PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) EFFECTS OF PF-06648671, A NOVEL GAMMA SECRETASE MODULATOR (GSM), FOLLOWING SINGLE AND MULTIPLE DOSE ADMINISTRATION IN HEALTHY VOLUNTEERS

Abstract

Unlike gamma secretase inhibitors, GSMs shift the cleavage of amyloid-β (Aβ) peptides in favor of shorter forms without inhibiting overall Aβ precursor protein processing, thus preferentially lower the production of longer, amyloidogenic forms. This study aimed to characterize PF-06648671 plasma exposure and cerebrospinal fluid (CSF) Aβ (Aβx-42, Aβx-40, Aβx-38 and Aβx-37) response relationship in healthy subjects. Clinical data were obtained from three Phase 1 studies: first-in-human single ascending dose (PK), single dose CSF biomarker (PK/PD; 150, 300 mg, and placebo), and multiple dose (PK/PD; 40, 100, 200, 360 mg and placebo) studies. Drifts in baseline (a rising tendency) were observed in placebo subjects after serial CSF sampling over 36 hours, which was taken into account in the model. Indirect response model was applied in a way that PF-06648671 plasma concentrations change the production rate of CSF Aβ peptides (decreased Aβ42 and Aβ40; increased Aβ37 and Aβ38). Population PK/PD modeling was performed using NONMEM 7.3. The inhibitory effect on CSF Aβ42 was greater than on Aβ40, whereas the stimulatory effect on Aβ37 was greater than on Aβ38. Preliminary results suggested CSF Aβ42 reductions after 100 and 350 mg q.d. administrations at steady state are approximately 50% and 66% on average, and about 200% and 400% increase in Aβ37, respectively. Indirect response model was developed to characterize exposure-dependent and differential effects of PF-06648671 on CSF Aβ's in healthy subjects. PK/PD relationship of PF-06648671 in human demonstrated a good translatability from preclinical model. The clinical PK/PD model has been used to predict the drug effect on individual Aβ peptides as well as the ratio of these Aβ peptides in CSF across a range of PF-06648671 doses. These results will guide dose selection in future Phase 2/3 trials.