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.

• Authors: Holly D Soares, Maciej Gasior, Jeremy H Toyn, Jun-Sheng Wang, Quan Hong, Flora Berisha, Michael T Furlong, Joseph Raybon, Kimberley A Lentz, Francis Sweeney, Naiyu Zheng, Billy Akinsanya, Robert M Berman, Lorin A Thompson, Richard E Olson, John Morrison, Dieter M Drexler, John E Macor, Charlie F Albright, Michael K Ahlijanian, Malaz AbuTarif
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 358 Issue 1 Pg. 138-50 (Jul 2016) ISSN: 1521-0103 [Electronic] United States
• PMID: 27189973 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2016 The Author(s).

Chemical References

• 7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta(d)pyrimidine-2,4-diamine
• Amyloid beta-Peptides
• Aniline Compounds
• Anti-Inflammatory Agents, Non-Steroidal
• Pyrimidines
• Amyloid Precursor Protein Secretases

Topics

• Adolescent
• Adult
• Alzheimer Disease (drug therapy, enzymology)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (blood, cerebrospinal fluid)
• Aniline Compounds (adverse effects, chemistry, pharmacokinetics, pharmacology)
• Anti-Inflammatory Agents, Non-Steroidal (adverse effects, chemistry, pharmacokinetics, pharmacology)
• Area Under Curve
• Chromatography, Liquid
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Healthy Volunteers
• Humans
• Limit of Detection
• Male
• Mass Spectrometry
• Middle Aged
• Pyrimidines (adverse effects, chemistry, pharmacokinetics, pharmacology)
• Young Adult