Cross-species analysis of cerebrospinal fluid (CSF) beta-amyloid reductions by the BACE1 inhibitor PF-05297909 indicates species differences in PK/PD relationships: Relevance to clinical translation

PF-05297909 is a novel, brain-penetrable, small molecule inhibitor of BACE1, the enzyme involved in the formation of toxic species of amyloid-β (Aβ) in the brain. Since Aβ peptides can also be measured in the CSF in both animals and humans, changes in CSF Aβ represent mechanistically-relevant, translatable pharmacodynamic endpoints. In the present study, we have evaluated acute brain Aβ-lowering efficacy of PF-05297909 in rats, and compared the pharmacokinetic/pharmacodynamic (PK/PD) relationship for reduction of CSF Aβ across multiple species (rat, dog, non-human primate, human). PF-05297909 (cell based IC50=32 nM) or vehicle was administered acutely to rats, dogs and non-human primates at doses ranging up to 100 mg/kg. In separate cohorts of rats, brain and CSF were harvested at multiple time points post-dose for measurement of Aβ40, Aβ42 and total Aβ by ELISA. In dogs and non-human primates, serial CSF samples were collected over a 72-hour period via an indwelling cisterna magna cannula. Human PK/PD data was obtained, as described by Bell et al. (AAIC, 2013). The efficacy of PF-05297909 to decrease amyloidogenic peptides was demonstrated in rats, with maximum reductions of brain and CSF Aβ40 by 49% and 87%, respectively. Acute administration of PF-05297909 in dogs (25 mg/kg) and non-human primates (30 mg/kg), reduced CSF concentrations of all Aβ analytes measured, with reduction of Aβ40 by 25% and 62% at Tmax, compared to baseline levels. Exposure-response analysis revealed that the compound's potency to inhibit CSF Aβ40 varied about 5-fold between species, with IC50=97, 80 and 20 nM (expressed as unbound drug concentration) for non-human primate, rat and dog, respectively. Present studies demonstrate robust CSF Aβ reductions in multiple preclinical species following acute BACE1 inhibitor treatment. Cross-species comparison of the PK/PD relationships indicate that the dog is the most sensitive species in CSF Aβ modulation, however predictions based on dog PK/PD failed to translate to the clinic. Present results provide a greater understanding of how preclinical models of efficacy may be correlated to a clinical effect. These data also indicate that using dog as a preclinical model may overestimate the clinical Aβ-lowering efficacy of BACE1 inhibitors.