Pharmacokinetic and Pharmacodynamic Effects of a γ‐Secretase Modulator, PF‐06648671, on CSF Amyloid‐β Peptides in Randomized Phase I Studies

Abstract

γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-β (Aβ) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects of PF-06648671 on multiple Aβ species in cerebrospinal fluid (CSF). Healthy subjects (n = 120) received single doses or multiple-ascending doses of PF-06648671/placebo for 14 days. No serious adverse events occurred; severe adverse events were deemed not drug related. PF-06648671 decreased Aβ42 and Aβ40 concentrations in CSF, with greater effects on Aβ42, and increased Aβ37 and Aβ38 levels, particularly Aβ37. No significant change in total Aβ was observed. The PK/PD model well described the tendency of observed CSF Aβ data and the steady-state effects of PF-06648671, supporting its use for predicting central Aβ effects and optimal dose selection for GSMs in future trials.Dementia is a progressive, neurodegenerative disorder affecting ~ 50 million people worldwide, 1 of which Alzheimer's disease (AD) is most common. 1 Treatments including cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists help with AD symptoms. 2 However, a medical need exists for agents capable of modifying and slowing AD progression. AD pathology in the brain is characterized by senile, amyloid plaques comprising a core of amyloid-β (Aβ) peptide fibrils, 3,4 and neurofibrillary tangles of primarily hyperphosphorylated tau protein. 4,5 Amyloid precursor protein (APP) is a transmembrane protein that is cleaved during processing by γ-secretase to generate Aβ peptides of various lengths, including Aβ37,38,40, and 42. 6,7 Aβ42 has a higher aggregation

Turning the tide on Alzheimer’s disease: modulation of γ-secretase

“…6 ). A study from Pfizer investigated PF-06648671, derived from bicyclic pyridinones, in three phase I trials [ 70 ]. In 14 day single-dose and multiple-ascending daily doses in healthy normal subjects, the oral GSM was well tolerated.…”

Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention

“…R-flurbiprofen has weak in vitro GSM activity and, although safe, did not show efficacy in phase 3 human trials ( Green et al, 2009 ). More recent discovery efforts have yielded several newer GSMs that were tested in early-phase clinical trials, primarily single ascending dose (SAD) and multiple ascending dose (MAD) phase 1 studies, and yet none of these has moved beyond these primary safety evaluations ( Ahn et al, 2020 ; Kounnas et al, 2019 ; Soares et al, 2016 ; Toyn et al, 2016 ; Yu et al, 2014 ). Lack of clinical development of prior GSM drug candidates could be due to the lack of establishing a suitable therapeutic index for dosing regimens able to substantially lower CSF Aβ42 levels without eliciting significant adverse effects.…”

“…Another MAD study involved the GSM NGP555, which showed a trend toward increasing ratios of Aβ37/Aβ42 and Aβ38/Aβ42 in CSF at doses of 200 mg and 400 mg, but without demonstrating statistical significance ( Kounnas et al, 2019 ). The most recently published clinical studies involved both SAD and MAD regimens with the GSM PF-06648671 ( Ahn et al, 2020 ). Study designs differed between SAD and MAD stages.…”

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects

“…Due to the limited amount of CSF A␤ data collected (only at baseline and a single trough measurement at steady state), the parameters for CSF A␤ turnover rates were fixed to 0.084/h for A␤ 1-40 and 0.12/h for A␤ 1-42 , which were estimated in a separate, PK/PD study with serial CSF collections [25]. Due to the similarity in study populations, it was assumed that A␤ dynamics in the PK/PD model described here would be the same as those from the separate PK/PD study [25]. The estimated exposure-response relationship was specific to PF-06751979, based on the current multiple-dose data.…”