Dec. 1, 2005--Hepatitis C
virus (HCV) is deadly, widespread, grossly under-diagnosed,
and drastically under-treated. With the U.S. market alone valued
at more than $800 million in 2004, it is an enticing field for
drug development. Many small improvements in treatment are
anticipated over the next few years. These advances could be
followed by a giant leap within the next two-to-five years thanks
to completely new approaches. Making that leap will be tricky
because everything from how the disease develops to the
actual structure of key viral protein targets make this virus hard
to eradicate, but the progress so far is tantalizing with some new
approaches now at the critical Phase II trial stage.
Therapy
for chronic HCV has evolved a lot over the past 20 years, and the
gold standard is now a combination of pegylated interferon and
ribavirin, although some patients will receive interferon alone (Strader,
Hepatology, 2004). Interferon works by improving
the body's own immune response, while ribavirin is an antiviral.
The good news is that some patients can actually be completely
cured of this disease, unlike more stubborn viral infections such
as herpes or HIV. However, it has been tough to find a quick,
convenient, and effective way to treat many patients.
Today, more
than 170 million people worldwide suffer from chronic HCV,
according to the World Health Organization (WHO,
HCV Fact Sheet). Many of these individuals live in developing
countries and simply cannot afford the expensive treatments, which
are given over many months. Among the approximately 10 million HCV
patients in Europe and the United States, even those with access
to top-line medicines may end up dying from the disease. Today's
drugs, while a big improvement over earlier regimens, have serious
side effects and a dismal cure rate–about half of patients are
still unresponsive. The HCV genotype 1 strain, which is the most
common strain in the United States, is particularly hard to treat
with current drugs. The disease is also stealthy, often showing
few signs. As a result, even in the United States, only about half
the estimated 2.7 million people carrying HCV are diagnosed and
only a small number of those (approximately 80,000) receive
treatment.
Reaching
for Breakthroughs
With so
much room for improvement and so many intriguing new development
approaches maturing, the competition is heating up around new
chronic HCV treatments. Some of the emerging drugs are merely new
forms of interferons and/or nucleoside analogues, which represent
important advances but not real breakthroughs.
Work is
also being done on other immunomodulators and similar agents
designed to shore up the body's own defenses against the HCV. The
most advanced of these agents is SciClone Pharmaceuticals' Zadaxin
(thymalfasin), which is a synthetic version of thymosin alpha 1
and is already in Phase III trials as a combination therapy with
interferon. This drug is already approved for treating
hepatitis B and C in many countries, though not the US or Europe.
Another, particularly active, emerging immune research field
involves the Toll-like receptors. Both Anadys Pharmaceuticals and
Coley are hoping to develop Toll-receptor-targeting drugs for HCV
(Pollack,
The New York Times, 2005).
The
best news, however, is that there are now completely novel
approaches that target HCV specifically, including therapies that
target either HCV-specific enzymes or human enzymes that are
essential for viral replication in the host cell. (See Table 1.)
Two HCV-specific enzymes being targeted are
Source: Sannes & Associates, Inc.
and Cambridge Healthtech Institute.
HCV NS3/4A is an essential enzyme for
viral replication (Chen,
Curr Med Chem, 2005, and Chung,
Antimicrob Agents Chemother, 2005). Protease inhibitors
emerged as a new and powerful tool against HIV in the mid 1990s.
Yet, development of an HCV protease inhibitor has progressed
slowly, in part because the protease's structure makes it hard to
design an inhibitor with a snug fit: The active site, which is the
spot drugs must latch onto, is just a shallow dent on the surface
(Venkatraman,
J Med Chem, 2005). It has taken many years as well as a
great deal of careful structural analysis and experimentation to
find potent inhibitors of this molecule (da Silveira, BMC
Struct Biol, 2005).
In 2002, Boehringer Ingelheim created
considerable excitement when it announced results of a clinical
study evaluating an HCV protease inhibitor (BILN-2061) that
appeared to be extremely potent in preclinical studies. For the
first time, it seemed like it might be possible to swiftly and
easily wipe the virus out of an infected person's blood (Goudreau,
Expert Opin Investig Drugs, 2005, and
Lemon,
Hepatology, 2005). Unfortunately, Boehringer Ingelheim
has since put the development of this compound on hold because of
worrisome side effects seen in primates receiving high
doses (Francesco, Nature, 2005).
Work in this area has continued at a
fast pace. The most advanced protease inhibitor appears to be
Vertex Pharmaceutical's VX-950, which is headed for a 28-day,
Phase II combination study with pegylated interferon by the end of
2005. This drug is also very potent. In one early trial, 50% of
patients treated with VX-950 had virtually unmeasurable blood HCV-RNA
levels after just two weeks on the drug. Several other companies
are working on research-stage or early clinical HCV protease
projects, including Enanta, Gilead Sciences (GS-9132), InterMune,
Medivir, and Schering-Plough (SCH-503034).
New HCV drugs should not just be
powerful but also able to outmaneuver resistance-conferring
mutations. Such mutations somewhat dampened the joy
surrounding the introduction of protease inhibitors against HIV.
As a result, researchers are already putting consider effort into
trying to solve this problem in HCV, and they are starting to
understand which specific mutations cause the most trouble and how
to avoid them (Mo,
Antimicrob Agents Chemother, 2005). Nonetheless,
multiple drugs may always be required to treat HCV, just as
protease inhibitors have become part of a critical
"cocktail" of therapies for HIV.
An alternative target is the HCV RNA
polymerase, which is also required for viral replication. At least
two drugs that target this enzyme have reached Phase II clinical
trials--Idenix Pharmaceuticals' valopicitabine (NM-283) and Japan
Tobacco's JTK-002. Even more companies have HCV RNA
polymerase inhibitors programs in earlier stages of development.
Other convenient drug targets are the
human (host) enzymes that HCV requires to replicate. For
example, Vertex Pharmaceuticals' merimepodib (VX-497) inhibits
inosine monophosphate dehydrogenase, an enzyme that regulates
cellular production of nucleotides. Merimepodib has been evaluated
in a couple of Phase II clinical trials, one of which involved
more than 300 patients taking standard therapy along with the
drug. But Vertex recently announced that it is
"minimizing" its investment in this drug and is not
conducting additional trials, which suggests the results are not
promising.
Another intriguing and recent entrant
to this race is Migenix's Celgosivir (MX-3253), an alpha-glucosidase
I inhibitor. This enzyme is involved in early glycoprotein
processing, which helps stabilize the virus and facilitate its
replication. The drug is currently being evaluated as a
monotherapy in a Canadian Phase II trial. A combination therapy
Phase II trial, with Pegintron, is also beginning.
A completely new host target is the
microRNA (miRNA) miR-122, which is also necessary for HCV
replication in human cells. Work on microRNAs is in its infancy,
but evidence is growing that the workings of these tiny molecules
can explain a lot of poorly understood biology (Gough,
Science
STKE, 2005). Alnylam Pharmaceuticals and Isis
Pharmaceuticals recently established a co-exclusive license with
Stanford University around RNA-based anti-HCV therapeutics (Jopling,
Science, 2005).
Reshaping the Market
Despite the limitations of current HCV
treatments, this market is already a healthy one. For 2004, Roche
reported combined sales of Pegasys (pegylated alpha-interferon)
and Copegus (ribavirin) of approximately $1.26 billion.
Schering-Plough, which has faced significant competition from
Pegasys as well as generic forms of ribavirin, reported sales of
$563 million for its PEG-Intron and $287 million for Rebetol (ribavirin)
in 2004.
When safer and more effective
breakthrough HCV therapies eventually reach the market, the number
of patients treated is expected to expand substantially, making
this market an even juicier target for pharmaceutical development.
(See Figure 1.) In a recent presentation, Vertex CEO Joshua Boger
estimated that by quadrupling the number of treated patients, the
world market for chronic HCV treatment could swell to $9 billion
by 2010. That much expansion is feasible because so many patients
are currently untreated. In its 2010 forecast, Vertex was
assuming that, in the United States, for example, only approximately
20% of all chronic HCV carriers would be diagnosed and treated.
Vertex estimates that only 5% of U.S. patients are currently being
treated.
Source:
Cambridge Healthtech Institute
None of
these therapies has gotten past Phase II trials yet, and many
candidates have already faltered along the way. The protease
inhibitors in particular have been hailed as potential
breakthroughs for several years already, and still major questions
remain about how best to inhibit these new targets, how to avoid
resistance, and, most importantly, how these new drugs will affect
real patients.
But this is
an area where several start-ups, as well as established companies
such as Vertex and Gilead Sciences, are investing substantial
resources. A truly breakthrough HCV treatment would also be
a likely candidate for the FDA's fast track pathway to approval.
Vertex, which has already launched two protease inhibitors against
HIV, is focusing on VX-950 as one of its top development
priorities. If everything goes perfectly, the company could file
an NDA for this drug within two years. Enanta is also very serious
about protease inhibitors for HCV and recently licensed Chiron's
portfolio of such drugs. Those two companies have been working
together on such products since 2002. Anadys, meanwhile, recently
received a big helping hand from Novartis, which provided $20
million upfront, with as much as $550 million in possible later
payments, for work on Toll-like receptor targeting drugs,
including ANA-975.
The other
silver lining to finding new treatments for chronic hepatitis C is
the validation it would provide for the approaches involved. If
the protease inhibitors succeed, it will be one of just a few
examples so far of real rational (i.e., structure-based) drug
design. If the miRNA approach bears any fruit, it will be one of
the first areas of medicine to boast any such products. As
a result, anti-HCV drug development is a critical arena to watch.
Malorye
Allison Branca contributed to this report.
References
and Available Links
Chen, SH,
and Tan, SL. "Discovery of small-molecule inhibitors of HCV
NS3-4A protease as potential therapeutic agents against HCV
infection." Curr Med Chem. 2005;12(20):2317-2342.
Mo, H, et
al. "Mutations conferring resistance to a hepatitis C virus (HCV)
RNA-dependent RNA polymerase." Antimicrob. Agents
Chemother. 2005;49:4305-4314.
Click here for more info
Pollack, A.
"A revival for immunity." The New York Times.
Oct. 5, 2005.
Click
here for more info
Strader, D,
et al. "AASLD practice guideline: Diagnosis, management
and treatment of hepatitis C." Hepatology.
2004;39(4):1147-1171.
Click
here for more info
Venkatraman,
S, et al. "Design and synthesis of depeptidized macrocyclic
inhibitors of hepatitis C NS3-4A protease using structure-based
drug design." J Med Chem. 2005 Aug
11;48(16):5088-5091.
