From Medscape Gastroenterology
Hepatitis C Expert Column
Specifically Targeted Antiviral Therapy (STAT-C) for Patients With Chronic
Hepatitis C
Posted 06/01/2007

Zobair M. Younossi, MD, MPH, FACP, FACG

Introduction
Chronic hepatitis C is one of the most common causes of chronic liver
disease worldwide. It is estimated that, globally, approximately 170 million
people are infected with hepatitis C, and that approximately 15% develop
hepatitis C-related cirrhosis. Evidence suggests that the future burden of
hepatitis C-related liver disease will increase with the increasing rates of
liver-related mortality, morbidity, and liver cancer. Additionally, the
economic burden of hepatitis C-related liver disease is estimated to be
enormous.[1]

Several therapeutic regimens have been developed in an attempt to treat
hepatitis C virus (HCV)-related liver disease. The current standard of care
for the treatment of hepatitis C is combination therapy with pegylated
interferon alfa and ribavirin. This combination regimen can be very
effective in patients infected with HCV genotype 2, with more than 80% of
patients achieving a sustained virologic response. The response rate is
lowest among patients with genotype 1 disease, with approximately 40%
achieving a sustained virologic response.[2]

The Challenge of Achieving a Sustained Virologic Response
Recent reports on viral kinetics suggest that rapid virologic clearance
(undetectable HCV RNA by polymerase chain reaction after 4 weeks of
treatment) has an excellent positive predictive value for sustained
virologic response.[3] In contrast, the failure to achieve early virologic
response by week 12 of treatment (a minimum of a 2-log drop in HCV RNA from
the baseline value) is a reliable negative predictor of response to this
combination therapy regimen.[3,4] Furthermore, recent reports suggest that
maintaining the optimal dose of both pegylated interferon alfa and ribavirin
is associated with the best response to combination therapy. Achieving this
goal requires careful and proactive management of side effects, including
cytopenias and depression.[ 5]

Knowledge of these viral kinetic data and better management of side effects
can ensure adherence to the optimal regimen and help clinicians maximize the
efficacy of antiviral therapy. Despite these recent gains in the field, many
patients fail to achieve a sustained virologic response or are unable to
tolerate the side effects associated with these drugs, necessitating the
development of new strategies in HCV therapy. Research has focused on the
development of agents with novel mechanisms of action and on the
modification of existing drugs. The anti-HCV regimens currently in
development can be divided into 3 main categories, including specifically
targeted antiviral therapy for HCV (STAT-C), immunomodulatory agents, and
antifibrotic agents. Additionally, novel ribavirin-like drugs as well as
interferons with more optimal pharmacokinetics (such as albumin-bound
interferon) are also in development. [6] This report discusses the most
recent data regarding the STAT-C regimens, with a view toward the potential
future implications of these agents.

STAT-C Agents
The STAT-C regimens comprise the most exciting group of therapies on the
horizon for hepatitis C. These agents are based on the model of
antiretroviral therapy for HIV infection, targeting specific enzymes
important in the replication of HCV. Investigators have overcome many
challenges in the development of these compounds -- most important, the
development of "enzyme inhibitors" required a detailed knowledge of the
hepatitis C replication cycle. In turn, knowledge of these steps in the
cycle of hepatitis C replication required the development of an effective
replication cell culture system or HCV replicon system and a 3-dimensional
structure analysis of important HCV enzymes such as the NS3-4A protease and
NS5B polymerase.[ 7,8] Many HCV protease and polymerase inhibitors have been
developed over the past 5 years and tested in phase 1 and 2 clinical trials.

Protease Inhibitors
BILN-2061. HCV NS3 is a serine protease that mediates polyprotein processing
and that has a shallow hydrophobic binding region. BILN-2061 (Boehringer
Ingelheim, Ingelheim, Germany), a potent inhibitor of NS3, was one of the
first HCV protease inhibitors tested. A phase 1 clinical trial assessing the
antiviral efficacy of BILN-2061 showed that this agent rapidly reduced viral
load within the first 48 hours. Although BILN-2061 demonstrated potent
antiviral activity against HCV genotype 1, the virologic response was less
pronounced and more variable in HCV genotype 2 and 3 patients. Despite early
enthusiasm, further development has been halted because of concerns related
to potential cardiotoxicity in animal models.[9,10]

VX-950. VX-950 (Telaprevir, Vertex Pharmaceuticals, Cambridge,
Massachusetts) is a selective, specific, and potent peptidomimetic inhibitor
of the HCV NS3-4A serine protease. In this phase 1 clinical trial, patients
with HCV genotype 1 were randomized to placebo or to VX-950 monotherapy
administered at doses of 450 mg or 750 mg every 8 hours or 1250 mg every 12
hours for 14 days.[11] Results of this preliminary study showed that VX-950
administered at a dose of 750 mg every 8 hours resulted in a 4.4-log drop in
HCV RNA from baseline. In fact, this reduction in viral load occurred within
the first 4 days of treatment. A subsequent study examined efficacy during
dosing with VX-950 in combination with pegylated interferon alfa-2a. In this
study, one cohort of subjects received VX-950 in combination with pegylated
interferon alfa-2a for 14 days. At the end of the 14 days of the study
period, a 5.5-log decline in HCV RNA was noted. In fact, 6 of 8 patients had
undetectable HCV RNA (< 30 IU/mL) by day 14. After the completion of 14 days
of the study period, in an off-study follow-on treatment, all patients were
given a combination of pegylated interferon alfa-2a plus ribavirin for
another 24 weeks.[12]

Of the 6 patients who have completed 24 weeks of combination therapy with
pegylated interferon alfa-2a and ribavirin, 5 remain HCV RNA undetectable
after 12 weeks of follow-up.[12, 13]

In another larger study with longer duration, in a double-blind,
placebo-controlled fashion (phase 2b PROVE1 clinical trial), the safety and
efficacy of VX-950 in combination with pegylated interferon alfa-2a and
ribavirin in treatment-naive HCV genotype 1patients are being assessed.[14]
In this study, patients received at least 1 dose of VX-950 or placebo in
addition to pegylated interferon alfa-2a plus ribavirin. An interim analysis
presented during the 42nd Annual Meeting of the European Association for the
Study of the Liver (EASL) showed that 88% of patients receiving the triple
combination regimen achieved a rapid viral response (HCV RNA < 30 IU/mL);
79% achieved a rapid viral response as measured by HCV RNA levels < 10 IU/mL
at week 4 of treatment. In comparison, 16% of patients who received the
pegylated interferon alfa-2a, ribavirin, and placebo combination achieved a
rapid viral response (HCV RNA < 30 IU/mL) and 11% achieved a rapid viral
response as measured by HCV RNA < 10 IU/mL. The virus remained undetectable
after 20 weeks of follow-up (sustained virologic response "SVR 20") in 6 of
9 patients who completed their treatment. Although these data have not been
fully analyzed, the occurrence of rash has been reported in some subjects.
The final data regarding the efficacy and safety of this regimen are still
pending. Additional trials investigating the efficacy of combination
regimens involving VX-950, pegylated interferon-alfa, and ribavirin in
patients who were nonresponders to standard therapy with pegylated
interferon-alfa plus ribavirin are underway.

SCH503034. SCH503034 (Shering-Plough, Kenilworth, New Jersey) is another NS3
serum protease inhibitor. In a phase 1 clinical trial,[15] 61 patients
infected with HCV genotype 1 who were nonresponders to previous treatment
with pegylated interferon alfa were randomized to receive SCH503034 (100 mg
twice daily, 200 mg twice daily, 400 mg twice daily, 400 mg thrice daily) or
placebo for 14 days. Preliminary results showed that after 14 days of
monotherapy, SCH503034 given at a dose of 400 mg thrice daily was associated
with an approximately 2-log drop in HCV RNA from the baseline value. A
follow-up study assessed the virologic response of combination SCH503034
plus pegylated interferon alfa-2b in patients infected with HCV genotype 1
who were previous nonresponders to pegylated interferon alfa-2b-based
therapy.[16] Preliminary results suggested that the best viral response
occurred when pegylated interferon alfa-2b was given in combination with
SCH503034 400 mg thrice daily for 14 days; a 2.88-log reduction in HCV RNA
occurred among patients in this treatment group. Ongoing phase 2 clinical
trials are assessing the efficacy of SCH503034 given in combination with
pegylated interferon alfa-2b ± ribavirin in HCV genotype 1 patients who are
nonresponders to previous treatment. The results have not been fully
reported to date.

Other Protease Inhibitors. The antiviral activity of ACH-806 (also known as
GS-9132; Achillion Pharmaceuticals/ Gilead Sciences), another HCV protease
inhibitor, has been tested in a phase 1 clinical trial. In data presented at
the recent EASL meeting in Barcelona, Spain, treatment with ACH-806 was
associated with a 2.38-log drop in HCV RNA within 5 days of therapy.[17] It
is important to note that there has been concern about an increase in
beta-2-microglobuli n and serum creatinine that was observed during this
study. Finally, ITMN B (Intermune, Brisbane, California) is another HCV
protease inhibitor that has been tested in replication model(s).[6] Although
protease inhibitors represent an exciting class of compounds in development
for the treatment of HCV infection, they have a short half-life and require
dosing every 8 hours.

HCV RNA Polymerase Inhibitors
In addition to protease inhibitors, many other agents are being developed to
target the HCV RNA-dependent RNA polymerase. One of these agents, NM283
(Valopicitabine, Idenix Pharmaceuticals, Cambridge, Massachusetts) , is a
ribonucleoside analog that targets the viral RNA polymerase and is a viral
RNA chain terminator. Godofsky and colleagues[18] presented the results of a
phase 1/2 dose-escalation trial of NM283 in the range of 50 mg per day to
800 mg per day. Results showed that the best response to NM283 occurred at a
dose titrated between 400 mg and 800 mg/day. However, higher doses were
associated with significant side effects, specifically nausea and vomiting.
In a study presented at the recent EASL meeting, NM283 was administered in
combination with pegylated interferon alfa-2a to HCV genotype 1 patients who
were nonresponders to previous pegylated interferon alfa and ribavirin-based
therapy.[19] Despite early enthusiasm, this trial failed to demonstrate an
enhanced sustained virologic response in this difficult-to- treat group of
patients with hepatitis C. A study assessing the safety and efficacy of this
agent given in combination with pegylated interferon alfa and ribavirin is
currently underway.

R1626 (Roche Pharmaceuticals, Basel, Switzerland) , another nucleoside analog
oral polymerase inhibitor, has been administered at doses ranging from 500
mg to 1500 mg twice daily for 14 days in treatment-naive HCV genotype 1
patients. The initial clinical trial involving this agent demonstrated a
clinically significant approximately 1.2-log reduction in HCV RNA associated
with the 1500-mg twice-daily dosing regimen.[20] A subsequent multiple
ascending dose study of R1626 (500 mg, 1500 mg, 3000 mg, and 4500 mg twice
daily for 14 days) was conducted in previously untreated patients with HCV
genotype 1 infection.[21] Mean (median) HCV viral reductions of 0.3 (0.2),
1.2 (0.8), 2.6 (2.7), and 3.7 (4.1) log10 were observed for doses of 500 mg,
1500 mg, 3000 mg, and 4500 mg, twice daily, respectively.

The nonnucleoside polymerase inhibitor HCV-796 (ViroPharma, Exton,
Pennsylvania and Wyeth Research, Philadelphia, Pennsylvania) has been
studied in a phase 1 clinical trial at doses ranging from 50 mg per day to
1500 mg per day. Approximately a 1.2-log drop in the HCV RNA viral load was
observed among patients receiving the higher doses (500-1500 mg/day).
However, this drug seems to be associated with an increase in HCV RNA
levels, which may be the result of the emergence of HCV variants.[22] A
phase 2 clinical trial of this agent given in combination with pegylated
interferon alfa-2a with or without ribavirin in both treatment-naive and
nonresponder patients is currently underway. In addition to these agents,
several other polymerase inhibitors, including MK-0608, A-837093, and
AG-021541, are also under development in the preclinical setting.[6]

Conclusion
In summary, research regarding the STAT-C agents suggests that protease
inhibitors can achieve a greater than 2.5-log reduction in serum HCV RNA
within 14 days when used as monotherapy. This is in contrast to polymerase
inhibitors, which achieve about a 1-log reduction in HCV RNA when used in
the same fashion and for the same duration of treatment. The efficacy of
administering these STAT-C drugs in combination with interferon with or
without ribavirin is currently being assessed in phase 2 clinical trials
using double or triple combination therapy regimens.

It is likely that future strategies for treating hepatitis C will involve a
cocktail of multiple agents that can target both the polymerase and protease
enzymes of the hepatitis C virus. In the short term, it seems likely that
these agents will be used in addition to the current standard of care,
combination pegylated interferon and ribavirin. Despite our tremendous
enthusiasm for the potential of these new therapeutic targets in hepatitis
C, many questions remain unanswered. First, how many drugs can be combined
to achieve optimal response and acceptable toxicity? Second, for what
duration do we need to use these combination regimens to achieve an
undetectable HCV RNA that will remain sustained in the long term?
Furthermore, with these new agents, will the current viral kinetic data from
combination therapy (rapid virologic and early virologic response) still be
applicable? It is likely that the development of new drugs will increase
costs, at least temporarily, and require close monitoring of both expected
and unexpected side effects.

The introduction of these targeted antiviral therapies is expected to
advance our therapeutic arsenal for patients with hepatitis C, especially
nonresponders to the current standard of care and the more
difficult-to- treat HCV genotype 1 patients. Nevertheless, it is critical
that the efficacy and safety of these drugs be established and that their
cost effectiveness and their impact on a patient's health-related quality of
life be carefully assessed.

Supported by an independent educational grant from Vertex

http://www.medscape .com/viewarticle /556641_1

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