guanosine-monophosphate and Hepatitis-C--Chronic

Treatment for chronic hepatitis C virus (HCV) infection is evolving from interferon (IFN)-based therapy to direct-acting antiviral (DAA) agents, yet some safety concerns have arisen involving cardiac toxicity. In this study, we sought to better understand the potential off-target toxicities of new DAAs. We retrospectively evaluated the clinical and pathological findings of the sentinel case in a phase II study that led to clinical development discontinuation for BMS-986094, an HCV nucleotide polymerase (nonstructural 5B) inhibitor. We also report on outcomes from other patients in the same study, including electrocardiogram changes, cardiovascular biomarkers, and transthoracic echocardiograms. Thirty-four patients received IFN-free BMS-986094 regimens. Six patients had left ventricular ejection fractions (LVEFs) <30%, 8 had LVEFs 30%-50%, and 11 required hospitalization for suspected cardiotoxicity. Of the patients with LVEF <50%, 6 had normalization of systolic function after a median of 20 days. T-wave inversions were the most sensitive predictor of LVEF dysfunction. B-type natriuretic peptide levels increased over time and correlated with the degree of LVEF dysfunction. Pathological analysis of cardiac tissue revealed severe myocyte damage with elongated myofibrils without gross necrosis. These findings were consistent with some results of recent primate studies that were conducted to further investigate the potential mechanisms of BMS-986094 toxicity.. A novel nucleotide analog polymerase inhibitor developed for HCV treatment may cause a toxic cardiomyopathy. Ongoing surveillance of DAAs for cardiotoxicities may be beneficial, especially among patients at higher risk for cardiovascular disease.

Topics: Adult; Aged; Antiviral Agents; Cardiomyopathies; Cohort Studies; Female; Follow-Up Studies; Guanosine Monophosphate; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Male; Middle Aged; Protease Inhibitors; Retrospective Studies; Risk Assessment

IDX184 is a liver-targeted nucleotide prodrug that selectively inhibits HCV NS5B polymerase.. This randomized, double-blind, placebo-controlled, ascending-dose study investigated the antiviral activity, safety and pharmacokinetics of IDX184 plus pegylated interferon-α2a and ribavirin (P/R) in treatment-naive patients with genotype-1 HCV. A total of 81 patients with baseline HCV RNA≥5 log10 IU/ml, alanine aminotransferase ≤3× upper limit of normal and compensated liver disease were dosed. Sequential cohorts of 20 patients, randomized 16:4 (active:placebo), received IDX184 for 14 days at rising daily doses of 50, 100, 150 or 200 mg in combination with P/R for 14 days.. At the end of triple dosing, HCV RNA changes from baseline (mean ±sd log10) and proportion of patients achieving undetectable viral load (<15 IU/ml) based on the efficacy-evaluable population were -2.7 ±1.3 (13%), -4.0 ±1.7 (50%), -4.2 ±1.9 (50%), -4.1 ±1.2 (40%), -4.3 ±1.5 (29%) and -3.7 ±1.2 (25%) for the 50 mg once daily, 50 mg twice daily, 100 mg once daily, 150 mg once daily, 100 mg twice daily and 200 mg once daily IDX184 doses, respectively. P/R alone resulted in a reduction of -1.5 ±1.3 log10 with only 6% of patients with undetectable viral load. Patients with genotypes-1a or -1b responded similarly. No viral breakthrough or resistance associated with IDX184 was observed. Anti-HCV activity of IDX184 correlated with plasma exposure of its nucleoside metabolite 2'-methylguanosine. Most adverse events were mild or moderate in severity and were consistent with those associated with P/R. The most common adverse events were fatigue and headache.. IDX184 in combination with P/R for 14 days was well tolerated and demonstrated greater antiviral activity with more patients achieving undetectable viral load than P/R.

Topics: Adult; Antiviral Agents; Drug Interactions; Drug Therapy, Combination; Female; Genotype; Guanosine Monophosphate; Hepatitis C; Hepatitis C, Chronic; Humans; Interferon-alpha; Interferons; Interleukins; Male; Middle Aged; Polyethylene Glycols; Polymorphism, Genetic; Recombinant Proteins; Ribavirin; Treatment Outcome; Viral Load

IDX184 is a liver-targeted prodrug of 2'-methylguanosine (2'-MeG) monophosphate. This study investigated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184 as a single agent in treatment-naïve patients with genotype-1 chronic hepatitis C virus (HCV) infection. Forty-one patients with baseline HCV RNA ≥ 5 log(10) IU/ml, alanine aminotransferase (ALT) ≤ 2.5× the upper limit of normal, and compensated liver disease were dosed. Sequential cohorts of 10 patients, randomized 8:2 (active:placebo), received 25, 50, 75, and 100 mg of IDX184 once daily for 3 days, with a 14-day follow-up. There were no safety-related treatment discontinuations or serious adverse events. The adverse events and laboratory abnormalities observed for IDX184- and placebo-treated patients were similar. At the end of the 3-day treatment period, changes from baseline in HCV RNA levels (means ± standard deviations) were -0.5 ± 0.6, -0.7 ± 0.2, -0.6 ± 0.3, and -0.7 ± 0.5 log(10) for the 25-, 50-, 75-, and 100-mg doses, respectively, while viral load remained unchanged for the pooled placebo patients (-0.05 ± 0.3 log(10)). Patients with genotype-1a and patients with genotype-1b responded similarly. Serum ALT levels decreased, especially at daily doses ≥ 75 mg. During the posttreatment period, plasma viremia and serum aminotransferase levels returned to near pretreatment levels. No resistance mutations associated with IDX184 were detected. Plasma exposure of IDX184 and its nucleoside metabolite 2'-MeG was dose related and low. Changes in plasma viral load correlated with plasma exposure of 2'-MeG. In conclusion, the results from this proof-of-concept study show that small doses of the liver-targeted prodrug IDX184 were able to deliver significant antiviral activity and support further clinical evaluation of the drug candidate.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antiviral Agents; Area Under Curve; Demography; Double-Blind Method; Drug Delivery Systems; Female; Guanosine Monophosphate; Half-Life; Hepatitis C, Chronic; Humans; Liver; Male; Middle Aged; Nucleic Acid Synthesis Inhibitors; Prodrugs; RNA, Viral; Viral Load; Young Adult

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.

Topics: Animals; Female; Guanosine Monophosphate; Heart; Hepatitis C, Chronic; Kidney; Macaca fascicularis; Male; Mice; Muscle, Skeletal; RNA-Dependent RNA Polymerase; Toxicokinetics; Viral Nonstructural Proteins

Toxicity has emerged during the clinical development of many but not all nucleotide inhibitors (NI) of hepatitis C virus (HCV). To better understand the mechanism for adverse events, clinically relevant HCV NI were characterized in biochemical and cellular assays, including assays of decreased viability in multiple cell lines and primary cells, interaction with human DNA and RNA polymerases, and inhibition of mitochondrial protein synthesis and respiration. NI that were incorporated by the mitochondrial RNA polymerase (PolRMT) inhibited mitochondrial protein synthesis and showed a corresponding decrease in mitochondrial oxygen consumption in cells. The nucleoside released by the prodrug balapiravir (R1626), 4'-azido cytidine, was a highly selective inhibitor of mitochondrial RNA transcription. The nucleotide prodrug of 2'-C-methyl guanosine, BMS-986094, showed a primary effect on mitochondrial function at submicromolar concentrations, followed by general cytotoxicity. In contrast, NI containing multiple ribose modifications, including the active forms of mericitabine and sofosbuvir, were poor substrates for PolRMT and did not show mitochondrial toxicity in cells. In general, these studies identified the prostate cell line PC-3 as more than an order of magnitude more sensitive to mitochondrial toxicity than the commonly used HepG2 cells. In conclusion, analogous to the role of mitochondrial DNA polymerase gamma in toxicity caused by some 2'-deoxynucleotide analogs, there is an association between HCV NI that interact with PolRMT and the observation of adverse events. More broadly applied, the sensitive methods for detecting mitochondrial toxicity described here may help in the identification of mitochondrial toxicity prior to clinical testing.

Topics: Antiviral Agents; Cell Line; Deoxycytidine; DNA Polymerase gamma; DNA-Directed DNA Polymerase; DNA-Directed RNA Polymerases; Guanosine Monophosphate; Hepacivirus; Hepatitis C, Chronic; Humans; Mitochondria; Nucleosides; Oxygen Consumption; Protein Biosynthesis; RNA; RNA, Mitochondrial; Sofosbuvir; Transcription, Genetic; Virus Replication