You have reached the HIVandHepatitis.com legacy site. Please visit our new site at hivandhepatitis.com

HOME
HIV and AIDS
Hepatitis C
Hepatitis B
HIV-HCV Coinfection
HIV-HBV Coinfection
HIV and Hepatitis.com Coverage of the
59th Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD 2008)

October 31 - November 4, 2008, San Francisco, CA
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 Patrick 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).

About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV).

Pharmasset is currently developing three product candidates. Clevudine, for the treatment of chronic HBV infection, is enrolling Phase 3 clinical trials for registration in North, Central and South America and Europe. Clevudine is already approved for HBV in South Korea and marketed by Bukwang Pharmaceuticals in South Korea under the brand name Levovir. R7128, an oral treatment for chronic HCV infection, is in a 4-week Phase 1 clinical trial in combination with Pegasys and Copegus. Racivir, which is being developed for the treatment of HIV in combination with other approved HIV drugs, has completed a Phase 2 clinical trial.

About R7227 (ITMN-191)

R7227 is an inhibitor of HCV NS3/4A protease activity, and has produced multi-log10 reductions in circulating HCV RNA in chronic HCV patients when administered for 14 days as monotherapy. In support of clinical studies that will combine R7227 with R7128, including the INFORM-1 study, InterMune, Roche and Pharmasset have investigated in vitro the combined antiviral effect of these compounds. [Editor's note: see AASLD report at the beginning of this article.]

About InterMune

InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the Phase 3 program, CAPACITY, which is evaluating pirfenidone as a possible therapeutic candidate for the treatment of patients with IPF and a research program focused on small molecules for pulmonary disease. The hepatology portfolio includes HCV protease inhibitor ITMN-191 (R7227) in Phase 1b, a second-generation HCV protease inhibitor research program, and a research program evaluating a new target in hepatology. For additional information about InterMune and its R&D pipeline, please visit www.intermune.com

About Roche

Headquartered in Basel, Switzerland, Roche is one of the world's leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world's biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, and is a market leader in virology. It is also active in other major therapeutic areas such as autoimmune diseases, inflammatory and metabolic disorders and diseases of the central nervous system. In 2007 sales by the Pharmaceuticals Division totaled 36.8 billion Swiss francs, and the Diagnostics Division posted sales of 9.3 billion Swiss francs. Roche has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai, and invested over 8 billion Swiss francs in R&D in 2007. Worldwide, the Group employs about 80,000 people. Additional information is available on the Internet at www.roche.com.

11/14/08

Reference
H Tan, S Rajyaguru. T Wu, and others. Combination of the NS3/4A Protease Inhibitor ITMN-191 (R7227) with the Active Moiety of the NS5B Inhibitors R1626 or R7128 Enhances Replicon Clearance and Reduces the Emergence of Drug Resistant Variants. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1885.

Other source
Pharmasset, Inc. Roche, and InterMune, Inc. Roche, InterMune and Pharmasset Announce Initiation of INFORM-1, the First Dual-Combination Clinical Trial with Oral Antivirals in Hepatitis C. Press release. November 10, 2008.

The material posted on HIV and Hepatitis.com about AASLD 2008 is
not approved by nor is it a part of AASLD 2008.