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Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer’s disease


Maher-Edwards, G., Zvartau-Hind, M., Hunter, A. J., Gold, M., Hopton, G., Jacobs, G., Davy, M., Williams, P.


Current Alzheimer Research, Volume: 7, No.: 5, Pages.: 374-385

Year of Publication



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 Alzheimer’s 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 Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+) score and change from baseline in Alzheimer’s 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 > or =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.;


5ht6, aged, aged, 80 and over, alzheimer disease, antagonist, double-blind method, drug therapy, female, humans, male, middle aged, physiology, psychology, quinolines, receptor, receptors serotonin, serotonin antagonists, sulfones, therapeutic use

Countries of Study


Types of Dementia

Alzheimer’s Disease

Types of Study

Randomised Controlled Trial

Type of Outcomes


Type of Interventions

Pharmaceutical Interventions

Pharmaceutical Interventions