The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients.
β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.
Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ 07033, USA. matthew.kennedy@merck.com andy.stamford1@gmail.com ericmcparker@comcast.net mark.forman@merck.com.
Matthew E
ME
Kennedy
Department of Global Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA. matthew.kennedy@merck.com andy.stamford1@gmail.com ericmcparker@comcast.net mark.forman@merck.com.
Andrew W
AW
Stamford
Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Xia
X
Chen
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Kathleen
K
Cox
Department of Global Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Jared N
JN
Cumming
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Marissa F
MF
Dockendorf
Department of Clinical Research, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Michael
M
Egan
PAREXEL, Glendale, CA 91206, USA.
Larry
L
Ereshefsky
Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Robert A
RA
Hodgson
Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Lynn A
LA
Hyde
PAREXEL, Glendale, CA 91206, USA.
Stanford
S
Jhee
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Huub J
HJ
Kleijn
Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Reshma
R
Kuvelkar
Department of Global Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Wei
W
Li
Department of Safety Assessment, Merck Research Laboratories, West Point, PA 19446, USA.
Britta A
BA
Mattson
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Hong
H
Mei
Department of Biostatistics, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
John
J
Palcza
Department of Global Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Jack D
JD
Scott
Translational Biomarkers Department, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Michael
M
Tanen
Department of Translational Medicine, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Matthew D
MD
Troyer
Department of Translational Medicine, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Jack L
JL
Tseng
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Julie A
JA
Stone
Department of Neuroscience, Merck Research Laboratories, Kenilworth, NJ 07033, USA. matthew.kennedy@merck.com andy.stamford1@gmail.com ericmcparker@comcast.net mark.forman@merck.com.
Eric M
EM
Parker
Department of Translational Medicine, Merck Research Laboratories, Kenilworth, NJ 07033, USA. matthew.kennedy@merck.com andy.stamford1@gmail.com ericmcparker@comcast.net mark.forman@merck.com.
Mark S
MS
Forman
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D020134:Catalytic Domain; D002490:Central Nervous System / Q000378:metabolism*; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D005947:Glucose / Q000378:metabolism; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009186:Myelin Sheath / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011817:Rabbits; D051381:Rats; D013829:Thiadiazines / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D003499:Cyclic S-Oxides; D010455:Peptides; D013829:Thiadiazines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C509281:Bace1 protein, rat; D005947:Glucose; C000613570:verubecestat