From the Cover: Investigative Nonclinical Cardiovascular Safety and Toxicology Studies with BMS-986094, an NS5b RNA-Dependent RNA Polymerase Inhibitor

Toxicol Sci. 2017 Feb;155(2):348-362. doi: 10.1093/toxsci/kfw211. Epub 2016 Nov 17.

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BMS-986094, a 2'-C-methylguanosine prodrug that was in development for treatment of chronic hepatitis C infection was withdrawn from Phase 2 clinical trials because of unexpected cardiac and renal adverse events.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.

Keywords: NS5b RNA dependent RNA polymerase inhibitors; biomarkers; cardiovascular toxicity; hepatitis C.; renal toxicity; skeletal muscle toxicity.

MeSH terms

  • Animals
  • Female
  • Guanosine Monophosphate / analogs & derivatives*
  • Guanosine Monophosphate / therapeutic use
  • Guanosine Monophosphate / toxicity
  • Heart / drug effects*
  • Heart / physiology
  • Hepatitis C, Chronic / drug therapy
  • Kidney / drug effects
  • Macaca fascicularis
  • Male
  • Mice
  • Muscle, Skeletal / drug effects
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • Toxicokinetics
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Viral Nonstructural Proteins
  • BMS-986094
  • Guanosine Monophosphate
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase