+ R7128 or R1626 Performs Well in Laboratory Study; STAT-C Combination Clinical
Trial Now Underway|
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.
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.
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
(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.
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.
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.
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
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.
Combination Clinical Trial
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.
is an edited excerpt from a press release announcing the new study:
InterMune and Pharmasset Announce Initiation of INFORM-1, the First Dual-Combination
Clinical Trial with Oral Antivirals in Hepatitis C
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.
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
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.
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.
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.]
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."
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
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."
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).
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).
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.
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.]
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
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
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.
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,