P2‐375: Efficacy of the novel γ‐secretase inhibitor, PF‐3084014, in reducing Aβ in brain, CSF, and plasma in guinea pigs and Tg2576 mice

Abstract

Reducing levels of Aβ, the principal component of amyloid plaques, has been proposed as a disease-modifying approach for the treatment of Alzheimer's disease. Here we report the efficacy and exposure over time of PF-3084014, a novel potent γ-secretase inhibitor. PF-3084014 was dosed at 0.03–10 mg/kg subcutaneously in guinea pigs at multiple time points ranging from 0.75 to 30 hours. Aβ1-X was measured in brain, CSF, and plasma at each dose and time point, and PF-3084014 levels were measured in brain and plasma at selected time points. Dose-response relationships were observed in all compartments. At 10 mg/kg, Aβ levels were reduced by 70% in brain and plasma, and 50% in CSF, which was maintained at 30 hours post-dose. At all time points assessed, a linear relationship was observed between efficacy and exposure. PF-3084014 exhibited a brain-to-plasma ratio of approximately 1, and brain and plasma Aβ levels were reduced to a similar degree. Other γ-secretase inhibitors have been shown to strongly elevate plasma Aβ at low doses or in a rebound following a period of inhibition in guinea pigs; however, this pattern was not observed with PF-3084014. To further determine changes in specific Aβ isoforms, PF-3084014 was administered to young (plaque-free) Tg2576 mice. Brain, CSF, and plasma were harvested following PF-3084014 dosing at 1–18 mg/kg. In mice, a lower brain-to-plasma ratio correlated with greater Aβ reductions in plasma versus brain. Aβ1-X, Aβ1–40, and Aβ1–42 were reduced in a dose-responsive manner; at 18 mg/kg Aβ levels were reduced by 78% in brain, 72% in CSF, and 92% in plasma. As in guinea pigs, a linear efficacy-exposure relationship across doses was observed in mice. Aβ1–40 was most potently inhibited in all compartments, followed closely by Aβ1-X. Aβ1–42 showed approximately 20% less reduction than Aβ1–40 in all compartments, a feature shared by other published “nonselective” γ-secretase inhibitors. PF-3084014 effectively reduces Aβ levels in brain, plasma, and CSF, and exhibits a linear efficacy-exposure relationship across doses.