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 Idenix’s lead HCV nucleoside polymerase inhibitor candidate. This nucleoside program is based on Idenix’s proprietary liver-targeting technology, which delivers high levels of nucleoside triphosphate in the liver, potentially maximizing drug efficacy and limiting systemic side effects. In preclinical studies using an HCV replicon assay, IDX184 exhibited 10 times greater potency than nucleosides currently in clinical development. In preclinical studies in monkeys, no toxicities at doses ≥ 600 mg/kg/day were observed and once-daily oral administration of 10 mg/kg of IDX184 produced rapid and potent antiviral activity.  The company has filed an IND and initiated clinical testing for this product candidate.

Protease Inhibitor Program
Idenix is evaluating multiple scaffolds in its protease inhibitor discovery program. Compounds from two of these scaffolds have demonstrated potent and selective antiviral activity in in vitro preclinical studies to date. Several compounds have demonstrated subnanomolar potency against the HCV NS3 protease target, single nanomolar potency in the HCV replicon, and no inhibition of 8 human cellular proteases. Initial preclinical pharmacokinetic evaluation of these compounds suggests the potential for once-daily or twice-daily dosing.  The company has chosen two compounds to move into IND-enabling studies and plans to file an IND/CTA for a lead protease inhibitor candidate in the first half of 2009.

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 2008 Materials

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

EASL 2008 Materials

 Standring et al, EASL 2008, 4.24.08
"In VitroActivity and Pharmacologic Properties of Two Novel Series of HCV Protease Inhibitors”

 Standring et al, EASL 2008, 4.25.08
“Potent Antiviral Activity of Second Generation Nucleoside Inhibitors, IDX102 and IDX184, in HCV-Infected Chimpanzees”

 Cretton-Scott et al, EASL 2008 Poster #588
"In VitroAntiviral Activity and Pharmacology of IDX184, a Novel and Potent Inhibitor of HCV Replication”