PI Perspective #38
July 2004 View PDF En
español
Entry Inhibitors
Entry inhibitors are a new class of anti-HIV drugs that work by
blocking the virus’ ability to infect a cell. There are two
general types of entry inhibitors: fusion inhibitors and attachment
inhibitors. They may be joined by a third type in future years.
Enfuvirtide (T20, Fuzeon), a fusion inhibitor approved by the Food
and Drug Administration in 2003, is the first of this new class
available for wide scale use. While enfuvirtide has proven to be
potent, its side effects, mostly associated with the fact that it
has to be injected with a syringe, have discouraged many people
from using it. Still, others have been denied access because of
the extremely high cost of the drug, which prevents many states
from including it in their AIDS Drug Assistance Programs (ADAP).
For more information on enfuvirtide, call Project Inform’s
toll-free hotline at 1-800-822-7422.
Many believe the greater promise for entry inhibitors will be realized
with small molecule drugs. When large molecule drugs, like enfuvirtide,
are taken orally, the digestive process breaks them into smaller
pieces, thus rendering them ineffective. Therefore, they must be
taken by injection. Small molecules drugs, however, are unaltered
by the digestive system and can be taken by mouth, avoiding the
problems associated with injections. Several are in development,
including six that are in human studies, which we report on here.
HIV viral entry involves four steps. First, the virus attaches
to the CD4+ protein, a receptor that appears on certain cells of
the immune system. Then, it binds to a second surface protein on
these cells, called a co-receptor. The most common co-receptors
for HIV are CCR5 and CXCR4. Once it’s anchored to the two
receptors, the virus fuses its outer coat to the coat of the cell.
Lastly, HIV sheds its own coat and injects its genetic material
from its core into the cell.
There are compounds in development that target each of these entry
steps. Most are still in test tube studies. The six entry inhibitors
currently in human studies can be divided into two categories—those
that block the first step (virus attachment to the CD4+ protein)
and those that block the second step (binding to a co-receptor).
BMS-488043
is an oral attachment inhibitor drug that binds to CD4+ receptors.
By binding, it blocks the virus from attaching to the cell. It is
currently being studied at two doses, 800mg and 1,800mg, twice a
day. Preliminary data show that among the 12 people who were given
the lower dose (800mg twice daily), viral load decreased an average
of .73 logs compared to .02 log decrease among the three people
who received a placebo. Information was not presented on the higher
dose group, but will be forthcoming. Further studies are being planned.
TNX-355
is a monoclonal antibody of CD4+. It’s a man-made antibody,
binding to CD4+ cells in hopes of blocking the first step in the
viral entry process—attachment to the CD4+ receptor. In a
small study, 22 people were given TNX-355 by injection either weekly
or every two weeks in addition to their standard anti-HIV regimen
for nine weeks. Viral load reductions of approximately 1 log were
observed within 2 weeks of initiating TNX-355. However, viral load
returned to pre-study levels by the end of nine weeks, with evidence
of resistance. CD4+ cell counts fluctuated during the study, and
maximum increases ranged between 103 and 257, with greatest increases
being seen among those receiving weekly injections. One inherent
limitation of many monoclonal antibodies is that the human body
sometimes makes antibodies against the antibody, diminishing their
effectiveness. An additional concern is that monoclonal antibodies
are very expensive to make in the large quantities needed for chronic
treatment.
PRO 542
from Progenics, mimics CD4+ cell receptors, causing HIV to bind
to PRO 542 instead of CD4+ cells. In one study of heavily pre-treated
people whose drug regimens were failing, viral load reductions of
60–80% were seen after a single dose of PRO 542. The results
are promising and follow-up studies are planned. However, the drug
must be given by subcutaneous injection, a clear liability.
Schering D
is a small molecule oral drug that binds to the CCR5 receptor and
thus prevents HIV from binding to this co-receptor. Recent data
from a small dose finding study were encouraging. A total of 36
people, who were not on other anti-HIV drugs, received one of 4
doses (10mg, 25mg and 50mg) of Schering D every 12 hours for two
weeks. An additional 12 people received a placebo. Viral load decreases
were reported in all groups receiving Schering D, with the largest
decrease seen at the highest doses (-1.08 logs, -1.56 logs and -1.62
logs respectively). No significant changes in viral load were seen
in the placebo group.
UK-427,857
is another oral CCR5 blocker. Data presented last year from a small
dose finding study, show it to be potent and well tolerated. A total
of 16 people were given UK-427,857 at two dose levels and were compared
to eight people given a placebo. At the higher dose, 100mg two times
a day, seven out of eight people had a 1 log reduction in HIV viral
load. Half the people taking the lower dose of 25mg two times a
day had viral load decreases of greater than 0.5 logs. No serious
side effects were reported in the study. As is the case with the
Schering D drug, it is not clear whether the optimal dose has yet
been determined for this drug.
GW-873140
is also an oral CCR5 blocker. In a small safety and dose finding
study, the drug was found to be safe, with no serious side effects
reported. The most common side effects were nausea, diarrhea and
abdominal cramping. No data on anti-HIV effects were reported. Follow-up
studies are planned.
Commentary
The promise of entry inhibitors, especially small molecules, has
many companies working on their own novel drugs. Many are still
in pre-clinical development, and are years away from being available.
However there are a number of promising candidates already in human
studies. If these continue to show promise, some might reach wider
human use within two or two and a half years.
People living with HIV need drugs that address new targets, which
are easier to take and have fewer side effects. Entry inhibitors
hold promise in these ways, but as always, the proof will come from
clinical studies.
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