The safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of BMS-708163 in 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. We evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of BMS-708163 in young and elderly subjects in this randomized, double-blind, placebo-controlled, ascending-dose study. Healthy young men (n = 72) were randomized to single doses of BMS-708163 0.3-800 mg or placebo (sequential panels) and elderly men and women (n = 44) to BMS-708163 50 mg or placebo. 115 of 116 enrolled subjects completed the study. A maximal tolerated dose was not identified. One young male discontinued due to positive occult blood test (mild). Three serious adverse events (SAEs) occurred in 3 elderly subjects (all unrelated to study drug). Most adverse events (AEs) were mild to moderate in severity. Most common AEs were procedural pain, oropharyngeal pain, back pain, dizziness, headache, abnormal dreams, and rash. There were no dose-related effects on mean QTcF, change in QTcF, HPA, thyroid function, renal function, immunophenotyping, or liver function tests. There were no effects on WBC and differential except up to 35% increases of leukocytes in the 800-mg panel and up to 37% increases of lymphocytes in the 400-mg and 800-mg panels. There were no clinically significant effects on exploratory safety biomarkers (plasma TFF3, and whole blood HES1, DUSP6, BIRC3 mRNA gene expression). BMS-708163 was quickly absorbed (median Tmax, 1-2h); plasma profiles were biphasic; mean terminal T1/2 was ∼40h. Plasma AUC was dose proportional in the range 1.5-200 mg and was ∼60% (90% CI: 10% to 127%) higher in subjects > = 75 years of age. BMS-708163 was safe and well tolerated at single doses of up to 800 mg, with no evidence of Notch-related dose-limiting toxicities. BMS-708163 produced dose-dependent decreases in plasma Aβ1-40 levels. Single-dose pharmacokinetics were linear up to 200 mg, with no gender-related differences. Pharmacokinetics were similar across all age groups except for higher AUC in subjects aged > = 75 years.