A special report provided by EASL of the EASL-AASLD Conference on - Therapy of Hepatitis C: Clinical Application and Drug
Development held this month in Prague, Czech Republic, is now available for viewing - Download PDF.
Highlights Include:
Therapy of Hepatitis C:Clinical Application and Drug Development
HCV transmission and therapeutic intervention
One year of triple combination therapy New HCV drugs in development
Overcoming resistance and treatment failure
New ways to search for novel anti-HCV drugs
*New HCV drugs in development (provided below)
New HCV drugs in development
“We have come a long way with interferon treatment since it was
first introduced in 1991 to the use of pegylated interferon as part
of triple HCV therapy today. Some are predicting therapy will be
interferon-free. But we need all the tools we can get to improve the
management of HCV and novel interferons and IFN inducers may
have an important role in some patient subgroups,” said Dr. Michael
Manns, Medical School of Hannover, Germany.
He suggested that
interferon-based therapies have several potential advantages compared
to direct antiviral agents:
• No viral resistance
• Comparatively low cost
• Vast clinical experience
• Potential use in other viral infections such as HBV.
For the future, INF-based therapy may be appropriate for easy to treat
patients, but new interferons have to be developed that are much safer
and better tolerated than current options.
Newer NS3/4A protease inhibitors in combination with peg-IFN and
ribavirin achieve high rates of SVR with simpler dosing schedules and
generally better tolerability than older agents, according to Dr. Michael
Fried, University of North Carolina, USA. He said that two years of clinical
experience with the currently available PIs have shown that ribavirin
is required for achieving SVR, rapid virological response is associated
with highest SVR and adverse events can generally be managed but
that certain populations are less responsive. New PIs in development
include simeprevir and faldeprevir (phase 3) and asuneprevir and ABT-
450/r (phase 2), mostly with peg-INF + RBV backbone. Trials so far show
encouragingly high rates of SVR and generally good tolerability, but we
have to wait for more data, he concluded.
“It’s becoming clear that nucleoside/nucleotide analogues provide
a very strong backbone for future HCV therapies,” argued Dr. David
Nelson, University of Florida, USA. They work by causing premature chain
termination during viral nucleic acid synthesis. The active binding site in
the target – NS5B RNA-dependent RNA polymerase – is highly conserved
across HCV genotypes, conferring pangenotypic activity and there is a
high barrier to resistance. Three agents are currently in development:
sofosbuvir (phase 3), mericitabine (phase 2) and ALS-2200 (phase 2),
while some others have been put on hold due to toxicity.
“Sofosbuvir (previously GS-7977) will be the most important compound
during the next 2-4 years,” predicted Professor Wedemeyer. He noted
that sofosbuvir therapy was successful in various IFN-free regimens and
may also help to shorten IFNa-based therapies. “However, we have
learned over the last few months that there will be no ‘one-size-fits-all’
regimen with sofosbuvir.”
Non-nucleoside inhibitors of HCV RNA polymerase have no role in
monotherapy and limited role in triple therapy, but they may be useful in
quadruple therapy, suggested Dr. Paul Pockros, La Jolla, USA. Reviewing
the available data, he noted that these agents have low to moderate
potency, a low barrier to resistance and are unlikely to have crossgenotype
activity. “Of the 13 non-nucleoside inhibitors in development in
2008, a lot have given disappointing results, with only six remaining,” he
said. Of these, Vx-222 is the most potent, achieving a 3.4 log10 reduction
in viral load (at a dose of 400mg bid) and is currently in phase 2. However,
some compounds may still be used in IFN-free treatment regimens if
combined with other highly potent DAAs.
Therapeutic vaccines represent a scientifically valid approach to
treating HCV but there is a long way to go to optimise vaccine response,
suggested Professor Heiner Wedemeyer. He questioned whether
vaccines for HCV are needed at all, with all the new drugs currently in
development, but suggested several reasons why they may be useful.
“First, HCV is not HIV,” he pointed out. “Immune control of HCV is
possible, in contrast to HIV infection.” Clinical observations show – quite
remarkably – that 10-50% of cases of acute hepatitis C are cleared
without treating, suggesting a major role for the immune system.
Combinations including NS5A inhibitors appear likely to address many
of the current unmet medical needs in HCV, especially for patients who
remain difficult to treat with currently available therapies, including
those with cirrhosis and patients undergoing liver transplant, according
to Dr. Stanislas Pol, Hopital Cochin, France. Reviewing the data with
daclatasovir, the first agent in the class, he said it is very potent, has
broad genotypic coverage and has a pharmacokinetic profile supportive
of once daily dosing, making it easy to take. A recent study with
quadruple therapy including daclatasovir, asapravir and peg-interferon/
ribavirin has shown ‘fantastic results,’ he said, with SVR4 of 90-100% in
a difficult to treat group of genotype 1 null responders. Moreover, NS5A
inhibitors are part of many IFN-free treatment regimens.
Cyclophilin inhibitors offer the benefits of a high barrier to resistance
and no cross-resistance with protease or polymerase inhibitors, Professor
Robert Flisiak, Medical University of Bialystok, Poland, told the meeting.
They act on NS5A, NS5B and NS2 HCV viral proteins, as well as preventing
HCV-mediated mitochondrial and endogenous interferon production.
Alisporivir – the most advanced agent in the class – has shown effects
in treatment naïve, previous non-responders and in HIV/HCV coinfected
patients. It has demonstrated antiviral efficacy against the four
most prevalent genotypes (1,2,3 and 4). It is effective in interferon-free
regimens, as well as providing additional antiviral effects in combination
with peg-interferon plus ribavirin, and is well tolerated. However, it is
currently on hold due to toxicity in combination with PEG-IFNa. Future
trials may therefore focus on IFN-free regimens including alisporivir.
Entry inhibitors, which block the entry of HCV into cells, are at an early
stage of development but proof of the concept has been demonstrated
in cell culture and in vivo models, reported Professor Thomas Baumert,
University of Strasbourg, France. They are pangenotypic, prevent
infection with escape variants and provide a complementary mechanism
of action of direct antiviral agents, demonstrating marked synergy. “They
offer a very attractive antiviral strategy for the prevention of liver graft
infection in patients who have undergone transplantation, as well as for
difficult to treat patients and those with multiresistance,” he suggested.
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