In
Vitro Studies Suggest Promising Outcomes with New HCV Protease Inhibitor ACH 806
in Combination with Interferon, Telaprevir, or NM 107 The
current standard of care for chronic hepatitis C virus (HCV) infection is pegylated
interferon in combination with ribavirin, which produces a cure
in only about 40% of patients with genotype 1 HCV, the most difficult form of
the virus to treat and the predominant genotype among HCV-infected patients in
the U.S. and Europe. In addition, pegylated interferon/ribavirin combination therapy is often is associated with serious
adverse
effects
that limit its tolerability and utility. Several
new experimental anti-HCV agents that act directly on the virus are currently
in various stages of development. These include the oral HCV
protease inhibitor boceprevir (SCH 503034) from Schering Plough; ACH 806, an HCV protease
inhibitor from Gilead/Achillon;
telaprevir
(VX-950), an oral HCV protease inhibitor from Vertex; and NM 107, a polymerase inhibitor
from Idenix/Novartis. Due
to the high mutation rate of HCV, various combinations
of these investigational drugs with complementary
mechanisms of action may be needed to effectively and durably suppress the emergence
of drug-resistant virus. In
the current study, presented at the 42nd
Annual Meeting of the European Association for
the Study of the Liver this week in Barcelona,
Spain, the short-term
and long-term in vitro antiviral activity
of the protease (replicase) inhibitor ACH-806 was evaluated in combination
with interferon, telaprevir, and NM 107.
HCV
1b-Con-1 replicon-containing cells were utilized to evaluate combination therapy. For short-term combination assays, serial dilutions of ACH-806 were
combined with serial dilutions of interferon,
telaprevir, or NM 107 in a checkerboard manner. Three days after addition of the
compounds, the level of HCV RNA replication
was quantified using a luciferase reporter assay. For
long-term combination assays, replicon-containing
cells were grown for 7-10 days in the presence of ACH-806 or ACH-806 plus one
of the 3 other drugs. To examine the proportion of cells in which HCV replicon
RNA was still present after 7-10 days of exposure, replicon cells were plated
in equal densities and were treated with G418 until formation of colonies became
visible.
Results
- Combinations of ACH-806 with telaprevir,
NM 107, or interferon were not antagonistic
over a range of concentrations.
- ACH-806 was synergistic in combination with telaprevir and NM 107 at or below
drug concentrations corresponding to the EC90 values for each agent.
- The benefit of combination treatment was sustained over time,
such that only a minor fraction of cells were left infected after 7-10 days.
In
conclusion, the study authors wrote, “Our results suggest that ACH-806 has the
potential to be used effectively in combination
with different classes of HCV inhibitors for the treatment of HCV infection.” Commentary ACH-806
(also known as GS 9132) is a potent small molecule inhibitor of HCV replication
originally identified through a research program at Achillon Pharmaceuticals.
In November 2004, Achillon entered into a collaboration and exclusive licensing
agreement with Gilead Sciences for the research, development, and commercialization of compounds
for the treatment of chronic hepatitis C, including ACH-806. Under
the terms of the collaboration with Gilead, Achillon
is responsible for preclinical development, regulatory filing, and clinical development
of ACH-806 through the completion of
a proof-of-concept clinical trial in HCV patients, according to a jointly agreed
upon research plan. Achillon is also responsible for research activities associated
with the identification of a back-up compound
until such time as proof-of-concept is achieved with respect to one compound. Gilead
Sciences is otherwise responsible for all development and commercialization of compounds,
including all regulatory filings and clinical trials after proof of concept. Gilead
Sciences is responsible for the manufacturing of compounds
throughout all stages of development and commercialization. Gilead
and Achillon believe that ACH-806 has the following benefits:
- Novel Mechanism of Action. Based upon extensive virology and
biochemistry studies, it has been established that the mechanism of action of
ACH-806 is novel and involves an interaction with NS3 protease, which is distinct
from that observed with other known NS3 protease inhibitors. ACH-806 prevents
the formation of the replicase complex,
a necessary step in viral replication that occurs before copying the viral RNA
genome (the step that polymerase inhibitors affect), but after viral protein processing
(the step that protease inhibitors affect). Accordingly, this unique mechanism
may contribute to the lack of cross-resistance between ACH-806 and other HCV inhibitors.
- Potency. Data obtained from standard laboratory assays used to determine
anti-HCV activity against genotype 1 virus demonstrate that ACH-806 has potency
in vitro in a range similar to that
described in the published data on Boehringer Ingelheim’s protease inhibitor [no
longer in development] and 14-21 times more potency in vitro than either
the Schering-Plough or Vertex HCV protease inhibitors now under clinical development,
according to Achillon.
- Lack of Cross-resistance. In
laboratory studies,
ACH-806 has not demonstrated cross-resistance to any of the polymerase inhibitors
or protease inhibitors now under development.
- Ease of Administration. Based on current animal studies, it
is believed that ACH-806 could be administered orally.
- Potential for Combination Treatment. Because of the lack of cross-resistance
with all other known classes of HCV inhibitors, ACH-806 is well positioned for
evaluation as a treatment for chronic hepatitis C in combination with the current standard of care
and/or in combination with other directly
targeted antiviral agents.
Preliminary
Phase I results revealed that ACH-806 was safe and well-tolerated in healthy volunteers.
The new results presented at the EASL meeting suggest that the compound is synergistic with interferon, telaprevir,
and NM 107, and in combination with
one or more of these drugs, may help to prevent the development of drug resistance
04/13/07 Reference
M Huang, W Yang, J Fabrycki, and others. In Vitro
Evaluation of Combination Treatment of ACH 806 with Interferon, VX 950 and NM
107. 42nd Annual Meeting of the European Association for the Study of the Liver.
April
11 - 15, 2007, Barcelona,
Spain .
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