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APABETALONE BET-INHIBITION AND COGNITION: A MOCA ASSESSMENT IN THE PHASE 3 CVD-OUTCOMES TRIAL BETONMACE
Abstract
Aims
Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that control gene expression. They may contribute to cognitive decline including Alzheimer’s disease (AD) and vascular dementia (VaD). Our objective was to assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized clinical trial of post-acute coronary syndrome patients with diabetes which lowered ischemic CVD events 18% (p=0.11).
Methods
MoCA (Montreal Cognitive Assessment) was performed on patients 70 years or older. In a prespecified analysis, participants were assigned to one of three groups: MoCA score ≥ 26 (normal performance), MoCA score 25 – 22 (mild cognitive impairment), and MoCA score ≤ 21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group.
Results
464 participants were randomized to apabetalone or placebo in the cognition sub-study. Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of ≤ 21 (p=0.02) mostly contributed by the abstraction and recall domains, both of which saw greater improvements in the apabetalone treated participants compared to those on placebo (both p≤0.1). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% vs 7.9%).
Conclusions
Apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.