ITMN-191 + R7128 or R1626 Performs Well in Laboratory Study; STAT-C Combination

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ITMN-191 + R7128 or R1626 Performs Well in Laboratory Study; STAT-C Combination Clinical Trial Now Underway By Liz Highleyman

The limited efficacy and side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection have prompted investigators to study several novel drugs that directly target various stages of the viral lifecycle -- an approach known as "STAT-C." But HCV can develop resistance to these small molecule agents when used as monotherapy, presenting a barrier to long-term efficacy.

Most clinical trials of STAT-C agents to date have studied them in combination with pegylated interferon + ribavirin, the standard of care for chronic hepatitis C. This week, however, Roche, InterMune, and Pharmasset jointly announced initiation of the first dual-combination clinical trial using oral anti-HCV agents.

Preclinical Data

In a poster presented at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers from the 3 companies reported results from a laboratory study of the combined antiviral activity of the investigational HCV protease inhibitor ITMN-191 (also known by its Roche designation, R7227) administered with the active forms of 2 nucleoside analog HCV polymerase inhibitors, R7128 (active moiety PSI-6130) or R1626 (active moiety R1479). All 3 compounds have demonstrated potent ant-HCV activity when administered for short durations as monotherapy.

In an HCV clearance assay, cells carrying an HCV genotype 1b replicon were treated for 2 weeks with ITMN-191, active R7128, active R1626, or a combination. 18 nM ITMN-191 and low mcM concentrations of active R1626 and R7128 (18 mcM and 27 mcM, respectively) eliminated the HCV replicons. Addition of the lowest tested concentration of ITMN-191 (6 nM) to the lowest concentrations of active R1626 or R7128 (0.3 mcM and 0.45 mcM, respectively) also resulted in replicon clearance, demonstrating a significant combined antiviral effect.

In a colony formation assay, cells were treated with either 1 or 2 of the compounds at 1, 10, or 15 times their respective EC50 (50% effective concentration) levels. Treatment with ITMN-191 alone selected for drug-resistant colonies, but these were suppressed by adding a polymerase inhibitor. Finally, in drug interaction studies, HCV replicon cells were treated for 3 days with 2 inhibitors, demonstrating additive to slightly synergistic interactions between the HCV inhibitor classes.

Based on these findings, the investigators concluded, "The combination of ITMN-191 with the active moeity of either R1626 or R7128 results in enhanced antiviral activity and suppression of ITMN-191 resistant variants. These findings suggest that the combination of ITMN-191 with R1626 or R7128 may confer significantly greater antiviral activity than has been observed with these agents in previous monotherapy trials."

These promising results suggest that anti-HCV therapy may come to resemble antiretroviral treatment for HIV, combining agents from different classes (for example, nucleoside/nucleotide reverse transcriptase inhibitors and protease inhibitors) that target multiple steps of the viral lifecycle, thereby making it more difficult for resistant mutant strains to emerge. Hepatitis C treatment, however, has the advantage of being able to eradicate the virus, so therapy duration is limited.

First Combination Clinical Trial

Encouraged by these results, the 3 companies designed a clinical trial to test ITMN-191/R7227 (being developed jointly by InterMune and Roche) in combination with R7128 (being developed by Roche and Pharmasset), without pegylated interferon or ribavirin, in patients with genotype 1 chronic hepatitis C.

Below is an edited excerpt from a press release announcing the new study:

Roche, InterMune and Pharmasset Announce Initiation of INFORM-1, the First Dual-Combination Clinical Trial with Oral Antivirals in Hepatitis C

Princeton, NJ -- November 10, 2008 -- Pharmasset, Inc., Roche, and Intermune Inc. today announced that the first patients have been dosed in an innovative clinical trial in patients chronically infected with the hepatitis C virus (HCV). The trial (run in centers in Australia and New Zealand) is the first to investigate the combination of two oral antiviral molecules in the absence of interferon.

The initial study will evaluate the safety and combined antiviral activity of R7227 (ITMN-191), a protease inhibitor, and R7128, a polymerase inhibitor, in 14 days of combination therapy in treatment-naive patients infected with HCV genotype 1.

This direct antiviral combination study represents an important first step in evaluating the therapeutic potential of an all-oral, interferon-free combination treatment for HCV. Roche is uniquely positioned to develop all-oral combination studies in HCV through its collaborations with InterMune and Pharmasset, which provide access to both protease and polymerase inhibitors, respectively.

With InterMune, Roche is developing R7227, an HCV protease inhibitor compound to be used in combination with Pegasys (peginterferon alfa-2a) and Copegus (ribavirin), the current standard of care (SOC). Concurrently with Pharmasset, Roche is developing R7128, an HCV RNA polymerase inhibitor, also for therapy in combination with Pegasys and Copegus. Both of these molecules have successfully completed Phase 1 monotherapy studies, have been dosed in combination with Pegasys and Copegus and both have individually demonstrated their efficacy against HCV.

Current standard of care for HCV comprises pegylated interferon plus ribavirin, for a duration that is dependent upon factors such as genotype of the virus. For the most difficult to treat genotype 1 virus, a 48-week treatment course generally results in sustained viral response in about 50% of patients. Pegasys and Copegus are the current foundation of HCV treatment and the preferred pegylated interferon therapy of choice for most HCV antiviral agents in development. [Editor's note: Schering-Plough's pegylated interferon alfa-2b (PegIntron) + Rebetol brand ribavirin is also considered standard-of-care.]

Nick Cammack, Leader of the Virology Disease Biology Leadership Team at Roche stated: "It is exciting to be at the forefront of designing innovative clinical approaches in fighting this chronic disease together with our partners, InterMune and Pharmasset. Our approach demonstrates our strong interest in combining molecules in development and investigating all possibilities that may enable us to deliver a new standard of care for patients with HCV."

Dan Welch, Chairman, Chief Executive Officer and President of InterMune, said, "The goal is to develop a treatment regimen that is better tolerated, shorter in duration and delivers higher sustained viral response rates. We are pleased to participate in the first clinical exploration of an all-oral, direct antiviral regimen towards that goal."

"The combination of oral antiviral therapies for HCV represents an exciting step in the evolution of HCV treatment," stated Higgins, Executive Vice President of Marketing and Sales at Pharmasset. "We believe the development of an all oral treatment regimen may help attract many more patients into therapy that are currently not on treatment."

About R7128

R7128, being developed for the treatment of chronic HCV infection, is a pro-drug of PSI-6130, a cytidine nucleoside analog inhibitor of HCV RNA polymerase. A pro-drug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. R7128 has shown in vitro activity against all of the most common HCV genotypes (1, 2, 3 and 4).