Language:
  
[Sign in] [Register]   

EIAab logo

EIAab news detail, please contact eiaab@eiaab.com if you have any questions about online orders and payment.
Investigative Nonclinical Cardiovascular Safety and Toxicology Studies with BMS-986094, an NS5b RNA-Dependent RNA Polymerase Inhibitor
Update time:2016-12-12 18:52:50   【 Font: Large  Medium Small

Abstract

BMS-986094, a 2’-C-methylguanosine prodrug that was in development for treatment of chronic hepatitis C infection was withdrawn from Phase 2 clinical trials because of unexpected cardiac and renal adverse events. Investigative nonclinical studies were conducted to extend the understanding of these findings using more comprehensive endpoints. BMS-986094 was given orally to female CD-1 mice (25 and 150 mg/kg/d) for 2 weeks (53/group) and to cynomolgus monkeys (15 and 30 mg/kg/d) for up to 6 weeks (2–3/sex/group for cardiovascular safety, and 5/sex/group for toxicology). Endpoints included toxicokinetics; echocardiography, telemetric hemodynamics and electrocardiography, and tissue injury biomarkers (monkey); and light and ultrastructural pathology of heart, kidney, and skeletal muscle (mouse/monkey). Dose-related and time-dependent findings included: severe toxicity in mice at 150 mg/kg/d and monkeys at 30 mg/kg/d; decreased left ventricular (LV) ejection fraction, fractional shortening, stroke volume, and dP/dt; LV dilatation, increased QTc interval, and T-wave flattening/inversion (monkeys at ≥ 15 mg/kg/d); cardiomyocyte degeneration (mice at 150 mg/kg/d and monkeys at ≥ 15 mg/kg/d) with myofilament lysis/myofbril disassembly; time-dependent proteinuria and increased urine β-2 microglobulin, calbindin, clusterin; kidney pallor macroscopically; and tubular dilatation (monkeys); tubular regeneration (mice 150 mg/kg/d); and acute proximal tubule degeneration ultrastructurally (mice/monkeys); and skeletal muscle degeneration with increased urine myoglobin and serum sTnI. These studies identified changes not described previously in studies of BMS-986094 including premonitory cardiovascular functional changes as well as additional biomarkers for muscle and renal toxicities. Although the mechanism of potential toxicities observed in BMS-986094 studies was not established, there was no evidence for direct mitochondrial toxicity.

 

Cited products
Source:Toxicological Sciences      by Gill M, Horn K, Hennan J, et al.
Hot Genes
ALCAM ACE KSR2 ASPRO C19orf80 Gdf5 Trap1a Atf2
Top Searches
Ubiquitin ELISA Ubiquitin-protein ligase metalloproteinase Asprosin Tumor necrosis TRAP1A vitamin d
Why choose EIAAB
Our products have been quoted by many publications in famous journals such as Cell; Cell Metabolism; Hepatology; Biomaterials.more
Further Information
About us Protein center Bank account Distributors Terms & Conditions Career eiaab.cn

Copyright & copy www.eiaab.com2006-2016 All Rights Reserved    EIAab         Email:eiaab@eiaab.com

Twitter