P3‐418: Evaluation of the efficacy and safety of the HSD‐1 inhibitor ABT‐384 in mild‐to‐moderate Alzheimer's disease

Abstract

The 11-b-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor, ABT-384, was hypothesized to improve cognition in mild-to-moderate Alzheimer's disease (AD). ABT-384 daily doses from 2 mg fully inhibit HSD-1 activity in human brain. This randomized, double-blind, placebo- and active-controlled, multi-national Phase 2 study enrolled 267 mild-to-moderate AD subjects (Mini-Mental Status Examination [MMSE] score of 10 to 24). Alternate diagnoses of dementia were excluded. Subjects were randomized equally to receive ABT-384 10 mg or 50 mg QD, donepezil 10 mg QD, or placebo for 12 weeks. The primary efficacy endpoint was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score. Secondary outcomes included the 11-item ADAS-Cog, Clinician Interview-based Impression of Change-plus (CIBIC-Plus), and MMSE. Significance was assessed at level 0.05, one-sided. Interim efficacy evaluations employed protocol-specified futility criteria. Adverse events (AEs), vital signs, ECGs, and clinical laboratory tests were monitored. The study was terminated for futility. 162 subjects (60.7%) completed treatment, 38 (14.2%) discontinued, and 67 (25.1%) were discontinued upon study termination. Subjects had a mean (SD) age of 72.0 (8.50) years and baseline MMSE of 19.2 (3.79). Overall incidence of AEs was similar among treatment groups. Subjects receiving ABT-384 had a higher number of serious AEs (10 mg, n = 6, 8.6%; 50 mg, n = 1, 1.5%) than placebo (n = 0), but this was not dose related. No clinically-significant changes were seen in vital signs, ECGs, or clinical laboratory tests. Neither ABT-384 group showed improved 13-item ADAS-Cog scores compared with placebo (least squares mean change from baseline = -0.35 for ABT-384 10 mg [p = 0.72], and -0.51 for 50 mg [P = 0.67]) compared to placebo (-0.96). Donepezil significantly improved performance on the 13-item ADAS-Cog (LS mean change from baseline = -3.06, P = 0.02), indicating adequate study sensitivity. Unlike either ABT-384 dose, donepezil also significantly improved the 11-item ADAS-Cog, MMSE, and CIBIC-plus compared to placebo. Although safe, well tolerated, and tested at doses associated with full inhibition of brain HSD-1, ABT-384 did not produce symptomatic improvement in mild-to-moderate AD. There remains the possibility of testing the mechanism in earlier stages of the AD spectrum.