Verubecestat linked to worse outcomes among patients with prodromal Alzheimer’s Disease compared to placebo
1. Verubecestat, an orally administered beta amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor , did not slow or prevent the progression of dementia among patients with prodromal Alzheimer’s disease.
2. Adverse events were more often noted in the verubecestat groups compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Prodromal Alzheimer’s disease is associated with increased deposition of amyloid beta plaques throughout the brain, and it is widely believed that accumulation of amyloid beta plaques a central role in the pathophysiology of Alzheimer’s disease. These plaques are produced when amyloid precursor proteins (APP) are cleaved by beta-site APP cleaving enzyme 1 (BACE-1). Verubecestat, a BACE-1 inhibitor, has been theorized as a medical agent that could slow or prevent the progression of prodromal Alzheimer’s disease by inhibiting the accumulation of amyloid-beta plaques. In this current analysis, researchers studied the efficacy of varying doses of verubecestat versus placebo on changes in cognitive function among patients with prodromal Alzheimer’s disease before they showed signs of cognitive decline. The study was stopped early by safety monitoring committees before the trial was scheduled to end. Preliminary analyses suggested that higher doses of verubecestat did not slow cognitive decline and may have accelerated dementia and Alzheimer’s-related cognitive symptoms among the study population as compared to placebo. Interestingly, in a PET sub-study, the verubecestat group did seem to have decreased beta amyloid burden. These findings present novel insights that should inform future research into therapeutic agents for Alzheimer’s disease.
Click to read the study in NEJM
Click to read an accompanying editorial in NEJM
Relevant Reading: Preliminary Results of a Trial of Atabecestat in Preclinical Alzheimer’s Disease
In-Depth [randomized control trial]: This randomized, double-blind, placebo-controlled trial enrolled 1454 participants from 238 centers across 22 countries from 2013 to 2018. Patients were randomized in a 1:1:1 ratio to receive oral verubecestat (either at 12mg or 40mg) or placebo dosed once daily. Patients were followed from baseline until 104 weeks post-randomization. The primary outcome of this study was the change in the Clinical Dementia Rating Scale-Sum of Boxes score (CDR-SB) from baseline until 104 weeks post-randomization. Higher scores on this scale indicate worsening cognitive function. Secondary outcomes included safety assessments and changes in hippocampal volume. This study ended early in 2018 due to recommendations from the safety monitoring committee and at this time, data was available for 234 patients in the 12mg verubecestat group, 231 patients in the 40mg verubecestat group and 239 in the placebo group. Overall, it was noted that the estimated change in CDR-SB scores from baseline was 1.65 in the 12mg group, 2.02 in the 40mg group and 1.58 in the placebo group (p=0.67 between the 12mg and placebo group; p=0.01 between the 40mg and placebo group). Estimated rate or progression to Alzheimer’s dementia was 24.5 events per 100 patient-years in the 12mg group, 25.5 events per 100 patient-years in the 40mg group and 19.3 events per 100 patient-years in the placebo group (HR 1.38 for 40mg versus placebo; 97.5% CI: 1.07 to 1.79). Hippocampal volume decreased by 6.1% in the placebo group versus 6.5-6.7% in the verubecestat groups. Adverse events were reported more often in the verubecestat group as compared to placebo and included side effects such as rash, sleep disturbances, weight loss and cough.
