|
2003 was a banner year for
HIV drug approval despite the fact that some of the drugs
are very similar to what already exists. Improvements in medical
treatment come slowly and incrementally, but lately there
seems to be a wave of new treatments that in conjunction with
new approved therapies may improve quality of life and benefit
those with fewer treatment options. The newer drugs are from
existing classes that are improvements on their predecessors,
some are easier to take, and some are entirely new classes
never used before, targeting other points in the HIV lifecycle.
Cumulatively, they may end up representing a new treatment
era in HIV.
The following are a few of
the drugs furthest along in development.
Repeat performance
Lexira (or 908/fos-amprenavir
as it is currently known) is the fourth in line for approval
this year. It is a new “pro-drug” formulation of
amprenavir (or Agenerase) an older, mostly unpopular protease
inhibitor. Out of all protease inhibitors, amprenavir was
only 5% of the market due to the fact that it required eight
horse pills twice a day. The new compound has been reformulated
to be easier to take; one tablet twice-a-day, and will metabolize
so that more drug gets into the bloodstream.
More data from clinical trials
are shedding light as to the effectiveness of this drug. The
NEAT study looked at 908 compared to Viracept with a background
regimen of Ziagen and Epivir in treatment naïve participants.
In those with initial viral levels of greater than 100,000,
71% (908) versus 35% (Viracept) saw their viral load drop
below 400. The SOLO study also looked at treatment naïve
participants with 908 boosted by ritonavir (Norvir). (As with
other protease inhibitors, this drug may be more effective
with a ritonavir boost.) The study compared once-daily boosted
908 to twice daily Viracept with a background regimen of Ziagen
and Epivir. Again, those with higher baseline viral loads
had a better viral load result.
One trial called CONTEXT
looked at people who had failed one or two protease inhibitors
and compared boosted 908 once daily or twice daily to Kaletra
twice daily with a nucleoside background. No non-nucleoside
reverse transcriptase inhibitors (NNRTIs) were allowed in
this study. 48 weeks of data showed little difference in viral
outcomes between the two arms, however based on a different
analysis the study was able to show that 908 was really worse
than Kaletra.
908 has not yet shown cross
resistance to other protease inhibitors in laboratory studies,
however, and according to the efficacy results thus far it
most likely will be better as a first line treatment. Common
side effects for 908 are gastro-intestinal and there are significant
drug interactions with other medications commonly used in
HIV. 908 represents the HIV treatment era we find ourselves
in today. While every effort has been made to make an easier
drug to take it is probably not any better than what is already
available.
Another protease inhibitor
in final stages of development is tipranavir, which has shown
to be a promising drug for those who are resistant to protease
inhibitors. Tipranavir requires up to 20 mutations to become
resistant. A Phase II study in protease resistant participants
showed a sustained virological suppression for up to 48 weeks.
There are two large Phase III studies underway looking at
tipranavir with a ritonavir boost in highly protease resistant
participants. It is dosed as 500 mg twice daily with a 200
mg ritonavir boost. All indications show tipranavir a useful
protease inhibitor in those with multiple resistant PI mutations
but the Phase III studies will put to rest any doubt that
the drug will be effective in this difficult to treat population.
The most common side effects seen were diarrhea. Tipranavir
will be next in line for approval.
Another new protease inhibitor
that was designed exclusively to work in those with PI resistance
is called TMC-114. A Phase II dose finding study in 50 multiple-experienced
participants showed that despite multiple resistance to protease
inhibitors, all three doses selected showed a median drop
of 1.35 log in viral load after 14 days. Again TMC-114 was
boosted in this study but it may be effective without the
ritonavir. GI side effects were seen in about a third of participants,
but that may be due to the ritonavir.
Curtain call
The three approved non-nukes—Sustiva,
Rescriptor, or Viramune—are highly cross resistant to
one another, but high technology is making it possible to
develop new NNRTIs which should not be cross resistant to
them. Capravirine is a NNRTI that is nearing Phase III studies.
After a significant intermission due to vasculitis in dogs
seen in early studies at higher doses than would be used in
humans, research in capravirine has restarted and larger studies
are being planned. Early indications from Phase II studies
involving NNRTI resistant participants show that it may be
effective in this group of people, but larger studies and
more time will determine if this is true. One good thing is
that the rash commonly associated with the older NNRTIs was
not seen in early studies.
TMC-125 is a novel approach
for those resistant to the current family of NNRTIs because
it is a unique compound that is flexible and can fit into
various binding pockets of HIV. In one short open label study
of 16 HIV participants with a wide range of NNRTI mutations,
TMC-125 was effective in suppressing HIV. Again, larger studies
need to be performed to fully elucidate the effectiveness
of this new drug in those who need a new NNRTI.
There are several other companies
looking into novel NNRTI compounds. We need new drugs in this
class!
Making a big entrance
Entry inhibitors have stepped
into the spotlight for people who have used all the older
anti-HIV drugs. This progress has led the way to more exciting
research, and definitely gives those whose viral load levels
are climbing and T-cells falling a degree of excitement and
hope. Certainly T-20, now known as Fuzeon, the first approved
entry inhibitor, was a milestone in creation of this new class
of HIV drugs. Its cousin, T-1249, has showed impressive results
in a small preliminary study looking at those who had failed
Fuzeon. A median log drop of 1.26 was seen after eleven days
of therapy. Participants switched out their Fuzeon for T-1249.
It was shown that those who had used Fuzeon for a longer period
of time didn’t do as well. But the longer people were
on T-1249 they continued to see viral load drops. Unfortunately,
Roche is moving painfully slow with development of this new
drug.
Like an arm holding a key
to open a door, another clever way HIV uses to attach and
infect T-cells is by using cell co-receptors. One of the co-receptors
most prevalent in HIV is called CCR5. This co-receptor is
associated with the early stage, slower progression of HIV.
Another co-receptor called CXCR4 is associated with rapid
progression and quick destruction of T-cells. Since CCR5 is
more common, several companies are looking at drug candidates
to block this co-receptor. In fact, two candidates are already
moving into Phase II studies. At least one CXCR4 compound
is in very early studies.
UK-427,857 has been tested
in HIV negative people and was found to be safe. This kind
of study is necessary in new drugs that have not been widely
tested to establish safety. A second short term, monotherapy
placebo controlled study looked at HIV positive people who
were screened for the CCR5 receptor. The study tested several
doses of the drug and saw a 1.42 log reduction in viral load
after eleven days of 100 mg twice-daily. This was in seven
patients. An eighth patient was later found to be dual tropic
at baseline (had both CCR5 and CXCR4 cells), and the drug
was ineffective for this patient.
The higher dose also had
a higher saturation of CCR5, more than 90%, compared to less
than 80% for the lower dose.
The drug seems to be safe
in this small, short study. Now, larger studies can be designed
to compare to existing HIV drugs, and to further evaluate
how safe this CCR5 compound is.
SCH-D is another CCR5 attachment
inhibitor in the treatment pipeline. Since some complications
developed with the sister compound in early studies, this
newer drug is now moving in a similar development path as
the UK-427 drug mentioned above.
One major hurdle to overcome
in co-receptor research is that if a person is treated with
a CCR5 antagonist, will their virus “switch” to
the more dangerous CXCR4 virus. In early studies this has
not been seen, but more work needs to be done to be sure.
There are four different
mechanisms that allow virus entry into a human T-cells. Research
is now looking at ways to target each of these mechanisms
alone and in combination. This discovery in entry inhibition
has opened the door to a whole new era in HIV research.
However, as with any drug
research there are many obstacles to overcome, and more clinical
trials will paint a fuller picture as to whether or not they
will play a role in the future of HIV treatment. What is encouraging
is that just a short time ago there were very few promising
drugs for people with HIV drug resistance. Now, the time is
ripe for a whole new generation of drugs. Encore, encore!
|
