
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”