title: From the Cover: Investigative Nonclinical Cardiovascular Safety and Toxicology Studies with BMS-986094, an NS5b RNA-Dependent RNA Polymerase Inhibitor.
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BMS-986094, a 2'-C-methylguanosine prodrug that was in development for treatment of chronic hepatitis C infection was withdrawn from Phase 2 clinical trials because of unexpected cardiac and renal adverse events.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.
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey, 08543 michael.gill@bms.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Kristen
authors.initials: K
authors.lastname: Horn
authors.affiliation: Bristol-Myers Squibb Company, Hopewell, New Jersey.
authors.forename: James
authors.initials: J
authors.lastname: Hennan
authors.affiliation: Bristol-Myers Squibb Company, Evansville, Indiana 47620.
authors.forename: Randy
authors.initials: R
authors.lastname: White
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey, 08543.
authors.forename: Denise
authors.initials: D
authors.lastname: Bounous
authors.affiliation: Bristol-Myers Squibb Company, Evansville, Indiana 47620.
authors.forename: Shawn
authors.initials: S
authors.lastname: Clark
authors.affiliation: Bristol-Myers Squibb Company, Hopewell, New Jersey.
authors.forename: John R
authors.initials: JR
authors.lastname: Megill
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey, 08543.
authors.forename: Evan
authors.initials: E
authors.lastname: Janovitz
authors.forename: Marc
authors.initials: M
authors.lastname: Davies
authors.affiliation: Bristol-Myers Squibb Company, Evansville, Indiana 47620.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sanderson
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey, 08543.
authors.forename: Michael
authors.initials: M
authors.lastname: Graziano
mesh_terms: D000818:Animals; D005260:Female; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D066007:Toxicokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D017361:Viral Nonstructural Proteins; C553340:BMS-986094; D006157:Guanosine Monophosphate; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: NS5b RNA dependent RNA polymerase inhibitors; biomarkers; cardiovascular toxicity; hepatitis C.; renal toxicity; skeletal muscle toxicity