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Despite improvements in treatment in recent years of hepatitis C patients
, currently treatment with pegylated interferon and ribavirin presents
failures in sustained viral response (approximately 50% for genotype 1
and 20% for genotype 2 and 3)
In the last (2007) Meeting of the
AASLD were introduced 16 new treatments under development. Providing
hope for patients who did not respond to therapy today. Below are
summarized the new treatments. (Click to continue link below right).
1)Albinterferon
Albinterferon alfa (alb-IFN) is a novel recombinant protein consisting of IFNa-2b genetically fused to human albumin.
Alb-IFN
in combination with oral RBV is safe and effective. Treatment with
1800mcg Q2w demonstrates significant antiviral activity in prior IFNa
non-responder patients.
2)Bavituximab
Bavituximab, an
investigational monoclonal antibody targeting phosphatidylserine (PS)
located on the surface of virus infected cells and enveloped viruses,
is being developed as an anti-HCV agent.
wice weekly IV doses of
bavituximab up to 6 mg/kg were safe and well-tolerated. Single-dose and
multiple dose pharmacokinetics of bavituximab are linear, predictable
and no accumulation appears to occur over time. Two weeks of dosing is
indicative of antiviral effect in a proportion of patients. Future
studies designed to optimize the dosing schedule and investigate
combining bavituximab with current standard therapy are planned.
3)Glycyrrhizin
A
significant number of patients with chronic hepatitis C genotype 1 fail
to respond to the standard therapy of PEG-IFN- plus RBV, or cannot be
treated for various reasons. There are no options for non-responders to
previous standard therapies. Glycyrrhizin (GL) is used in Japan for
more than 20 years to treat such cases (SNMC, Minophagen).
GL
appears to be effective and well tolerated in the treatment of chronic
hepatitis C not responding to IFN or PEG-IFN plus RBV therapy.
4)Infergen
Consensus
interferon (CIFN; infergen, interferon alfacon1) demonstrates enhanced
activity in vitro compared with other alfa interferons. Genotype 1
patients may benefit from an interferon with increased activity, more
favorable viral kinetics from daily dosing, and a longer duration of
therapy.
Patients with hepatitis C genotype 1 and
"difficult-to-treat" characteristics treated with daily CIFN+RBV
demonstrated a high RVR rate, with 33% virus-negative at 4 wks and 67%
virus negative by 24 wks. This compares favorably with RVR rates of
19-22% for genotype 1 patients treated with pegylated interferon
alfa-2a and ribavirin (Gastroenterology 2006;130:1086 and 131:451).
Although adherence and tolerability are limitations, these data
indicate that daily CIFN+RBV for initial treatment of U.S. genotype 1
patients have promise primarily via an enhanced RVR rate. (Supported by
Valeant Pharmaceuticals; Veterans Affairs Research Service)
5)Infliximab
High
levels of TNF may contribute to the pathogenesis of hepatitis C virus
(HCV) infection. This study evaluated the safety of infliximab in
HCV-infected patients and assessed the effect of infliximab induction
therapy on early virologic response and sustained virologic response (SVR).
The
anti-TNF effect of infliximab on HCV may provide viral decline during
the first 8 weeks of HCV therapy. It is unknown whether infliximab
treatment before combination PEG-2b + RBV therapy will translate into
greater SVR rates.
6)Locteron
Controlled-release
recombinant interferon-alfa 2b (Locteron) is a novel approach to
delivery of interferon (IFN) given every 2 weeks with improved
tolerability combined with a high level of hepatitis C virus (HCV)RNA reduction.
Locteron,
a controlled-release formulation of unmodified IFN-alfa 2b,
administered every 2 weeks to treatment-na ve patients with chronic
hepatitis C (genotype 1) demonstrated strong anti-viral activity
combined with an improved safety and tolerability profile compared to
currently marketed IFNs and those in development.
7)Nitazoxanide
Nitazoxanide
(NTZ), a thiazolide anti-infective agent approved in the United States
for treating emerging intracellular protozoan infections, blocks viral
protein synthesis at a cellular level by selectively inhibiting
dephosphorylation of eukaryotic initiation factor 2 (eIF2 ).
The
addition of NTZ to PegIFN or PegIFN-RBV improved RVR, EVR and ETR rates
compared with PegIFN-RBV therapy without increase in adverse events.
Patients are being followed to evaluate SVR rates. Further trials are
being conducted in the United States in patients with genotype 1.
8)HCV Polymerase ( NM107 ) and Protease ( Boceprevir ) Inhibitors
Combination
of small-molecule antiviral agents directed against different molecular
targets offer an attractive strategy for the effective therapy of
hepatitis C. As monotherapies, valopicitabine (NM283)
(Idenix/Novartis), an investigational nucleoside NS5B polymerase
inhibitor, and boceprevir (SCH 503034) (Schering-Plough), an
investigational NS3 protease inhibitor, have demonstrated antiviral
activity against hepatitis C virus (HCV) in clinical studies.
In
these in vitro studies, the combination of the polymerase and protease
inhibitors showed enhanced anti-replicon activity with no
cross-resistance and a greater genetic barrier to resistance. These
results support clinical evaluation of this combination in patients
with chronic hepatitis C.
9)R1626
The novel nucleoside,
R1626, is a potent inhibitor of the HCV RNA polymerase. When
administered as monotherapy to patients with chronic hepatitis C, R1626
demonstrates dose-dependent decreases in HCV RNA blood levels.
This
Phase 2a study evaluated the safety and efficacy of R1626 administered
for 4 weeks in combination with 180 g peginterferon alfa-2a (PEG-IFN
-2a) 1000-1200 mg ribavirin (RBV) in HCV genotype 1 treatment-naive patients.
A
robust synergistic antiviral effect was observed when R1626 is combined
with PEG-IFN -2a RBV, with up to 81% of patients undetectable by week
4. Dosing of R1626 may be limited mainly by neutropenia; additional
studies of different dosages of R1626 in combination with PEG-IFN -2a
and RBV are underway.
10)R7025
R7025 is a novel human
pegylated IFN molecule generated using DNA Shuffling (Maxygen, Inc.)
technology that exhibits ~50-fold higher antiviral activity compared to
PEG-IFN -2a
R7025 doses up to 80 g were well tolerated with 20 g
being the lowest pharmacologically active single dose studied. R7025
doses of 40 g and greater produced a level of serum neopterin and 2,5
OAS induction which was comparable to a 180 g dose of PEG IFN -2a. Most
AEs were mild and consistent with those observed after administration
of IFN . At a dose of 120 g transient severe flu-like symptoms were
observed. Changes in hematological parameters observed across all doses
were mild and reversible. The findings from this study warrant further
evaluation of R7025 in CHC patients.
11)R7227
Is a potent HCV NS3/4A protease inhibitor in clinical development.
ITMN-191
is a highly potent, slowly dissociating inhibitor of the HCV NS3/4A
protease. The strong inhibition of genotype 1-6 proteases supports the
use of ITMN-191 to treat multiple genotypes of HCV.
12)R7128
R7128
is a prodrug of PSI-6130, an oral cytidine nucleoside analog polymerase
inhibitor, currently in development for the treatment of HCV.
All
subjects had HCV genotype 1 , had previously failed alpha-interferon
and were non-cirrhotic. There were no SAEs reported and no AEs required
dose modification; no clinically significant changes in vital signs,
ECGs, hematology, renal or other laboratory parameters occurred.
Preliminary data on adverse events (AEs) reported during treatment in
subjects receiving R7128 include a total of 32 events in 14 of 24
subjects, most of mild intensity as compared to 26 events in 5 subjects
receiving placebo. 18 AEs were reported in 7 subjects that received
750mg QD, 3 AEs in 3 subjects receiving 1500mg QD, and 11 AEs in 4
subjects receiving 750mg BID. The most frequently reported AEs for
patients receiving R7128 were headache , dry mouth , nausea, and upper
respiratory infection ; in subjects on placebo, headache (3) and
diarrhea (3) were most commonly reported. The baseline HCV RNA
concentrations, ranging from 5.2 to 7.4 (log10 IU/mL), and mean change
from baseline observed, ranging from -0.7 to -2.9 (log10 IU/mL) for
active, are summarized in the table below. Plasma exposure to the
prodrug, R7128, was negligible; exposure to PSI-6130 and a uridine
metabolite, PSI-6206, increased with increasing doses of R7128.
Terminal half-life was approximately 5 h for PSI-6130 and 20 h for
PSI-6206. Conclusion: R7128 monotherapy was generally well-tolerated
and resulted in significant, dose-dependent suppression of HCV
replication following 14 days of monotherapy. These results support
continued development of R7128 for the treatment of HCV infection in
combination with pegylated interferon and ribavirin. Results for the
1500 BID cohort will be available for presentation.
13)Telaprevir
Telaprevir
(TVR) is a highly selective inhibitor of the hepatitis C virus (HCV)
NS3/4A protease with highly effective blocking of HCV replication in patients with hepatitis C.
In
patients treated with TVR with and without peginterferon alfa 2a for 2
weeks followed by standard therapy with peginterferon and RBV for 24 or
48 weeks mutations conferring resistance to TVR can be detected after
relapse. The significance of TVR resistance mutations for the
probability of relapse has to be investigated in future studies.
14)Thymosin alpha – 1
Early
pilot studies suggested that an immunomodulatory peptide, thymosin
alpha-1 (TA-1) may play a role in enhanced viral clearance, histologic
improvement and sustained viral response.
Among treatment
experienced subjects with HCV infection, retreatment with PEG + TA-1
resulted in a similar sustained virologic response when compared to use
of PEG monotherapy. Studies utilizing PEG, TA-1 and ribavirin are in
progress.
15)Valopicitabine
Future HCV therapy will
likely combine drugs with different modes of action and complementary
resistance profiles. We investigated the pharmacokinetics, antiviral
activity and safety of valopicitabine, an investigational NS5B
polymerase inhibitor, combined with PegIFN and RBV.
Valopicitabine
combined with PegIFN/RBV demonstrated additive antiviral activity. HCV
RNA PCR-negativity rates at all timepoints were consistently greater in
the triple regimen compared with PegIFN/RBV. However, the incidence of
GI-related adverse events and lab abnormalities was higher in the
valopicitabine-containing arms. After comprehensive review of the
valopicitabine clinical program, the development of this molecule has
been discontinued due to its overall risk/benefit profile.
16)VCH – 759
VCH-759
is a novel, orally bioavailable non-nucleoside inhibitor of hepatitis C
virus RNA-dependent RNA polymerase. It has demonstrated sub-micromolar
IC50s against the HCV replicons of genotype 1a and 1b.
VCH 759
achieved a 2 log10 or larger decline in HCV RNA at doses of 800 mg tid
and bid. VCH-759 was well tolerated with no serious adverse events and
no discontinuation. Genetic sequencing of NS5B is ongoing. Further
studies combining VCH-759 with current therapies are warranted.
http://clinicaltrialsweb.blogspot.com/2007/11/16-new-treatments-for-hepatitis-c.html
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