title: BIIB042, a novel γ-secretase modulator, reduces amyloidogenic Aβ isoforms in primates and rodents and plaque pathology in a mouse model of Alzheimer's disease.
abstract: Reducing the production of larger aggregation-prone amyloid β-peptides (Aβ) remains an untested therapeutic approach for reducing the appearance and growth of Aβ plaques in the brain, which are a hallmark pathological feature of Alzheimer's disease. γ-Secretase modulators (GSMs) are therapeutics that impact γ-secretase-dependent cleavage of amyloid precursor protein to promote the production of shorter Aβ peptides that are less prone to aggregation and plaque deposition. This is accomplished without inhibiting overall γ-secretase function and cleavage of other substrates, which is believed to be a source of deleterious side effects. Here, we report the pharmacokinetic and pharmacodynamic properties of BIIB042, a novel bioavailable and brain-penetrant GSM. In cell-based assays, BIIB042 reduced the levels of Aβ42, increased the levels of Aβ38 and had little effect on the levels of Aβ40, the most abundant Aβ species. Similar pharmacodynamic properties were confirmed in the central nervous system and in plasma of mice and rats, and also in plasma of cynomolgus monkeys after a single oral dose of BIIB042. BIIB042 reduced Aβ42 levels and Aβ plaque burden in Tg2576 mice, which overexpress human amyloid precursor protein and serve as a model system for Alzheimer's disease. BIIB042 did not inhibit cleavage of other γ-secretase substrates in cell-based and in vivo signaling and cleavage assays. The pharmacodynamic effects of lowering Aβ42 in the central nervous system coupled with demonstrated efficacy in reducing plaque pathology suggests modulation of γ-secretase, with molecules like BIIB042, is a compelling therapeutic approach for the treatment of Alzheimer's disease.
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA. Electronic address: robert.scannevin@biogen.com.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Chollate
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Brennan
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Snodgrass-Belt
authors.affiliation: Medicinal Chemistry, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Hairuo
authors.initials: H
authors.lastname: Peng
authors.affiliation: Drug Metabolism and Pharmacokinetics, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Jung
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bussiere
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Mahin F
authors.initials: MF
authors.lastname: Arastu
authors.affiliation: Medicinal Chemistry, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Talreja
authors.affiliation: Medicinal Chemistry, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xin
authors.affiliation: Pathology, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Dunstan
authors.affiliation: Pathology, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Fahrer
authors.affiliation: Drug Metabolism and Pharmacokinetics, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Rohde
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Anthone W
authors.initials: AW
authors.lastname: Dunah
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medicinal Chemistry, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Gnanasambandam
authors.initials: G
authors.lastname: Kumaravel
authors.affiliation: Medicinal Chemistry, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Taveras
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: H
authors.initials: H
authors.lastname: Moore Arnold
authors.affiliation: Neurology Research, Biogen Inc., Cambridge, MA 02142, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rhodes
mesh_terms: D000447:Aldehydes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D058225:Plaque, Amyloid / Q000378:metabolism; D020033:Protein Isoforms / Q000097:blood; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000447:Aldehydes; D016229:Amyloid beta-Peptides; C572522:BIIB042; D020033:Protein Isoforms; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; Amyloid precursor protein; Amyloid β; γ-Secretase; γ-Secretase modulator