TY - JOUR T1 - The <em>γ</em>-Secretase Modulator, BMS-932481, Modulates A<em>β</em> Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 138 LP - 150 DO - 10.1124/jpet.116.232256 VL - 358 IS - 1 AU - Holly D. Soares AU - Maciej Gasior AU - Jeremy H. Toyn AU - Jun-Sheng Wang AU - Quan Hong AU - Flora Berisha AU - Michael T. Furlong AU - Joseph Raybon AU - Kimberley A. Lentz AU - Francis Sweeney AU - Naiyu Zheng AU - Billy Akinsanya AU - Robert M. Berman AU - Lorin A. Thompson AU - Richard E. Olson AU - John Morrison AU - Dieter M. Drexler AU - John E. Macor AU - Charlie F. Albright AU - Michael K. Ahlijanian AU - Malaz AbuTarif Y1 - 2016/07/01 UR - http://jpet.aspetjournals.org/content/358/1/138.abstract N2 - The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a γ-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) Aβ39, Aβ40, and Aβ42 while increasing Aβ37 and Aβ38, thereby providing evidence of γ-secretase enzyme modulation rather than inhibition. In plasma, reductions in Aβ40 and Aβ42 were observed with no change in total Aβ; in CSF, modest decreases in total Aβ were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70% CSF Aβ42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of Aβ lowering in Alzheimer’s disease, this study demonstrates that γ-secretase modulation is achievable in healthy human volunteers and supports further efforts to discover well tolerated GSMs for testing in Alzheimer’s disease and other indications. ER -