Efficacy and safety evaluation of HSD-1 inhibitor ABT-384 in Alzheimer's disease

Background: In this study we assessed increased cortisol in Alzheimer's disease (AD) patients. The selective 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor ABT-384 blocked regeneration of active cortisol and this tests the hypothesis that intracellular hypercortisolism contributes to cognitive impairment. Methods: In this double-blind, placebo- and active-controlled phase II study we examine the efficacy and safety of ABT-384 given 10 mg or 50 mg once daily, donepezil 10 mg once daily, or placebo for 12 weeks in subjects with mild-to-moderate AD. The primary efficacy end point was the change from baseline to final evaluation on the 13-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. Results: The study was terminated for futility after randomization of 267 subjects. ABT-384 did not improve ADAS-Cog scores or any secondary end point; however, donepezil significantly improved both cognition and functional end points. Overall incidence of adverse events was similar among treatment groups. Conclusion: ABT-384, when tested at doses associated with complete brain HSD-1 inhibition, did not produce symptomatic improvement in AD. (C) 2014 The Alzheimer's Association. All rights reserved.