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HIV and Coverage of the
45th Annual Meeting of the European
Association for the Study of the Liver (EASL 2010)

April 14 - 18, 2010, Vienna, Austria
HCV Polymerase Inhibitor IDX184, Protease Inhibitor IDX320, and Triple Combination Show Promising Antiviral Activity

SUMMARY: Two investigational direct-acting drugs for hepatitis C virus (HCV) infection -- the polymerase inhibitor IDX184 and the protease inhibitor IDX320 -- demonstrated good antiviral activity in a Phase 2a clinical trial and in laboratory and animal studies, respectively, researchers reported at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) last month in Vienna. Another in vitro study showed that these 2 drugs plus IDX375 (another polymerase inhibitor that works a different way) or an experimental NS5A inhibitor exhibited enhanced or synergistic viral suppression.

By Liz Highleyman

Idenix Pharmaceuticals is developing a set of directly targeted anti-HCV agents that work by different mechanisms, and therefore have the potential to be used together in all-oral combination regimens. Combining drugs that target different steps of the viral lifecycle may improve efficacy and reduce drug resistance.


Jay Lalezari from Quest Clinical Research in San Francisco and colleagues evaluated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184, a liver-targeted nucleotide analog prodrug that prevents the HCV polymerase from copying viral genetic material.

In this double-blind Phase 2a ascending dose trial, sequential groups of 20 previously untreated patients with genotype 1 chronic hepatitis C were (or will be) randomly assigned (16:4) to receive IDX184 at doses of 50, 100, 150, or 200 mg once or twice daily, or else placebo, for 14 days. All participants also received standard therapy consisting of 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin during the IDX184 dosing period and for 14 additional days thereafter.

Investigators reported interim results from the 50 mg and 100 mg cohorts at EASL; the study is continuing with the 150 mg cohort and those data are expected later this year.


After 14 days, HCV viral load decreased more in the IDX184 arms than in the placebo plus standard therapy arm:
50 mg once-daily IDX184: -2.7 log IU/mL;
50 mg twice-daily IDX184: -4.0 log IU/mL;
100 mg once-daily IDX184: -4.2 log IU/mL;
Placebo: -1.2 log IU/mL;
At the end of dosing, 13% of participants in the 50 mg once-daily IDX184 arm and 50% in both the 50 mg twice-daily and 100 mg once-daily groups achieved undetectable HCV viral load (< 15 IU/mL), compared with none in the placebo arm.
No viral breakthrough (> 1 log above the nadir or lowest-ever level) was observed during IDX184 dosing.
HCV viral load rebounded in most patients after the last day of IDX184 dosing, even though they remained on pegylated interferon/ribavirin.
Mean ALT and AST levels -- an indicator of liver inflammation -- decreased markedly in patients receiving IDX184 at all dose levels, but not in those receiving placebo plus standard therapy.
No participants discontinued treatment early.
No treatment-emergent serious adverse events were reported during the 14-day IDX184 dosing period.
In general, adverse events and laboratory profiles were consistent with those of pegylated interferon/ribavirin, and similar in the IDX184 and placebo arms.
The most common adverse events were fatigue, myalgia (muscle aches), headache, and nausea.
The most common laboratory abnormality was neutropenia (low white blood cell count, a known side effect of interferon).
The most common laboratory abnormality was neutropenia (low white blood cell count, a known side effect of interferon).
There were no significant differences in efficacy or safety between the IDX184 100 mg once-daily and 50 mg twice-daily doses.

Based on these findings, the researchers concluded, IDX184 "delivers significant antiviral activity with low systemic exposures."

In addition, IDX184 was "generally safe and well tolerated," leading an external safety review committee to recommend that the study should proceed to evaluate the 150 mg dose.


Idenix researchers presented 2 posters on IDX320, an non-covalent NS3/4A HCV protease inhibitor further back in the development pipeline.

L.B. Lallos and colleagues reported that IDX320 interfered with HCV protease activity in laboratory studies using purified proteases, an HCV replicon model, and an infectious HCV virus in cell cultures. IDX320 was found to bind tightly to the HCV NS3/4A protease, with a dissociation half-life of more than 9 hours. The drug inhibited the protease enzyme of HCV genotypes 1a, 1b, 2a, and 4a, as well as 3a at a higher concentration. In contrast, it did not interfere with 9 human cellular proteases.

In cell assays, IDX320 inhibited genotype 1a and 1b replicons and the genotype 2a JFH-1 HCV strain. Treatment of replicon cells for 14 days produced a maximum reduction of 3.7 logs. The NS3 mutation D168V was the signature resistance mutation for IDX320, but HCV with this mutations remained fully susceptible to interferon/ribavirin and different classes of direct-acting antiviral agents. The investigators concluded that, "IDX320 is a potent inhibitor of HCV NS3/4A protease and HCV replication in cell culture with broad genotypic coverage."

In the second poster, S.S. Good and colleagues reported preclinical pharmacokinetic and safety data from laboratory and animal studies. IDX320 had good bioavailability, with a mean plasma half-life of 6 hours in mice and 10 hours in monkeys after a 2 mg/kg IV dose. The drug was highly protein bound. Of the 8 human CYP450 enzymes that process drugs in the liver, only 3A4 metabolized IDX320, and the drug in turn did not significantly inhibit 5 of these enzymes.

IDX320 produced "negligible cytotoxicity" in laboratory cell cultures, and no adverse effects were observed in either mice or monkeys, including blood chemistry or organ abnormalities. The researchers concluded that, "IDX320 is a promising clinical candidate based on its favorable preclinical safety profile, with pharmacokinetics that suggest potential once-daily dosing in humans."

In the first clinical studied in healthy HCV negative volunteers, IDX320 continued to demonstrate a favorable pharmacokinetic profile. According to a press release issued by Idenix, the Phase 1 single and multiple ascending dose clinical study in healthy volunteers is now complete, and a 3-day proof-of-concept study in people with HCV is expected to begin in the second quarter of 2010.

Combination Therapy

Finally, M. La Colla and colleagues evaluated various 2- and 3-drug regimens containing IDX184, IDX320, the non-nucleoside NS5B HCV polymerase inhibitor IDX375, and a prototype HCV NS5A inhibitor (IDX-NS5A). This laboratory study exposed genotype 1b HCV replicons to the drugs alone or in combination.

During 3 days of exposure, treatment with IDX320 + IDX375 demonstrated additive activity (the level expected if adding the effects of each drug used alone), while IDX320 + IDX-NS4A produced additive to synergistic activity (greater than the expected additive effect). Triple combinations of IDX184 + IDX320 + either IDX375 or IDX-NS4A produced clear synergistic activity.

Over 14 days, exposure to IDX184, IDX320, or IDX375 individually produced viral load reductions of approximately 0.5 to 1.5 logs. Treatment with any 2-drug combination demonstrated additive activity, with reductions of about 2 logs. But combining all 3 drugs produced enhanced activity, with a viral load decrease of nearly 4 logs. No cytotoxic effects were observed during this period.

"This effect, coupled with the different resistance profiles of the 3 agents, suggests the potential value of triple combination regimens in future HCV clinical studies," the investigators concluded.

"The in vitro combination data presented today continue to support our belief that the future of HCV treatment will be a combination of direct-acting antivirals from different drug classes," said Idenix CEO Jean-Pierre Sommadossiin a company press release. "We are pursuing a drug development strategy to achieve that goal."

Researcher affiliations:

Lalezari study: Researcher affiliations: Quest Clinical Research, San Francisco, CA; Cedars-Sinai Medical Center, Los Angeles, CA; StudySite, Tuan Trong Nguyen, MD, San Diego, CA; Orlando Immunology Center, Orlando, FL; University Hepatitis Center at Bach & Godofsky, M.D., P.A., Sarasota, FL; Idenix Pharmaceuticals, Inc., Cambridge, MA.

Lallos study: Idenix Pharmaceuticals, Inc., Cambridge, MA; Idenix Pharmaceuticals, Inc., Cagliari, Italy; Idenix Pharmaceuticals, Inc., Montpellier, France.

Good study: Idenix Pharmaceuticals, Inc., Cambridge, MA; Idenix Pharmaceuticals, Inc., Montpellier, France.

La Colla study: Idenix Pharmaceuticals, Inc., Cambridge, MA.



J Lalezari, F Poordad, P Mehra, and others (IDX-08C-004 Investigator Group). Antiviral activity, pharmacokinetics and safety of IDX184 in combination with pegylated interferon (pegIFN) and ribavirin (RBV) in treatment-naive HCV genotype 1-infected subjects. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).

LB Lallos, J Mccarville, B Li, and others. In vitro antiviral activity of IDX320, a novel and potent macrocyclic HCV protease inhibitor. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).

S.S. Good, X-R Pan-Zhou, M Larsson, and others. Preclinical pharmacokinetic profile of IDX320, a novel and potent HCV protease inhibitor. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).

La Colla, LB Lallos, I Serra, and others. A triple combination of direct-acting antiviral agents demonstrates robust anti-HCV activity in vitro. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).

Other sources

Idenix. Idenix Pharmaceuticals Reports Positive Results With IDX184 From Interim Analysis of Phase IIa Hepatitis C Study. Press release. April 15, 2010.

Idenix. Idenix Pharmaceuticals Reports Favorable Pharmacokinetic Data for IDX320, a Potent, Multi-Genotypic Protease Inhibitor for the Treatment of Hepatitis C. Press release. April 16, 2010.