The γ-Secretase Modulator, BMS-932481, Modulates Aβ Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers.

The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a gamma-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 C-max and area under the curve and prolonged T-max by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) A beta 39, A beta 40, and A beta 42 while increasing A beta 37 and A beta 38, thereby providing evidence of gamma-secretase enzyme modulation rather than inhibition. In plasma, reductions in A beta 40 and A beta 42 were observed with no change in total A beta; in CSF, modest decreases in total A beta were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70% CSF A beta 42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of A beta lowering in Alzheimer's disease, this study demonstrates that gamma-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.