The safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of BMS-708163 in young and elderly Japanese 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. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses (SAD) and multiple ascending doses (MAD) of BMS-708163 in healthy young and elderly Japanese subjects in 2 randomized, double-blind, placebo-controlled studies. SAD: Healthy young Japanese men (n = 24) were randomized to single doses of BMS-708163 50, 100, or 200 mg, or placebo (sequential panels); MAD: Young Japanese men (n = 16) and elderly Japanese healthy volunteers (n = 16) were randomized to BMS-708163 50 or 100 mg or placebo for 14 days. SAD: There were no gastrointestinal tract-related adverse events (AEs) or clinically significant abnormalities in vital signs, electrocardiograms, clinical laboratory tests, fecal occult blood tests, stool frequency and consistency evaluations, urinary and salivary cortisol, thyroid function tests, or lymphocyte immunophenotyping. BMS-708163 was quickly absorbed (mean Tmax 1.0-1.3h); plasma profiles were biphasic; mean terminal T1/2 was ˜30h; plasma AUC was dose-proportional in the range 50-200 mg. BMS-708163 decreased plasma Aβ1-40 dose-dependently after dosing. MAD: The most common AE was positive fecal occult blood test (n = 7, all mild). BMS-708163 was quickly absorbed (median Tmax 1.0-1.5h); the exposure at 100 mg was 2- to 3-fold higher than that at 50 mg; mean terminal T1/2 was ˜32h (young) and ˜44-55h (elderly). BMS-708163 reduced plasma Aβ1-40 in a dose-dependent fashion. BMS-708163 was safe and well tolerated at single doses of up to 200 mg (young Japanese) and multiple doses up to 100 mg (young and elderly Japanese), with no evidence of Notch-related dose-limiting toxicities. In both studies, BMS-708163 demonstrated rapid absorption and dose-proportional exposure. T1/2 was longer in elderly patients vs. younger patients in the multiple-dose study. BMS-708163 produced dose-dependent marked decreases in plasma Aβ1-40 levels following single- and multiple-dose administration.