drug development & discovery

Since the discovery of the hepatitis C virus in 1989, many antiviral targets have been identified but most improvements in treatment have been centered on interferon and ribavirin. Many novel approaches to HCV infection are currently being evaluated. Recent technical advances in cell culture systems and replication assays have led to discoveries related to the mechanisms of HCV infection and new potential antiviral targets. Protease and polymerase enzyme targets have turned into successful therapeutic approaches in treating HIV and are becoming the focus of the multiple agents entering clinical development in HCV. The polymerase and protease inhibitors have shown to be excellent targets for selective anti-HCV therapy.¹ Clinical studies with a limited number of HCV protease and polymerase inhibitors have demonstrated encouraging early results.¹ However, preclinical evidence suggests that the virus may become rapidly resistant to such protease inhibitors.¹ Combination therapy of drugs with different modes of action and resistance profiles may be required.

Idenix has an ongoing HCV development and discovery program with the goal of building a critical mass of candidates in three different classes of drugs - nucleoside polymerase inhibitors, non-nucleoside polymerase inhibitors and protease inhibitors. 

Nucleoside Polymerase Inhibitor Program
IDX184 is a once-daily, oral nucleotide prodrug candidate based on Idenix’s proprietary liver-targeting technology.  This technology enables the delivery of high levels of nucleoside triphosphate in the liver, potentially maximizing drug efficacy and limiting systemic side effects.  In HCV genotype-1 infected chimpanzees, once-daily oral administration of 10 mg/kg/day of IDX184 produced a mean viral load reduction of 2.3 log₁₀ after four days of dosing. In a phase I study in healthy volunteers evaluating doses ranging from 5 to 100 mg/day, IDX184 was safe and well-tolerated; the most common adverse event reported in this study was dizziness and it was more frequently reported in subjects receiving placebo.  IDX184 is currently in a phase I/II proof-of-concept study in HCV-infected patients.

Protease Inhibitor Program
Idenix has scaled up manufacturing of two clinical candidates, IDX136 and IDX316, from its HCV protease inhibitor discovery program to support IND-enabling pharmacology and toxicology studies. Both IDX136 and IDX316 were developed through SAR (structural activity relationship) approaches aided by high-resolution co-crystal structures with the HCV protease. IDX136 and IDX316 have demonstrated single nanomolar potency against HCV genotype 1a and 1b purified HCV proteases and nanomolar potency against HCV genotype 1b replicon (EC₅₀ = 4 to 10 nM). Additionally, these compounds are highly selective, binding tightly to the HCV protease and demonstrating no activity against eight human cellular proteases. Both drug candidates appear to have a differentiated resistance profile when compared to other macrocyclic protease inhibitors in development. Favorable pharmacokinetic properties of IDX136 and IDX316 in non-human primates suggest the potential for once- or twice-daily dosing in man.

Non-nucleoside Inhibitor Program
Idenix has selected IDX375 as its lead clinical candidate from its HCV non-nucleoside polymerase inhibitor discovery program. Preclinical testing demonstrated that IDX375 targets the palm non-nucleoside pocket of HCV polymerase. IDX375 has exhibited single nanomolar in vitro potency against HCV genotype 1b replicon (EC₅₀ = 2 nM) and against HCV genotype 1a and 1b polymerases. Additionally, cellular cytotoxicity testing in Huh-7 cells demonstrated that IDX375 is not cytotoxic (CC₅₀ >100 μM), resulting in a selectivity index >33,000 for IDX375. In preclinical in vitro studies, IDX375 did not inhibit human cellular DNA polymerases α, β and γ (IC₅₀ >100 μM), demonstrating selectivity for the HCV 1a and 1b polymerases. Based on favorable preclinical pharmacokinetics, IDX375 has the potential for once- or twice-daily dosing in man.  IDX375 is currently in IND-enabling pharmacology and toxicology studies.

1 Neyts et al. Antiviral Research 71 (2006) 363–371
2 Pawlotsky JM. Hepatitis C virus genetic variability: pathogenic and clinical implications. Clinical Liver Dis 2003;7:45–66. 
3 NIH: HIV and AIDS. An Overview; NAID Fact Sheet

EASL 2009 Materials

 Lallos et al, EASL 2009, 4.23.09
"Preclinical Profiles of IDX136 and IDX316, Two Novel Macrocyclic HCV Protease Inhibitors”

 Good et al, EASL 2009, 4.23.09
“Preclinical Pharmacokinetic and Safety Profile of IDX375, A Novel and Potent Non-Nucleoside HCV Polymerase Inhibitor”

 Standring et al, EASL 2009, 4.24.09
“Antiviral Activity of the Liver-Targeted Nucleotide HCV Polymerase Inhibitor IDX184 Correlates with Trough Serum Levels of the Nucleoside Metabolite in HCV-Infected Chimpanzees”

 Zhou et al, EASL 2009, 4.25.09
“IDX184, A Liver-Targeted Nucleotide HCV Polymerase Inhibitor: Results of a First-in-Man Safety and Pharmacokinetic Study”

AASLD 2008 Materials

 Bilello et al, AASLD 2008, 10.31.08
"In VitroActivity and Pharmacologic Properties of IDX375, a novel HCV non-nucleoside inhibitor”