PI Perspective #45
April 2008 View PDF En
español
Update from CROI 2008 on
experimental HIV drugs
by Paul Dalton
Compared to the recent fast pace of new HIV drug development,
the next couple of years look relatively quiet. In just over two
years, five new drugs were approved by the FDA, including ones
from two new classes. While most people — including those with
extensive treatment experience — are now able to build potent regimens,
there remains a need for new drugs.
The Conference on Retroviruses and
Opportunistic Infections (CROI) held recently in Boston, MA is
the most important annual HIV science conference in the US. This
article reviews some of the presentation on experimental HIV drugs
at this year’s meeting.
Vicriviroc (Schering-D)
Data were presented from a study called VICTOR-E1, looking
at the CCR5 antagonist vicriviroc in people with experience taking
HIV drugs. While generally positive the results raise further questions
about this drug’s future.
The study compared two doses of
vicriviroc (20 and 30mg, both once daily) to placebo, each combined
with the best available background regimen in people with extensive
experience taking HIV drugs. The study was relatively small, with
about 40 people in each of the three groups.
After 48 weeks, about
half the people taking either dose of vicriviroc had HIV levels
below 50 copies/mL, compared to 14% taking placebo. Average decline
in viral loads were greater for people on vicriviroc as well: 1.77
and 1.75 logs for the vicriviroc groups vs. 0.7 logs for placebo.
Vicriviroc was generally well tolerated with few people stopping
due to side effects.
While these results suggest fairly potent anti-HIV
activity for vicriviroc, further analysis raises significant questions.
People with high HIV levels — defined
as above 100,000 copies/mL — at the beginning of the study were very unlikely
to get to below 50 copies/mL (33% for the 30mg group, 17% for the 20mg group,
and 10% for the placebo group). Also, many more people taking vicriviroc than
placebo were also taking the protease inhibitor Prezista (darunavir) as part
of their background regimen. At the very least his confounds any positive results
seen in this study.
There were a couple of other presentations on vicriviroc,
including two that looked at resistance and one that found no affect
of vicriviroc on HCV. A couple of years ago vicriviroc was locked
in a head-to-head race with two other drugs, GSK’s aplaviroc
and Pfizer’s Selzentry (maraviroc),
to become the first CCR5 drug approved by the FDA. Aplaviroc’s
development was halted due to rare, but serious liver toxicity.
Selzentry was approved a few months ago. The results presented
at CROI are generally positive, but do little to overcome the perception
that this once promising drug’s uncertain
future. The company has chosen the 30mg dose for future development.
Other CCR5 antagonists
There
were a couple of presentations on other experimental CCR5 drugs
at CROI. Other than vicriviroc, the drug furthest along in development
is INCB9471. Data were presented on a 14-day study of multiple
doses of the drug compared to placebo in people with R5-only HIV.
Overall 49 people were studied, with 9 given a placebo and the
rest one of three doses of INCB9471 (100, 200 and 300mg, once daily).
No data were presented on reductions in HIV levels or changes in
CD4 count. Instead they presented data on people who had X4 HIV
emerge during the study. As seen with studies of other R5 drugs,
most of the emergence of X4 on these drugs seems to be from a minority
population of dual/mixed HIV that was not detected at the start
of the study. This highlights the need for better screening tests
for R5.
Another experimental R5 drug, called PF-232798, was tested
against HIV that had grown resistant to Selzentry. The researchers
grew HIV in a lab that was resistant to Selzentry and tested PF-232798
against it. While the activity of PF-232798 dropped off somewhat
compared to against non-resistant HIV, it retained sufficient activity
to move the drug forward in clinical development.
All of the currently
tested CCR5 drugs work by attaching to the R5 protein in such a
way that HIV has a difficult time attaching to it. While this strategy
can be effective, HIV can develop resistance to these drugs by
changing the way it attaches to R5. At CROI, researchers presented
early research on another approach to blocking R5 — using a drug
to force R5 to move out of the cell membrane to inside the cell.
This approach, if proven safe and effective should be less susceptible
to resistance. Researchers tested a large number of compounds for
their ability to internalize CCR5. They found one, called ESN-196,
that they think warrants further testing as an R5 blocker.
NNRTIs
Several new non-nucleoside reverse transcriptase inhibitors
are in pre-clinical development. UK-452,061 is being developed
by Pfizer. A poster presentation detailed an experiment where UK-452,061
was tested against HIV taken from people who had developed resistance
to approved NNRTIs. In all they looked at 62 samples of NNRTI-resistant
HIV, and the compound showed good activity against 61 of them.
The tests were done in a laboratory, not in people.
Another experiment
reported in a poster compared resistance to the experimental NNRTI,
IDX899 to the widely used NNRTI Sustiva (efavirenz). In this study,
researchers exposed a laboratory strain of HIV to different concentrations
of both drugs to try and force resistant HIV to emerge. This type
of experiment is done commonly in early drug development. The researchers
reported that resistance to IDX899 emerged more slowly compared
to Sustiva and neither drug appears to be highly cross-resistant.
Still
another experiment looked at two experimental NNRTIs — RDEA427
and RDEA640 — compared to Sustiva against HIV with the most
common NNRTI mutations. Both experimental drugs worked better than
Sustiva. This is not surprising as the HIV tested would be expected
to be highly resistant to Sustiva.
They also tested these two along
with another experimental NNRTI, RDEA860, to see how affected they
are by human proteins. The extent to which drugs attach to human
proteins has a profound affect on how easily therapeutic levels
of the drug can be achieved. While each of the drugs was significantly
affected by protein binding, they were less so than Sustiva, Intelence
(etravirine) or rilpivarine (TMC-278).
Bevirimat
Bevirimat is an experimental maturation inhibitor being
developed by Panacos. Maturation inhibitors work at the same step
in HIV’s
replication cycle as protease inhibitors, but in a different way.
Its development has been slowed by problems with formulating the
drug. The drug is currently in Phase IIb.
Two poster presentations
looked at the development of resistance to bevirimat. One found
that protease inhibitor resistant HIV may be less likely than wild
type HIV to have resistance to bevirimat. This is a potentially
important finding, because bevirimat is being developed for people
with extensive HIV treatment experience, who are likely to have
HIV that is resistant to PIs. The other study identified several
mutations that reduced bevirimat’s activity.
As the drug moves closer to possible approval, this information
will help researchers, regulators and activists as we evaluate
the results from clinical studies.
Other drugs
A poster presented at CROI suggests that GS-9148, an experimental
NRTI being developed by Gilead, might cause fewer kidney problems
than Viread (tenofovir) and might have very good penetration into
lymph nodes.
GS-9148 is a nucleotide reverse transcriptase
inhibitor (NtRTI). Other NtRTIs, including Viread, cidofovir and
adefovir, have caused kidney damage. This poster showed data looking
at GS-9148’s
affect on kidney cells, from both laboratory and animal studies.
Compared to other NtRTIs, little of GS-9148 was taken up into kidney
cells. This suggests it is less likely to harm those cells.
Gilead
is also looking at how well GS-9148 gets into lymph node cells.
Lymph nodes are a major site of HIV replication, and most HIV drugs
fail to penetrate well into this important area of the immune system.
The
NRTI class of drugs has lagged in development for some years now.
As a class they have been hampered by relatively low potency and
high toxicity. A new NRTI with low toxicity would be welcome, if
it is shown to reduce HIV levels well. More research will be needed
to see if the promise of this new NRTI can be achieved.
A poster
presented at CROI shows potential for another experimental NRTI,
apricitabine. The results were from the AVX-201 study, which Project
Inform reported about earlier. AVX-201
compared apricitabine to Epivir (lamivudine, 3TC) in people with
HIV that harbors the M184V mutation, which is associated with resistance
to Epivir and Emtriva (emtricitabine, FTC).
In the first phase of
the study, people on failing Epivir regimens were randomly assigned
to either stay on Epivir or switch to apricitabine. After 21 days
everyone was switched to a background regimen made up of the best
available HIV drugs. Results from this second phase were presented
at CROI.
After 24 weeks there was a trend toward better outcomes
for people taking apricitabine, but the difference wasn’t
significant. The authors speculated that the potency of the background
regimens and the small number of people in the study made this
difference too small to be considered significant. There were more
treatment related side effects among people taking apricitabine
than Epivir. This is not surprising as everyone in the study had
experience taking Epivir.
The development course for apricitabine
is unclear. Many people have developed resistance to either Epivir
or Emtriva, so a viable option for them is needed. Avexa, the developer
of apricitabine, will need to show that its drug is potent and
well tolerated in larger trials before we will know if it can be
that option.
GlaxoSmithKline and Shianogi presented resistance data
on a potential integrase inhibitor, called S/GSK364735. Unfortunately
this drug appears to have similar resistance patterns as both Isentress
(raltegravir) and Gilead’s elvitegravir.
However, development of this drug is expected to move forward.
In
addition to more traditional approaches to HIV therapy, there’s
quite a bit of interest in testing anti-inflammatory drugs for
activity against HIV. One drug, called Aprepitant which is approved
for use against nausea caused by cancer chemotherapy, was tested
against a broad range of HIV types. The researchers found potent
activity against HIV, with little evidence of damage to cells.
The fact that this drug is already approved for people with cancer
makes it easier to study in people with HIV, as there is already
enough data on its use in humans to believe it is safe. While much
more study will be needed to know if this could be an effective
approach against HIV, the approach of examining approved drugs
against HIV should be examined further.
Final thoughts
Compared to the last couple of meetings, there wasn’t
a lot to be truly excited about for experimental HIV drugs at CROI
2008. While the recent flood of new and important drugs is certain
to slow for awhile, potentially important new drugs continue to
be studied. While some look at the current anti-HIV armamentarium
and think it might be sufficient, this is hardly clear. While many
of the recently approved drugs have performed quite well in clinical
trials, long-term, real-world use will tell the full story. New
and better drugs — probably
many of them — are still needed. Project Inform continues
to work to ensure that these compounds are studied and, when warranted,
developed.
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