Short-Term Monotherapy with IDX184, a Liver-Targeted Nucleotide Polymerase Inhibitor, in Patients with Chronic Hepatitis C Virus Infection

Abstract

e 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. There are an estimated 170 million people worldwide with chronic hepatitis C virus (HCV) infection, representing a global prevalence of approximately 3%. The annual rate of new infections remains high (about 3 to 4 million/year). Most of those infected develop persistent, chronic infection, and an estimated 20% to 50% of patients are at risk for developing long-term complications, including cirrhosis and hepatocellular carcinoma (HCC) (18).The most widely available treatment option for patients with chronic HCV infection is the combination of parenterally administered pegylated interferon and orally administered ribavirin (pegIFN/RBV). Rates of cure, indicated by sustained virologic response (SVR), with this regimen are less than 50% in treatmentnaïve patients with the hard-to-treat genotype-1 infection (5, 7). Both pegIFN and RBV have poor tolerability and are not suitable for patients with advanced liver diseases or concurrent medical conditions. Over the past decade, major efforts have been devoted to developing direct-acting antivirals (DAAs) blocking specific steps in the HCV replication cycle. The addition of HCV NS3/4A protease inhibitors to pegIFN/RBV has shortened the treatment duration for man...

Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection

“…However, no data on resistance have been presented for these drugs so far. 92,93 Nonnucleoside analogs. At least 4 different allosteric binding sites have been identified for inhibition of the NS5B polymerase by nonnucleoside inhibitors (Table 1).…”

Design, Synthesis and Antiviral Evaluation of 2′- C -Methyl Branched Guanosine Pronucleotides: The Discovery of IDX184, a Potent Liver-Targeted HCV Polymerase Inhibitor

“…However, in February 2011 the FDA removed the full clinical hold on the IDX184, allowing IDX184 to be progressed in the clinic under a partial clinical hold [96]. And, in a short-term monotherapy study, IDX184 at doses of 25 to 100 mg administered once daily for 3 days in treatment-naive patients with genotype-1 HCV infection produced significant exposure-related anti-HCV activity and a decrease in serum aminotransferase levels, with no safety-related treatment discontinuations, no serious adverse events and no clinically discernible patterns of ECG abnormalities [97]. Furthermore, in a clinical Phase IIa trial, IDX184 was well-tolerated and demonstrated potent antiviral activity when combined with pegylated IFN-α and ribavirin in treatment-naive genotype 1 HCV-infected subjects, approximately 4 log HCV RNA reduction with up to 50% of subjects who achieved undetectable HCV RNA by day 14 with IDX184 at daily oral doses of 100 mg [98][99][100].…”

Structural Flexibility in HCV NS5B Polymerase and Molecular Modelling of Anti-HCV Drugs

“…IDX184, a prodrug of 2´-methylguanosine is clinically active and has effectively suppressed the emergence of viral resistance in combination with non-nucleoside inhibitors (NNIs) [99,100]. Some other examples of NIs entered in clinical phase are PSI6130 (β-D-2´-deoxy-2´-fluoro-2´C-methylcytidine) [101], PSI6206 (uridine analog) [102,103], PSI7851 [104], PSI7977 [103], R7128 (prodrug of cytidine analog) [105], R1479 (4´-azidocytidine) [106], and R1626 (prodrug of 4´-azidocytidine) [107].…”