O4–03–02: The gamma secretase inhibitor MK–0752 acutely and significantly reduces CSF Abeta40 concentrations in humans

The gamma secretase inhibitor MK–0752 is currently in Phase I trials for development as a disease–modifying agent for Alzheimer Disease (AD). The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK–0752 following single oral doses were investigated in healthy young men. Twenty–seven subjects were administered single doses of placebo or MK–0752 at doses ranging from 110 to 1000 mg at two study sites. CSF samples were obtained continuously via an indwelling catheter, from –3 to +12, +24, or +30 hours relative to dosing. At both sites, plasma PK and PD samples were collected for 96 hours postdose. The drug was generally well tolerated at single doses up to 1000 mg, and the pharmacokinetics were dose proportional with a half–life of ∼20 hours. Following single doses, MK–0752 concentrations in CSF were similar to estimated free concentrations in plasma, suggesting that there are no substantial barriers to MK–0752 penetration into the central nervous system; however a slight time shift was noted in the CSF concentration profile relative to the plasma concentration profile (∼2 hours later for CSF Tmax), consistent with relatively rapid, but not instantaneous, equilibration of drug between CSF and plasma. CSF Aβ40 declined over the period 4–12 hr postdose in 18 out of 19 subjects administered single doses of 300 mg. CSF Aβ40 was significantly reduced (p<0.001) at 12 hours after administration of single doses of MK–0752 500 mg. The mean reduction was 35% for those doses. This effect was sustained over 24 hours at the highest dose of 1000 mg. In contrast, the measurement of plasma Aβ40 showed a dose–dependent decrease followed by rebound, resulting at times in an increase over baseline levels. The CSF Aβ40 response appeared to lag behind the timecourse of both the plasma and CSF drug concentrations, suggesting that a PK/PD model analysis that incorporates a time delay in PD response will be needed to characterize this relationship fully. The gamma secretase inhibitor MK–0752 can acutely and significantly lower CSF Aβ40 concentrations in humans.