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The
worldwide market for antiviral drugs is estimated to be approximately $10
billion and it is expected to grow rapidly as new therapies become
available. In 1990 there were just five licensed antiviral drugs; today
there are more than forty. Most of these drugs, however, are for treatment
of human immunodeficiency virus (HIV) and various herpesviruses. Most human
viruses are RNA viruses. There is an urgent need for drugs to treat the
numerous viral diseases caused by RNA viruses for which limited or no
therapeutic options are currently available. While virtually all major
pharmaceutical companies have antiviral discovery programs for HIV and HCV,
very limited drug discovery activity is being devoted to other viral
pathogens.
RNA VIRUSES
Hepatitis C virus (HCV)
HCV
is an RNA virus that causes chronic hepatitis that afflicts an estimated 170
million individuals worldwide, including approximately 4 million in the
U.S. The virus is transmitted by the transfer of body fluids (primarily
blood) from infected individuals. Those who abuse intravenous drugs, those
who received blood transfusions prior to 1992, and health-care workers,
account for the majority of infected patients. The level of morbidity and
mortality associated with HCV is high. The majority of infected patients
remain infected for life and a significant percentage of HCV-infected
patients ultimately progress to cirrhosis, liver failure, or hepatocellular
carcinoma (liver cancer). HCV infection has become the major reason for
liver transplantation in the U.S. By the year 2011, the U.S. Centers for
Disease Control predicts that the annual death toll from HCV and HCV-related
illness in the U.S. will exceed that from AIDS.
Unlike hepatitis A and B, no vaccine currently exists to prevent HCV
infection. The best available treatment is a combination of two
broad-spectrum antiviral agents, interferon and ribavirin. This therapy,
however, is only effective for about half of the patients and is associated
with serious side effects that cause 10-15% of patients to discontinue
therapy. The current market for treatment of HCV is estimated at $1.7
billion annually, and is expected to grow to a projected $6.6 billion by
2011. On June 10-12, 2002 the NIH Consensus Development Program held a
meeting to update the
Consenus Statement on the Management of Hepatitis C.
Similar to HIV, HCV has a high predeliction to develop resistance to
antiviral drugs during therapy. It is expected, therefore, that multi-drug
“cocktail” therapies, used in different combinations at varying stages of
the patient’s disease progression, will be necessary to effectively manage
chronic HCV infection. This suggests that the HCV market will be served by
numerous therapeutic agents.
Respiratory syncytial virus (RSV)
Contracted by virtually all children by the age of three, RSV spreads
rapidly through contact with respiratory secretions. RSV is the primary
cause of bronchopneumonia in infants and children in the U.S., and results
in approximately 100,000 hospitalizations and 4,000 deaths each year.
Premature infants, immunodeficient patients, and the institutionalized
elderly are at the greatest risk for significant morbidity and mortality
from RSV. Current treatments for RSV are suboptimal. Inhaled ribavirin is
difficult to administer, relatively toxic, and, as a result, infrequently
used. A prophylactically-administrated monoclonal antibody (Synagis,
MedImmune) is available for high-risk patients. The pipeline of potential
new therapies for RSV is limited and consists of a small number of drugs in
pre-clinical through Phase II development. RSV vaccines are under
development, but are not likely to eliminate the need for therapeutic agents
given the immunocompromised nature of those most at risk.
Other RNA viruses
The
vast majority of human viral pathogens are RNA viruses. There is a critical
medical need to develop effective therapies for a large number of these
viral pathogens. Among these are:
-
Other respiratory viruses (parainfluenza viruses, human metapneumovirus,
rhinoviruses, hantaviruses)
-
Enteric viruses (enteroviruses, rotavirus, caliciviruses, etc.)
-
Encephalitis-causing
viruses (West Nile virus, tick-borne encephalitis, etc.)
-
Hemorrhagic fever
viruses (Ebola,
Marburg,
Lassa fever, etc.)
These
viruses are not currently receiving significant research emphasis by the
drug-discovery industry. Apath’s antiviral screening platform, and
specifically our multi-virus drug screening assay, enables us to bring
multiple viral pathogens into our discovery program at very low incremental
cost, thereby leveraging the company’s identification and development of
lead antiviral compounds. Also, a number of RNA viruses are classified as
category A, B, or C agents of bioterrorism. Apath’s screening strategy is
well suited to identifying antiviral agents against potential bioterrorism
agents and other viral pathogens of concern to the military.
Apath Antiviral Drug Discovery Platform
Apath’s drug discovery program is focused on finding novel therapeutic
agents for RNA viruses. Apath has developed a broad-based proprietary
antiviral screening platform based on viral replicons. Replicons are
subgenomic, self-replicating RNA molecules that contain all the nucleotide
sequences required for RNA replication, transcription, and translation, but
are not themselves infectious. Apath is utilizing the HCV replicon as a
primary screening tool to identify inhibitors of HCV replication. Apath is
extending the replicon-based approach to antiviral drug discovery to other
medically important RNA viruses including both positive-stranded and
negative-stranded RNA viruses.
For
HCV, the subgenomic replicon represents the only robust viral replication
system in cell culture, and for other viruses subgenomic replicons represent
a tool for cell-based antiviral screening that avoids the problems
associated with using infectious virus. Whereas this is useful for any
viral pathogen, it is particularly important for BL-3 or BL-4 pathogens.
For several positive-strand RNA viruses such as Yellow fever virus (YFV),
Dengue virus (DV) and West Nile virus (WNV), infectious cDNA clones are
available and subgenomic replicons have been constructed in a manner very
similar to that of HCV. Using replicons of prototypical positive-strand
viruses such as Sindbis virus and Yellow fever virus, Apath has shown that
the replicon-based screening approach that we are using for HCV is adaptable
to many other positive-strand RNA viruses.
Apath
has also successfully demonstrated that the replicon concept can be applied
to medically important negative-strand RNA viruses. For many
negative-strand viruses important advances in reverse genetic systems have
identified the critical cis-acting elements and the trans-acting
factors required for viral genome replication. We have designed a
proprietary system based on ‘minigenomes’ that are replicated in trans
by viral replication proteins. A key step in the development of this
platform was achieved when the company successfully developed a subgenomic
or ‘minigenome’-based screening platform for respiratory syncytial virus
(RSV).
Multi-virus screening
Apath’s proprietary edge in the application of replicon-based screening for
antiviral compounds has been further enhanced by a new technology that
enables us to screen for antiviral activity against multiple viruses in the
same assay. Apath has filed a U.S. patent application covering this
invention. The essence of this technology is to pool multiple cell lines
each of which contains a specific viral replicon. An antiviral effect can
be tested against multiple subgenomic viral replication systems and the
relative efficacy of the candidate antiviral agent can be determined on each
viral replication system. Apath intends to develop and implement this
multi-virus assay as an integral element in our screening strategy going
forward. In addition to improving screening productivity for the two
principal viruses targeted by the company (HCV and RSV), implementation of
the multi-virus assay will allow Apath to add other RNA viruses to the
company’s drug screening and discovery program at very low incremental
cost. An additional advantage to this approach is that we will obtain
specificity information about ‘hits’ that will improve our prioritization
criteria as well as promote our efforts to identify broad spectrum antiviral
agents.
Broad-spectrum Antiviral drugs
The design and discovery of new antiviral drugs can be
directed against either viral or cellular targets. Drugs that inhibit viral
proteins are more likely to be virus-specific, are more prone to the
development of resistance, and, theoretically, are less toxic. However, the
significant toxicity seen with HIV protease inhibitors belies this last
assumption. Drugs that target cellular proteins are thought to be less
likely to promote resistance, but are presumed to be more prone to
toxicity. It is reasonable to predict, however, that there are cellular
targets that are unnecessary for cellular well-being, but critical to
replication of one or more viruses. Such cellular targets would be valuable
for antiviral drug development and possibly good targets for a
broad-spectrum antiviral agent.
Importance of
broad-spectrum antiviral agents
For any serious infections it is critical to start some form
of effective therapy as soon as possible and often well before a specific
diagnosis has been made. Treatment of suspected bacterial infections with
broad-spectrum antibiotics is commonplace in clinical practice. This
strategy would be a particularly attractive approach for treating severe RNA
virus infections such as viral hemorrhagic fevers which have a rapid
clinical progression and a high mortality rate. Defense against an outbreak
of a hemorrhagic fever syndrome would be much more effective if we could
treat infected patients early, and treat exposed individuals
prophylactically, with a broad spectrum agent, or a cocktail of agents,
while awaiting definitive diagnosis. Military personnel would also benefit
from early treatment of suspected exposure during an outbreak of a serious
viral disease.
Unfortunately, there are very few small molecule
broad-spectrum antiviral drugs. This is a consequence of the methods and
strategies used to discover antiviral compounds. Most antiviral discovery
programs focus on finding antiviral agents with specific activity against
particular viruses. This is because specificity is viewed as a desirable
feature, in that it is thought to correlate with higher potency and lower
toxicity. In addition, it is a relatively straightforward task to identify
and validate virus-specific targets because viral genomes are small and
relatively easy to manipulate. Herpesvirus DNA polymerases and the HIV
RNA-dependent DNA polymerase are examples of ‘obvious’ viral targets which
have been the focus of many successful antiviral development programs. In
addition, in the past cell-based screening programs involved viral
replication in permissive cell lines. This would generally be focused on
one virus, since setting up multiple viral replication screening assays is
cumbersome and not amenable to high throughput screening.
Replicon-based
screening is well-suited to finding molecules with broad-spectrum activity.
First, cellular targets are the likely targets of most inhibitors found in
cell-based antiviral screening. Also, having multiple viral replicon
systems allows us to have a low threshold to screen our libraries for
inhibitory activity against many viruses. Finally, Apath’s proprietary
multivirus screening platform (patent filed) facilitates these efforts.
Therefore, we are in a good position to leverage our capabilities into a
concerted effort directed to the identification broad-spectrum agents.
However, generating broad-spectrum ‘hits’ is just the beginning of the drug
discovery process. We have initiated a ‘hit-to-lead’ program (QSAR,
toxicity, etc.) that focuses on classes of compounds that have
broad-spectrum antiviral activity. This hit-to-lead program is distinct
from our virus-specific programs because each program is focused on
different compounds.
Biosafety
Office of
Biotechnology Activities, National Institutes of Health
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