P4‐353: A PHASE 2 TRIAL OF THE EFFICACY AND SAFETY OF THE ALPHA7 AGONIST ABT‐126 AS AN ADD‐ON TREATMENT IN MILD‐TO‐MODERATE ALZHEIMER'S DEMENTIA

In a previous Phase 2a monotherapy study, ABT-126, a novel a 7 neuronal nicotinic receptor agonist, was associated with a small improvement in cognition in mild-to-moderate Alzheimer's dementia (AD) patients. The current study evaluated ABT-126 as an add-on treatment to donepezil or rivastigmine. This randomized, double-blind, placebo-controlled, multinational study targeted enrollment of 420 subjects with mild-to-moderate AD (Mini-Mental Status Examination [MMSE] score of 12-24, inclusive). Subjects receiving stable doses of donepezil or rivastigmine were randomized to ABT-126 (25mg or 75mg QD) or placebo 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. It was analyzed by mixed-effects model for repeated measures using factors of treatment, site, visit and treatment-by-visit interaction, with baseline score and baseline-by-visit interaction as covariates. All P values shown are one-sided. A prespecified subgroup analysis examined the effects of ABT-126 by baseline disease severity (MMSE 12-19 or 20-24). Adverse events (AEs) were monitored, and sparse pharmacokinetic samples were collected. The study randomized 434 patients with mean (SD) age of 75.1 (7.7) years and mean (SD) baseline MMSE of 18.9 (4.4) (no significant difference across treatment groups). Fifty-seven (13.1%) subjects prematurely discontinued (comparable across treatment groups). Neither dose of ABT-126 separated significantly from placebo on the 11-item ADAS-Cog (LS mean [SE] difference from placebo: 25 mg: -0.80 [0.59], P =0.087; 75 mg: -0.13 [0.59], P =0.416). In subjects with mild AD (MMSE 20-24), the treatment difference between 25 mg ABT-126 and placebo on the ADAS-Cog was more pronounced (1.44 point improvement over placebo at Week 24, P =0.022). ABT-126 plasma levels were consistent with predictions. Among treatment groups, AE and serious AE rates (SAE) were comparable (placebo, 25 mg, and 75 mg): AE (68%, 64%, 70%), SAE (8.9%, 6.3%, 6.9%). Common AEs are shown in Table 1. ABT-126 did not improve performance on the AD AS-Cog in subjects with mild-to-moderate AD, but in subjects with mild AD the 25 mg dose showed a small, statistically significant improvement versus placebo. ABT-126 had an adequate safety profile in these mild-to-moderate AD patients.

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