O1‐05‐02: EFFICACY AND SAFETY OF THE ALPHA7 AGONIST ABT‐126 AS A MONOTHERAPY TREATMENT IN MILD‐TO‐MODERATE ALZHEIMER'S DEMENTIA: RESULTS OF A PHASE 2B TRIAL

Abstract

In a previous Phase 2a monotherapy study, administration of 25 mg ABT-126, a novel a 7 neuronal nicotinic receptor agonist, was associated with a small improvement in cognition in subjects with mild-to-moderate Alzheimer's dementia (AD). This Phase 2b study evaluated the effects of 25-75 mg dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. This randomized, double-blind, placebo- and active-controlled, multinational study targeted enrollment of 410 subjects with mild-to-moderate AD (Mini-Mental Status Examination [MMSE] score of 10-24, inclusive). Subjects were randomized to ABT-126 (25mg [n=77], 50mg [n=108] or 75mg [n=73] QD), donepezil 10mg [n=76] QD, or placebo [n=104] for 24 weeks. The primary efficacy endpoint was the change from baseline to Week 24 in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. The primary endpoint was analyzed by mixed-effects model for repeated measures using factors of treatment, visit, treatment-by-visit interaction and site, with baseline and baseline-by-visit interaction as covariates. All P values shown are one-sided. Adverse events (AEs) were monitored, and sparse pharmacokinetic samples were collected. The study randomized 438 patients with mean (SD) age of 74.2 (7.9) years. The mean (SD) baseline MMSE was 18.9 (4.1) and was comparable across treatment groups. Sixty-nine (15.8%) subjects prematurely discontinued (no significant difference across treatment groups). Only donepezil showed statistically significant improvement from baseline versus placebo on the 11-item ADAS-Cog (LS mean [SE] difference from placebo: 25 mg: -0.47 [0.94], P =0.309; 50 mg: -0.87 [0.85], P =0.153, 75 mg: -1.08 [0.94], P =0.127, donepezil: -2.29 [0.95], P =0.008). ABT-126 plasma levels were consistent with predictions. AE and serious AE (SAE) rates were (placebo, 25 mg, 50 mg, 75 mg, donepezil): AE (54%, 55%, 58%, 52%, 63%), SAE (4.8%, 7.8%, 5.6%, 2.7%, 4.0%). AEs reported most frequently (≥3%) in all ABT-126 treated subjects are shown in Table 1. Donepezil improved ADAS-Cog scores over placebo by 2.29 points (P =0.008). The 75 mg dose of ABT-126 showed the biggest improvement over placebo on the ADAS-Cog, but the change of 1.08 points did not reach statistical significance (P =0.127). ABT-126 had an adequate safety profile in these mild-to-moderate Alzheimer's dementia patients.