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Non-nukes
Non-nucleoside reverse transcriptase
inhibitors (NNRTIs) have the highest incidence of failure
because of resistance to HIV. There are several new NNRTIs
in development that were picked from the drawing board because
they are active against the current NNRTIs. TMC-125 from Tibotec
is being studied in Phase II trials in Europe. So far the
data looks compelling. Glaxo is screening a whole new class
of non-nukes that won’t be cross-resistant.
Integrase inhibitors
An interesting new class
of drugs that target the integrase enzyme in virus replication
are coming into the spotlight. Several years ago there was
work being done with integrase inhibition but the first compound
did not make it very far. Today there are two integrase inhibitors
that have made it to clinical trials. They are S-1360 from
GlaxoSmithKline/Shinogi that is in Phase I/II and Merck’s
L-870, 810 in early Phase I.
The science of entry inhibition
was inspired by Fuzeon’s success. Since that drug is proving
to work, scientists are looking at all the different ways
HIV attaches and enters the cell. Without all of the connecting
mechanisms in place, the virus cannot attach, fuse and then
finally enter and infect the cell. There are currently six
classes that make up 12 different types of entry inhibitors
in various stages of development, quite a bumper crop indeed.
One promising class is the
CCR5 antagonists that seek to stop co-attachment of HIV to
the CD4 cell. CCR5 co-receptors are a type of receptor that
are associated with most people with HIV, so in theory, it
is hoped they can work to stop attachment. The leading CCR5
inhibitors are Schering-Plough’s SCH C and Pfizer’s UK-427,
857. This technology holds great promise; however, one concern
is that many other cells use the CCR5 co-receptor, so until
more studies are done we won’t know if the drugs will harm
other cells.
Another attachment inhibitor
compound is PRO-452 that works in conjunction with human antibodies
to stop early attachment, before the fusion and entry steps.
The only problem is that this drug is also delivered by subcutaneous
injections.
Finally, Fuzeon’s sister
compound, T-1249, shows the most promise in early Phase II
development in people who are resistant to Fuzeon. From studies
so far, the drug shows a 1.12-log viral load drop in resistant
trial participants. Studies show the longer you have T-20
resistance the less effective T-1249 will be.
One out of the ordinary development
in Boston was the presentation of TNX-355, another new class
of anti-HIV drugs. It is a monoclonal antibody that inhibits
post binding on the CD4 cell. It is moving into Phase I in
an open-label study. Its big drawback thus far is that it
is given by a once monthly IV infusion. But as with Fuzeon,
it may be a good drug for those who are multi-drug resistant.
It is moving into dose escalation studies.
Brand new
One final drug class under
development and presented at the conference was what is being
called a “maturation inhibitor.” Panaco’s PA-457 has only
been studied in the laboratory but the company plans to submit
their Investigational New Drug (IND) application to the FDA
for clinical trials in a few months. This drug works by disrupting
the new RNA that is budding out of the cell in its baby virion.
However, how it does that is not entirely clear. This drug
is a surprise because it is a totally new class that few expected.
There’s more
Other drugs are coming down
the pike including zinc finger inhibitors (remember those?),
several cellular factor inhibitors, new protease inhibitors
and nucleoside and non-nucleoside reverse transcriptase inhibitors.
Also, we cannot forget the importance of treatment vaccines
in development and other immune-based technologies that often
get forgotten in the antiviral shuffle (see page 16).
This large group of AIDS
drugs has promise, simply in the fact that there is so much
new interest in developing therapies that work for more and
more people who have become drug resistant. I asked Ben Cheng
from the Forum for Collaborative HIV Research how many of
the 59 drugs he lists being studied would end up useful and
he replied, “Based on my very unscientific tracking of the
drugs that have been presented at conferences (usually starting
pre-clinical and have some in vitro activity), about 10-15%
make it to market.”
The pipeline for new HIV
drugs is indeed impressive and hopeful for the people who
have access. However, with the latest approval of Fuzeon,
it is clear that new high technology drugs from this point
on may be only available to a few people in developed countries,
and not at all in the rest of the world.
The pricing of new classes
of AIDS drugs must be monitored by the community. People with
AIDS must continue to proactively monitor pharmaceutical pricing
discussions during the development of all new drugs. There
should be a demand for worldwide access to all new drugs from
day one. It is simply our moral obligation. The American Foundation
for AIDS Research has a telling advertisement that reads,
“1 million treated for HIV …41 million to go.”
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