BMS-708163 (Avagacestat)

BMS-708163 is a potent selective and orally bioavailable inhibitor of γ-secretase with IC50 value of 0.3nM [1].

The cleavage of amyloid precusor protein APP by γ-secretase causes the production of Aβ40 and Aβ42, which are cytotoxic and cause AD. In vitro assay shows BMS-708163 inhibits the formation of Aβ40 and Aβ42 in H4-8Sw cells. It also inhibits the human recombinant CYPs in vitro with IC50 value of 20μM. Notch receptor is another substrate of γ-secretase. The inhibition of Notch signal pathway results in some side effects. It is shown that the activity of BMS-708163 to inhibit Notch is 190-fold weaker than to APP. In female rats, oral administration of BMS-708163 significantly reduces the production of Aβ in plasma and brain at 10mg/kg and 100mg/kg. In addition, BMS-708163 also reduces Aβ in brain and CSF in male beagle dogs [1].

References:
[1] Gillman KW, Starrett JE Jr, Parker MF, Xie K, Bronson JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA, Williams R, Meredith JE Jr, Burton CR, Barten DM, Toyn JH, Roberts SB, Lentz KA, Houston JG, Zaczek R, Albright CF, Decicco CP, Macor JE, Olson RE. Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor. ACS Med Chem Lett. 2010 Mar 22;1(3):120-4.

A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects.[Pubmed:23018531]

Clin Pharmacokinet. 2012 Oct 1;51(10):681-93.

BACKGROUND AND OBJECTIVES: Avagacestat is an orally active gamma-secretase inhibitor that selectively inhibits amyloid beta (Abeta) synthesis in cell culture and animal models. The objective of the current study was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of avagacestat over 28 days in healthy young men and elderly men and women in a placebo-controlled, sequential-panel, ascending multiple-dose study. METHODS: Thirty-three young men were assigned to four serial dose groups of avagacestat 15, 50, 100 or 150 mg (n = 6-7 per dose), or placebo (n = 2 per dose panel; 8 subjects total) once daily for 28 days. Elderly men and women were assigned to serial dose groups of avagacestat 50 mg and then 100 mg (n = 7 men, 6 women) or placebo (n = 2 men, 2 women) once daily for 14 days per dose level. RESULTS: Avagacestat was rapidly absorbed, had a terminal elimination half-life of 38-65 h, and reached a steady-state concentration by day 10 of daily dosing. Exposure in young subjects increased in proportion to dose. There were no apparent differences in steady-state area under the plasma concentration-time curve between young and elderly subjects; however, elderly subjects demonstrated a higher maximum plasma concentration for avagacestat. Doses of avagacestat >50 mg/day reduced steady-state trough concentrations of CSF Abeta(1-38), Abeta(1-40) and Abeta(1-42) in a dose-dependent fashion over 28 days of daily dosing. There were no signs of potential Notch-related dose-limiting toxicities. CONCLUSION: The results support continued evaluation of avagacestat in an elderly target population with predementia and mild to moderate Alzheimer's disease.

Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Abeta levels in healthy young men.[Pubmed:23018285]

Clin Drug Investig. 2012 Nov;32(11):761-9.

BACKGROUND: The concentration of amyloid beta (Abeta) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of gamma-secretase inhibition. Avagacestat is a selective gamma-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Abeta concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability. METHODS: This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses. RESULTS: 34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Abeta(1-38), Abeta(1-40) and Abeta(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups. CONCLUSION: Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Abeta concentrations, suggestive of gamma-secretase inhibition. The results warrant further clinical study in patients with AD.

Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral gamma-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers.[Pubmed:22381714]

Clin Ther. 2012 Mar;34(3):654-67.

BACKGROUND: gamma-Secretase inhibitors (GSIs) are being investigated for their potential to modify the progression of Alzheimer disease based on their ability to regulate amyloid-beta (Abeta) accumulation. BMS-708163 (Avagacestat) is an oral GSI designed for selective inhibition of Abeta synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Abeta synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class. Avagacestat produced up to 190-fold greater selectivity for Abeta synthesis than Notch processing in preclinical studies and may therefore produce less toxic adverse events than other less selective compounds. Presented here are the results of the first in-human study for this new GSI compound. OBJECTIVE: The goal of this study was to assess the tolerability profile, pharmacokinetic properties, and effects on pharmacodynamic markers (Abeta, trefoil factor family 3 protein, dual specificity phosphatase 6, and hairy and enhancer of split-1) of single, oral doses of avagacestat in healthy, young, male volunteers. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study in 8 healthy young men (age, 18-45 years) per dosing panel. Each study participant was randomized to receive a single dose of placebo (n = 2) or avagacestat (n = 6 for each dose) as an oral solution in 1 of 9 sequential dose panels (0.3, 1.5, 5, 15, 50, 100, 200, 400, and 800 mg). For determination of avagacestat, blood samples were obtained before dosing and for up to 144 hours after dosing. For participants in the 800-mg avagacestat dose panel, additional samples were obtained at 216, 312, and 648 hours. For 40-amino acid isoform of Abeta (Abeta(1-40)) assessment, plasma samples were collected before avagacestat administration and up to 72 hours after dosing. RESULTS: Avagacestat concentrations peaked quickly after oral administration and then had a biphasic decrease in concentrations with a prolonged terminal phase. Exposures were proportional with doses up to 200 mg. Avagacestat was well tolerated at single oral doses up to 800 mg, with a biphasic effect on plasma Abeta(1-40). Adverse events were predominately mild to moderate in severity with no evidence of dose dependence up to 200 mg. CONCLUSIONS: Results from this single-ascending dose study suggest that avagacestat was tolerated at a single-dose range of 0.3 to 800 mg and suitable for further clinical development.

Avagacestat (BMS-708163) is a potent inhibitor of γ-secretase, with IC50s of 0.27 nM and 0.30 nM for Aβ42 and Aβ40 inhibition; Avagacestat (BMS-708163) also inhibits NICD (Notch IntraCellular Domain) with IC50 of 0.84 nM and shows weak inhibition of CYP2C19, with IC50 of 20 μM.

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