A placebo-controlled, ascending, multiple-dose study to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-708163 in healthy young and elderly subjects

BMS-708163, in Phase II development for Alzheimer's Disease, selectively inhibits Aβ synthesis relative to Notch, and is a potent and orally active γ-secretase inhibitor. This placebo-controlled, randomized, double-blind, ascending dose study assessed the safety/tolerability and PK/PD of multiple-dose administration in healthy young and elderly subjects. Four groups (n = 8 each) of young healthy men (18-45 years) were assigned to sequential dose panels (15 mg, 50 mg, 100 mg, 150 mg) to receive BMS-708163 (n = 6) or placebo (n = 2) for 28 days. Elderly (> = 60 years) men and women (n = 8 each) received BMS-708163 50 mg daily for 2 weeks then 100 mg daily for 2 weeks. 45/50 randomized subjects completed. Three subjects discontinued due to AEs (motor vehicle accident; fever; CK and liver enzymes increased). Two SAEs (unrelated to study drug) occurred in 2 young subjects. Most AEs were mild or moderate in severity. The most frequent AEs were constipation, oropharyngeal pain, procedural pain, headache, back pain, and abnormal dreams. There was no evidence of cortisol response suppression and no dose-related effects on renal function, liver function, immunophenotyping, white blood cell, and differential counts. Adaptive changes of thyroid function were observed in the 150-mg panel. Exposures increased in proportion to dose. Tmax occurred 1-4h after dosing; mean terminal half-life was 38-65h. Steady-state was achieved approximately by Day 10; accumulation index at steady-state was ∼2-3 for AUCtau and Cmax. Cmax was up to 25% higher in elderly vs young subjects. Cmax was 40% higher in elderly females vs elderly males. No differences in AUC were observed between young and elderly subjects. At doses > = 50 mg qd, BMS-708163 reduced steady-state trough plasma and CSF Aβ1-38, Aβ1-40, and Aβ1-42 in a dose-dependent fashion, with plasma Aβ below baseline for at least 24h and CSF Aβ to 40% of baseline. Multiple-dose administration of BMS-708163 15-150 mg was safe and well-tolerated. Maximal tolerated dose was not achieved. There were no signs of Notch-related dose-limiting toxicities nor overall exposure differences between age groups, although elderly subjects demonstrated higher maximum concentrations. Doses > = 50 mg qd resulted in dose-dependent decreases in CSF Aβ concentrations.