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

Jae Eun Ahn, Charles Carrieri, Fernando Dela Cruz, Terence Fullerton, Eva Hajos-Korcsok, Ping He, Constantino Kantaridis, Claire Leurent, Richann Liu, Jessica Mancuso, Laure Mendes da Costa, Ruolun Qiu, Jae Eun Ahn, Charles Carrieri, Fernando Dela Cruz, Terence Fullerton, Eva Hajos-Korcsok, Ping He, Constantino Kantaridis, Claire Leurent, Richann Liu, Jessica Mancuso, Laure Mendes da Costa, Ruolun Qiu

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 eventswere 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.

Conflict of interest statement

J.E.A., C.C., F.D.C., T.F., C.K., J.M., L.MdC., and R.Q. are employees of, and hold stock options for, Pfizer Inc. P.H., E.H.‐K., C.L., and R.L. were employees of, and held stock options for, Pfizer Inc at the time of the research.

© 2019 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
PK and PD plots from study B7991003 (serial CSF sampling biomarker study). (a) Plasma concentration of PF‐06648671 over time. (b–f) CSF concentration over time for (b) Aβ42, (c) Aβ40, (d) Aβ38, (e) Aβ37, and (f) total Aβ. Mean profiles are shown as bold lines, profiles from individual subjects are shown as thinner lines. Aβ, amyloid‐β; CSF, cerebrospinal fluid; PD, pharmacodynamic; PK, pharmacokinetic.
Figure 2
Figure 2
PK and PD plots from study B7991002 at days 0 and 14 (multiple‐ascending dose). (a) Plasma concentration of PF‐06648671 by dose. (b–f) CSF concentration by dose for (b) Aβ42, (c) Aβ40, (d) Aβ38, (e) Aβ37, and (f) total Aβ. Box plot shows median (bold horizontal line) as well as quartiles (25% and 75%), with whiskers to the last data point within 1.5 times the IQR. Black dots represent the outlier values (values outside 1.5 times the IQR above the 75% quartile and below the 25% quartile). Aβ, amyloid‐β; CSF, cerebrospinal fluid; IQR, interquartile range; PD, pharmacodynamic; PK, pharmacokinetic.
Figure 3
Figure 3
PK/PD model schematic. γ, sigmoidicity constant; Aβ, amyloid‐β; Conc, plasma concentration of drug; CSF, cerebrospinal fluid; EC 50, plasma concentration at half Emax; Emax, maximum response achievable; IC 50, plasma concentration at half Imax; Imax, maximum inhibition achievable; kin, zero‐order rate of Aβ production; kout, first‐order turnover constant of Aβ; PD, pharmacodynamic; PK, pharmacokinetic.
Figure 4
Figure 4
Visual predictive check for multiple‐dose data on day 14 of B7991002. (a) Aβ42. (b) Aβ40. (c) Aβ38. (d) Aβ37. Circles represent observed data; gray solid and dashed lines represent observed median and 90% percentiles; black lines represent the corresponding simulation percentiles. Baseline was not presented for better visualization of dose response. Aβ, amyloid‐β; CSF, cerebrospinal fluid.
Figure 5
Figure 5
Predicted average steady‐state effects of PF‐06648671 on CSF samples. (a) Aβ42 percent change from baseline. (b) Aβ40 percent change from baseline. (c) Aβ37 percent change from baseline. (d) Ratio of Aβ42:Aβ40. (e) Ratio of Aβ42:Aβ38.* (f) Ratio of Aβ42:Aβ37. Dotted line represents the median, with the shaded area representing the 95% CI. *95% CI for ratio of Aβ42:Aβ38 prediction was truncated due to missing values. Aβ, amyloid‐β; CI, confidence interval; CSF, cerebrospinal fluid.

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