The γ-Secretase Modulator, BMS-932481, Modulates Aβ Peptides in the Plasma and Cerebrospinal Fluid of Healthy Volunteers

Abstract

The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a γ-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) Aβ39, Aβ40, and Aβ42 while increasing Aβ37 and Aβ38, thereby providing evidence of γ-secretase enzyme modulation rather than inhibition. In plasma, reductions in Aβ40 and Aβ42 were observed with no change in total Aβ; in CSF, modest decreases in total Aβ were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70% CSF Aβ42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of Aβ lowering in Alzheimer's disease, this study demonstrates that γ-secretase modulation is achievable in healthy human volunteers and supports further efforts to discover well tolerated GSMs for testing in Alzheimer's disease and other indications.

Fig. 1.

(A) Graphical representation of BMS-932481 structure. (B) Indirect-response modeling for brain Aβ lowering based on preclinical rat data. (C) Projected estimated doses with associated estimated brain Aβ42 lowering and exposures predicted from the model.

Fig. 2.

Relationship between dose and human pharmacokinetic parameters. (A) Log of C_max versus log dose on day 1 of the SAD study. (B) Log of AUC_0–∞ (AUCINF) versus log dose on day 1 of the SAD study. (C) C_max versus dose on day 14 of the MAD study. (D) AUC_τ (AUCtau) versus dose on day 14 of the MAD study.

Fig. 3.

Pharmacodynamic effects on CSF Aβ peptides after multiple-dose administration of BMS-932481 young healthy volunteers. Pharmacodynamics are expressed as percentage change from baseline. (A) Aβ37. (B) Aβ40. (C) Aβ42. (D) Aβ42/Aβ40 ratio. Values are means ± S.E.M. Analysis of covariance methods were applied to examine significance across groups (n = 6 per group for placebo and 50, 100, and 200 mg for 72 hours; n = 3 per group for 200 mg for 48 and 96 hours). *P < 0.05; **P < 0.01 (versus placebo). Postdose time was 28 days for the placebo and 50- and 100-mg groups. For 200 mg, postdose was 28 (or 24 days for those with emergent liver AEs) plus 48, 72, or 96 hours. (E) Exposure-response relationship of BMS-932481 (in nanograms per milliliter) versus CSF Aβ42% change baseline. (F) Percentage change baseline versus C_max exposure modeling based on MAD results. The shaded area represents 95% CIs. The dotted box highlights the exposure region associated with no liver toxicity and associated percentage changes in Aβ42.

Fig. 4.

BMS-932481 exposure versus plasma Aβ levels in the MAD study. (A) Time course of drug levels and plasma Aβ40 after daily dosing of 50-mg (n = 6 per group), 100-mg (n = 4), and 200-mg (n = 6 per group) doses (n = 6 per group for placebo). Data are presented as means ± S.E.M. (repeated-measures analysis of covariance). P < 0.0001 for decreases in plasma Aβ40 at day 14 all time points through day 28. (B) Correlation between BMS-932481 AUC_τ at steady state (day 14) versus percentage change of plasma Aβ40 on day 14.

Fig. 5.

BMS-932481 day 14 AUC_τ exposure versus maximum ALT relative to upper limit of normal (A), maximum AST (relative to ULN) (B), and maximal total bilirubin (relative to ULN) (C). AST, aspartate aminotransferase; ULN, upper limit of normal.