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

The pharmacokinetic, pharmacodynamic, safety and tolerability of BMS-932481, a gamma secretase modulator (GSM), was tested in healthy young and elderly volunteers following single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality following a single dose administration and approximately 3 fold accumulation following multiple dosing. High fat/caloric meals doubled Cmax and AUC and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased CSF Aβ39, Aβ40 and Aβ42 while increasing Aβ37 and Aβ38 thereby providing evidence of gamma secretase enzyme modulation rather than inhibition. In plasma, reductions in Aβ40 and Aβ42 were observed with no change in total Aβ while 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. While further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of Aβ lowering in Alzheimer9s disease (AD), 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 AD and other indications.