitation, while the key secondary endpoint was the percentage of participants who relapsed.¹ At entry into the double-blind period, the mean CMAI total score for the AXS-05 group was 43.7 (SD=10.2) and 44.9 (SD=10.9) for the placebo group, which were reduced compared to the baseline score before the open-label period.¹

The results from the open-label phase of the trial showed a statistically significant improvement in CMAI total score at all time points starting at week 1 compared to baseline with AXS-05 treatment (p<0.001).¹ A clinical response (≥30% reduction in CMAI score) was observed in nearly 80% of participants by week 6.¹ During the double-blind period, AXS-05 was found to substantially and statistically increase the time to relapse of agitation symptoms (primary endpoint) compared with placebo (HR=0.275; 95% CI: 0.091 to 0.836; p=0.014), translating to a 3.6-fold lower risk of relapse with AXS-05 compared with placebo.¹ AXS-05 also significantly prevented relapse (key secondary endpoint) compared with placebo (7.5% vs. 25.9% of participants; p=0.018).¹

AXS-05 was found to be generally safe and well-tolerated, with low discontinuation rates in the double-blind period due to adverse events (0% for AXS-05, 1.9% for placebo).¹ All serious adverse events reported were also not related to study medication and there was no evidence of cognitive decline or sedation associated with AXS-05.¹

In conclusion, the ACCORD trial showed that treatment with AXS-05 during the open-label period led to rapid and clinically meaningful improvements in AD agitation, as well as significant prevention and delay in time to relapse of AD agitation compared to placebo during the double-blind period.¹ The positive efficacy and favorable safety results with AXS-05 support its potential to fulfill a high unmet need in the treatment of AD agitation.¹