
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 the focus of multiple agents in 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 number of HCV protease and polymerase inhibitors have demonstrated encouraging early results.1 However, 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 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. In July 2009, the company announced the successful
completion of a phase I/II 3-day proof-of-concept study for IDX184
demonstrating antiviral activity and safety in HCV-infected patients. A
phase IIa clinical trial evaluating IDX184 in combination with pegylated
interferon and ribavirin in treatment-naive HCV genotype 1-infected patients is
ongoing.
Protease Inhibitor Program
IDX320 is a non-covalent macrocyclic inhibitor with nanomolar potency, broad
genotypic coverage and a favorable preclinical pharmacokinetic profile
supporting the potential for once-daily dosing in man. A Clinical Trial
Application for IDX320 was filed in December 2009 and a phase I clinical trial
evaluating single and multiple ascending doses in healthy volunteers is
ongoing.
Non-nucleoside Inhibitor Program
IDX375 is a novel non-nucleoside polymerase inhibitor. Preclinical testing
demonstrated that IDX375 targets the palm non-nucleoside pocket of HCV
polymerase. IDX375 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. A phase I study in
healthy volunteers is ongoing.
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
AASLD 2009 Materials
Lalezari et
al, AASLD 2009, 11.2.09
"Antiviral Activity, Safety and Pharmacokinetics of IDX184, a
Liver-Targeted Nucleotide HCV Polymerase Inhibitor, in Patients with Chronic
Hepatitis C”
Lallos et al,
AASLD 2009, 11.3.09
"Combination of IDX184, a Nucleotide Prodrug Polymerase Inhibitor, with
Other Classes of HCV Inhibitors is Additive to Synergistic in the HCV
Replicon in vitro”
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”