Double-Blind, Controlled Phase II Study of a 5-HT6 Receptor Antagonist, SB-742457, in Alzheimers Disease

Title: Double-Blind, Controlled Phase II Study of a 5-HT6 Receptor Antagonist, SB-742457, in Alzheimers Disease

Volume: 7 Issue: 5

Author(s): G. Maher-Edwards, M. Zvartau-Hind, A.J. Hunter, M. Gold, G. Hopton, G. Jacobs, M. Davy and P. Williams

Affiliation:

Keywords: SB-742457, Alzheimer's disease, serotonin, 5-HT6, cognition, global function

Abstract: Background: This randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of the 5-HT6 receptor antagonist, SB-742457, in subjects with mild-to-moderate probable Alzheimers disease (AD). Methods: Participating subjects had a Mini-Mental State Examination (MMSE) score of 12 to 26 after a 4-week, single-blind, placebo run-in phase, and were randomized (2:1:1:2) to receive placebo, SB-742457 5 mg, 15 mg, or 35 mg once daily for 24 weeks. Coprimary efficacy endpoints were the Clinicians Interview-Based Impression of Change with caregiver input (CIBIC+) score and change from baseline in Alzheimers Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score at Week 24, in the intent-to-treat (ITT) population. A model-based design provided 90% power to detect a linear trend in treatment response across increasing doses and ≥90% power to compare SB-742457 35 mg with placebo. Results: 371 subjects were randomized. In the ITT population (n=357), linear trend analysis at Week 24 suggested a dose response for CIBIC+ with a mean slope of -0.05 points/5-mg dose increase (95% confidence interval [CI]: -0.09, -0.01; p=0.016). The dose response slope for change from baseline in ADAS-Cog was -0.22 points/5-mg dose increase (95% CI: -0.45, 0.01; p=0.059). The adjusted mean treatment difference from placebo at Week 24 for SB-742457 35 mg (-0.31) was significant on CIBIC+ (95% CI: -0.62, -0.00; p=0.047) but non-significant on ADAS-Cog (-1.28 [95% CI: -2.96, 0.40]; p=0.135). Adverse events occurred in 24-37% in the SB-742457 groups vs 29% for placebo; 11-16% discontinued SB- 742457 vs 15% for placebo. Comments: SB-742457 was generally safe and well tolerated and may be efficacious in AD.

Cite this article as:

Maher-Edwards G., Zvartau-Hind M., Hunter A.J., Gold M., Hopton G., Jacobs G., Davy M. and Williams P., Double-Blind, Controlled Phase II Study of a 5-HT6 Receptor Antagonist, SB-742457, in Alzheimers Disease, Current Alzheimer Research 2010; 7 (5) . https://dx.doi.org/10.2174/156720510791383831