67 Potent Antiviral Activity of Second Generation Nucleoside Inhibitors, Idx102 and Idx184, in HCV-Infected Chimpanzees

Standring, David N.; Lanford, R.; Cretton-Scott, Erika; Licklider, L.; Larsson, Margareta; Pierra, Claire; Gosselin, Gilles; Philouze, Christian; Surleraux, Dominique; Mayes, Benjamin A.; Moussa, Adel; Selden, Jules R.

doi:10.1016/s0168-8278(08)60069-0

Cited by 16 publications

(15 citation statements)

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“…In preclinical studies, IDX184-treated animals had very low systemic exposure consistent with a high rate of liver extraction. In addition, significant activity against HCV has been observed in IDX184-treated chimpanzees (14,15).…”

Section: Discussionmentioning

confidence: 99%

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

Lalezari

Asmuth

Casiró

et al. 2012

Antimicrob Agents Chemother

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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...

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Section: Discussionmentioning

confidence: 99%

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

Lalezari

Asmuth

Casiró

et al. 2012

Antimicrob Agents Chemother

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“…In vitro experiments showed that the metabolism of IDX184 to 2Ј-MeG-MP takes place predominantly in liver cells and involves both cytochrome P450 (CYP450)-dependent and -independent processes (S. Good, unpublished data). 2Ј-MeG-TP is a potent inhibitor of the HCV polymerase NS5B, and IDX184 has demonstrated antiviral activity against HCV in vitro and in chimpanzees (1,6,7).The enhanced formation of active intracellular 2Ј-MeG-TP with IDX184 was demonstrated in vitro. In primary human and animal hepatocytes exposed to IDX184 and the nucleoside 2Ј-MeG, the formation of 2Ј-MeG-TP was about 100-fold higher with IDX184 than with 2Ј-MeG (S. Good, unpublished data).…”

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confidence: 98%

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confidence: 99%

Safety and Pharmacokinetics of IDX184, a Liver-Targeted Nucleotide Polymerase Inhibitor of Hepatitis C Virus, in Healthy Subjects

Zhou

Pietropaolo

Chen

et al. 2011

Antimicrob Agents Chemother

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IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the active triphosphate of 2-methylguanosine (2-MeG), a potent and specific polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. Plasma and urine pharmacokinetic sampling was performed over a period of 120 h after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a mean half-life (t 1/2 ) of approximately 1 h, while plasma concentrations of 2-MeG gradually increased. Consistent with a liver-targeting approach, plasma exposure of IDX184 and 2-MeG was low and was also dose related: the mean maximum concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 2-MeG, and the respective mean total area under the curve ranged from 1.2 to 22.7 and 17.3 to 334 ng ⅐ h/ml. Mean 2-MeG plasma concentrations 24 h after dosing were 0.6 to 3 ng/ml for the 25-to 100-mg doses. Mean 2-MeG t 1/2 values ranged from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2-MeG, respectively. IDX184 was safe and well tolerated; no serious adverse events (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were observed. The incidence of AEs and laboratory abnormalities was low and was similar among subjects receiving IDX184 or a placebo. All AEs were mild to moderate and resolved at the end of study. The favorable safety and pharmacokinetic profiles support further clinical evaluation of IDX184 in HCV-infected patients.Hepatitis C virus (HCV) infection is a global public health problem. The global prevalence of hepatitis C infection is estimated to average 3%, resulting in approximately 170 million HCV-infected persons worldwide (8).The current standard of care for patients with chronic hepatitis C and compensated liver disease is the combination of parenterally administered pegylated interferon and orally administered ribavirin. However, sustained virologic response rates are less than 50% in treatment-naive patients with genotype 1 infection (2, 4). In addition, many patients are not good candidates for treatment with these agents due to advanced liver disease or concurrent medical conditions, and many patients show poor tolerance of these treatments. Therefore, there is a need for new anti-HCV therapies, particularly for patients with genotype 1 HCV or those who have failed to respond to the available treatment options.While nucleoside HCV polymerase inhibitors have a higher genetic barrier to resistance and have demonstrated clinical anti-HCV activity, early nucleoside analogs have wide systemic exposure and inefficient phosphorylation of their 5Ј-monophosphate (MP) metabolite, resulting in limited formation of the active 5Ј-triphosphate (TP) in the liver, the site of HCV replication (1,3,5). In that context, IDX184 (Fig. 1) ...

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“…And it was reported that HCV-infected chimpanzees dosed with IDX184 (10 mg/kg/day p.o.) for just 4 days achieved rapid 2.5 -4 log10 reductions in HCV RNA levels with satisfactory tolerance [69]; of note, the chimpanzee model has previously been found to be a useful predictor of anti-HCV activity in CHC patients [47,56]. A Phase Ia clinical trial of IDX184 was recently completed in healthy volunteers, with the results reportedly indicating a satisfactory pharmacokinetic profile (e.g., for once-daily oral dosing) and satisfactory tolerance at all tested dosing levels [70].…”

Section: Initial Safety Observations For Current Clinical-stage Hcv Nmentioning

confidence: 98%

Progress towards improving antiviral therapy for hepatitis C with hepatitis C virus polymerase inhibitors. Part I: Nucleoside analogues

Brown

2009

Expert Opinion on Investigational Drugs

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Background: With an increasing worldwide burden of liver failure and liver cancer from chronic hepatitis C virus (HCV) infection, discovery and development efforts for new antiviral medicines for HCV are expanding rapidly. Two HCV protease inhibitors (PIs), telaprevir (VX950) and boceprevir (SCH503034), are now furthest along in clinical development, with Phase II data suggesting a potential treatment advance with triple combination regimens comprising a protease inhibitor, pegylated interferon and ribavirin. However, the current data suggest that such regimens will fail to produce sustained virologic responses in ≥ 30 -40% of patients, and tolerance of interferon/ribavirin treatment regimens is often problematic; hence, there is a need for continued development of new anti-HCV agents to further optimize treatment efficacy and safety. The HCV polymerase (HCV Pol) is an attractive target for antiviral therapy because the gene sequences encoding HCV Pol are relatively conserved across the six main HCV genotypes and the emergence of viral resistance is expected to be relatively slow for pharmaceutical agents, such as nucleoside analogues, that are targeted to the active (catalytic) site of HCV Pol. Methods: This review (Part I) of HCV Pol inhibitors focuses on the scientific rationale and recent development progress for nucleoside-type HCV Pol inhibitors; a subsequent review (Part II) will assess progress with non-nucleosidic HCV Pol inhibitors. Results/conclusions: Early clinical data for several nucleosides targeted to HCV Pol indicate marked antiviral effects and a likelihood of relatively slow HCV resistance, consistent with the profile of nucleosidic inhibitors of HIV and hepatitis B virus infection and supporting potentially important roles for nucleoside agents in optimizing combination therapies for HCV infection. Optimally effective future anti-HCV therapies are likely to be based on multi-class treatment regimens combining polymerase and PIs, together with pegylated interferon and ribavirin or pharmaceutical agents from other mechanistic classes.

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67 Potent Antiviral Activity of Second Generation Nucleoside Inhibitors, Idx102 and Idx184, in HCV-Infected Chimpanzees

Cited by 16 publications

References 0 publications

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

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

Safety and Pharmacokinetics of IDX184, a Liver-Targeted Nucleotide Polymerase Inhibitor of Hepatitis C Virus, in Healthy Subjects

Progress towards improving antiviral therapy for hepatitis C with hepatitis C virus polymerase inhibitors. Part I: Nucleoside analogues

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