title: Pharmacodynamics of selective inhibition of γ-secretase by avagacestat.
abstract: A hallmark of Alzheimer's disease (AD) pathology is the accumulation of brain amyloid β-peptide (Aβ), generated by γ-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, γ-secretase inhibitors (GSIs) may lower brain Aβ and offer a potential new approach to treat AD. As γ-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Aβ and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Aβ levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Aβ40 and Aβ42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending-dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Aβ40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Aβ levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.
authors.affiliation: Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut 06492, USA. charlie.albright@bms.com
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
authors.forename: Randy C
authors.initials: RC
authors.lastname: Dockens
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.forename: Richard E
authors.initials: RE
authors.lastname: Olson
authors.forename: Randy
authors.initials: R
authors.lastname: Slemmon
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Lentz
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: R Rex
authors.initials: RR
authors.lastname: Denton
authors.forename: Gary
authors.initials: G
authors.lastname: Pilcher
authors.forename: Paul W
authors.initials: PW
authors.lastname: Rhyne
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Raybon
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Catherine
authors.initials: C
authors.lastname: Burton
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Toyn
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Craig
authors.initials: C
authors.lastname: Polson
authors.forename: Valerie
authors.initials: V
authors.lastname: Guss
authors.forename: Randy
authors.initials: R
authors.lastname: White
authors.forename: Frank
authors.initials: F
authors.lastname: Simutis
authors.forename: Thomas
authors.initials: T
authors.lastname: Sanderson
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gillman
authors.forename: John E
authors.initials: JE
authors.lastname: Starrett
authors.forename: Joanne
authors.initials: J
authors.lastname: Bronson
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Sverdlov
authors.forename: Shu-Pang
authors.initials: SP
authors.lastname: Huang
authors.forename: Lorna
authors.initials: L
authors.lastname: Castaneda
authors.forename: Howard
authors.initials: H
authors.lastname: Feldman
authors.forename: Vlad
authors.initials: V
authors.lastname: Coric
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: John
authors.initials: J
authors.lastname: Houston
authors.forename: Robert M
authors.initials: RM
authors.lastname: Berman
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
mesh_terms: D000293:Adolescent; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C554092:BMS 708163; D010069:Oxadiazoles; D051880:Receptors, Notch; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases