PI Perspective #42
October 2006 View PDF En
español
Pipeline Update: Short Notes on
New Anti-HIV Drugs in Development
Project Inform follows HIV drug development closely, in order to
provide people living with HIV accurate and up-to-date information
on new drugs as they work their way through the development process.
HIV treatment activists use the term pipeline to refer to the collection
of all experimental HIV drugs. This article provides a very brief
overview of each of the most promising drugs now in the pipeline.
Integrase Inhibitors
MK-0518 is the first of an entirely new class of drug, called integrase
inhibitors, being developed by Merck. It is currently in Phase III
studies. Encouraging data on MK-0518 in people who have used anti-HIV
therapy (called treatment experienced people) were presented at
the 2006 Conference on Retroviruses
and Opportunistic Infections (CROI). This study showed the drug
to be remarkably effective in reducing viral load in people who
were highly resistant to nearly all other anti-HIV drugs.
More data, this time in people taking anti-HIV medications
for the first time, were presented at the 2006 International AIDS
Conference (IAC). Still more was presented at Interscience Conference
on Antimicrobial Agents and Chemotherapy (ICAAC) in September 2006.
Some of the more striking data shows that the drug appears to reduce
viral load more quickly than other potent anti-HIV drugs.
Yet another promising observation, from a study
that compared a regimen based on MK-0518 to one based on the popular
drug efavirenz, concluded that people treated with MK-0518 showed
lower levels in serum cholesterol and triglycerides, while efavirenz
like most other NNRTIs and protease inhibitors (PIs), increased
both. This is considered a welcome change since many people who
take anti-HIV drugs experience problems of increased cholesterol.
While there is still much to learn about MK-0518,
so far it looks exceptionally potent and well tolerated. The drug
is taken as a single pill twice a day and, unlike most PIs, it does
not require using Norvir (ritonavir) as a booster. Merck recently
announced the opening of their expanded
access program. We expect data to be submitted to the Food and
Drug Administration (FDA) for consideration for approval in 2007.
GS-9137 is a competing integrase inhibitor being
developed by Gilead Sciences. It is currently in Phase II studies.
Data were presented earlier this year from a Phase I study in HIV-negative
people. A Phase II study in HIV-positive people, comparing GS-9137
to Norvir-boosted PIs, is fully enrolled. This drug is taken once
daily but requires Norvir as a booster.
The integrase inhibitor currently known as 364735
is being developed by GlaxoSmithKline and Shionogi. The completion
of its Phase I studies was announced at the 2006 IAC. Data are expected
sometime in 2007.
Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
Etravirine (TMC-125) is being developed by Tibotec Therapeutics
and is currently in Phase III studies. Data thus far suggest it
is effective against HIV that is resistant to the available NNRTIs,
like Sustiva (efavirenz) and Viramune (nevirapine). In addition
to its stand-alone Phase III program, etravirine is being studied
together with the recently approved PI Prezista (darunavir, TMC-114),
in a landmark study called DUET. While this drug is designed to
overcome resistance to other NNRTIs, research has shown that HIV
that develops resistance to etravirine is also resistant to Tibotec’s
other experimental NNRTI, rilpivarine (TMC-278). Thus, if people
use etravirine now and eventually develop resistance, rilpivarine
will unlikely be an option for them in the future. An expanded access
program for etravirine opened recently and the details are posted
here.
Tibotec Therapeutics’ rilpivarine (TMC-278)
is currently in Phase II studies. Data were presented at the 2006
CROI showing adequate levels of drug in the blood (called pharmacokinetics)
and that HIV had difficulty developing resistance to the drug. Like
Tibotec’s etravirine, rilpivarine is designed to overcome
resistance to the approved NNRTIs. Little is known about the strength
or side effects of rilpivarine yet. A Phase II study in treatment
experienced people has fully enrolled, and data are expected in
2007.
BILR-355 is being developed by Boehringer Ingelheim
and is currently in Phase I/II studies. Early data suggest it will
work against HIV that is resistant to the approved NNRTIs. A Phase
II study in people on a failing anti-HIV drug regimen is ongoing.
BILR-355 must be taken with a booster dose of Norvir. No information
is yet available on whether BILR-355 is cross-resistant with etravirine
and rilpivarine.
Nucleoside reverse transcriptase inhibitors
(NRTIs)
Racivir is being developed by Pharmasset and is currently in Phase
II studies. This drug is very similar to Epivir (lamivudine, 3TC)
and Emtriva (emtricitabine, FTC). Racivir is active against the
hepatitis B virus as well as HIV. Early research suggests that it
takes longer for HIV to develop resistance to racivir than to either
Epivir or Emtriva. If more research confirms this, it might make
racivir an attractive alternative to those drugs for first line
therapy. There is an ongoing Phase II study evaluating racivir in
people with Epivir-resistant HIV.
Elvucitabine is being developed by Achillion and
is currently in phase II studies. In 2005, early information suggested
that this might be the first anti-HIV drug taken once a week, although
currently it is being studied as once a day. At the higher doses
(50mg and 100mg weekly) being studied once a week, the drug proved
too toxic, dangerously suppressing the development of new cells
in the bone marrow (called bone marrow toxicity). This hampered
drug development and the company is now studying it at lower doses
(5mg and 10mg) daily, where hopefully this side effect won’t
be a problem.
Apricitabine (AVX754) is being developed by Avexa
Pharmaceuticals and is currently in two ongoing Phase II studies.
One is an extension of an earlier study and is looking at safety
and tolerability of long-term use in people who had completed the
earlier study. The second is examining several doses of apricitabine
in people whose HIV shows evidence of the M184V mutation, which
is associated with resistance to the NRTIs Epivir and Emtriva. Earlier
research showed people who took different doses of apricitabine
averaged between 1 and 1.6 log reductions in HIV levels, which is
similar to the levels of viral suppression seen with drugs like
Epivir.
Entry inhibitors
Maraviroc (UK-427-887) is a type of entry inhibitor called a CCR5
inhibitor. It is being developed by Pfizer Pharmaceuticals and is
currently in Phase III studies. Maraviroc is expected to be the
first-in-class CCR5 drug when it is approved. Results from studies
so far have shown that it works well both in people new to HIV treatment
and treatment experienced people.
One of the concerns with all drugs that interfere
with CCR5 is that using them may force HIV to begin using another
entry point called CXCR4. HIV that uses CXCR4 has been associated
with more rapid disease progression. Data from studies thus far
have suggested that this feared switch is happening only rarely
and that it hasn’t been associated with more rapid disease
progression.
One of the open questions about maraviroc and other
co-receptor (CCR5 and CXCR4) inhibitor drugs is whether and how
to use lab tests to determine who could best benefit from them.
This blood test is called a tropism assay. A presentation at the
2006 IAC suggested that maraviroc could be used safely in people
with HIV that uses both receptors—called dual tropic virus.
An expanded access for maraviroc is being developed.
Details on this program will be posted on Project Inform’s
website when they are known.
Vicriviroc (Schering-D) is another CCR5 inhibitor.
It is being developed by Schering-Plough and is currently in Phase
II studies. Research has been slowed by underwhelming results and
concerns about the rate of cancers seen in people taking the drug.
In late 2005 a study comparing vicriviroc (together with approved
anti-HIV drugs) to Sustiva (also together with approved anti-HIV
drugs) was halted because significantly more people taking vicriviroc
experienced rises in viral load, compared to those on Sustiva. More
recently, a presentation at the 2006 IAC showed good reductions
in viral load for people taking vicriviroc. However, of concern
was the higher rate of cancers seen in the people taking the drug.
The rates were not considered high enough for the study to be halted.
There are several ongoing studies of vicriviroc.
A Phase II study is looking at two doses (20mg and 30mg once a day)
of vicriviroc together with more traditional anti-HIV therapies
(often called optimized background anti-HIV therapy as in these
studies researchers work with volunteers to devise potent regimens
with the existing drugs) in people with resistance to other HIV
drugs. Another planned study, that is not yet enrolling volunteers,
is a Phase III study which will look at vicriviroc in people with
dual tropic HIV.
TNX-355 is a type of entry inhibitor called an attachment
inhibitor. It is being developed by Tanox Pharmaceuticals and is
currently in Phase II studies. It is a kind of immune system protein,
called a monoclonal antibody (mAb). This particular artificial antibody
aims to stop HIV from attaching to the CD4+ receptor that it uses
to enter cells. It is given through a needle placed in a vein in
the arm, every two weeks. This route of delivery—called intravenous
(IV) infusion—likely will restrict its use to people with
extensive treatment experience and a lack of other treatment options.
Data presented thus far on TNX-355 have been somewhat
confusing. In addition to only modest reductions in HIV levels,
there was a lack of a dose dependant response. Typically the more
of a drug that is given to a person, the larger the anti-HIV reductions
they experience. This hasn’t been the case with TNX-355. While
the full implications of this finding aren’t yet understood,
it raises questions for activists and researchers alike. A final
concern about TNX-355 is what it is likely to cost if approved,
which is expected to be quite high.
Such concerns, however, should not prevent researchers
and companies from studying drugs like this. We do not yet know
where the next real advance might come from or what pathways of
research will eventually lead to a cure. Some approaches, such as
drugs that require IV infusion or might be unduly expensive, may
still have an important role to play in the overall progress of
AIDS research.
New production methods can perhaps overcome pricing
issues, while newer formulations may result in less frequent dosing.
For example, the current version of Fuzeon (enfuvirtide, T20) requires
two daily injections. This has been an obstacle for many people.
But things that were learned while developing the original drug
have now led to the testing of a second generation product that
may require dosing only once a week.
Conceptually, dosing once a month may someday become
possible. Thus, we must be careful not to reject new approaches
simply because their first generation products are less than ideal.
First generation protease inhibitors weren’t so good either,
but the current generation is proving to be far superior.
PRO-140 is another monoclonal antibody, but this
one is more like maraviroc and vicriviroc in that it is a CCR5 inhibitor.
PRO 140, from Progenics Pharmaceuticals, is currently in Phase IB.
Like TNX-355, it is given through IV infusion. The exact dosing
and dosing schedule have yet to be determined.
Data presented earlier this year show that at the
highest dose given to volunteers (5mg/Kg), PRO-140 remained attached
to cells 60 days after infusion. It is not yet clear what this means
about how often the drug will need to be given to patients, but
surely it won’t require daily dosing. Ongoing studies will
help choose an optimum dose and schedule for infusion. Because it
is given through an IV, it is likely to be restricted to people
with extensive treatment experience. There is also concern about
its cost if it is approved, as other drugs of this type are quite
expensive.
Protease inhibitors
PPL-100 is being developed by Ambrilia Biopharma and is just entering
Phase I studies. Data from test tube and animal studies suggest
it might work against HIV that is resistant to other PIs.
Brecanavir (GW640385) is being developed by GlaxoSmithKline
and is currently in Phase II studies. Brecanavir must be taken with
a booster dose of Norvir. Early data have been encouraging. Results
from a 48-week, 31-person open label study (where participants knew
they were taking the drug) of brecanavir plus two NRTIs were presented
in 2005. After 24 weeks most people had viral loads below 50 copies.
Average reductions in viral load ranged from over 3 logs in people
taking HIV drugs for the first time, to just over 2 logs in people
with protease resistant HIV. Phase II studies are ongoing now.
Other types of anti-HIV drugs
KP-1461 is a new type of anti-HIV drug, called a mutagenic nucleoside
competitor reverse transcriptase inhibitor. It is being developed
by Koronis Pharmaceuticals and is currently in Phase I studies.
Unlike other anti-HIV drugs that seek to limit HIV’s ability
to mutate, KP-1461 works by accelerating its mutations. The ultimate
goal is to force HIV to gather so many mutations that it is no longer
able to replicate—something called terminal mutagenesis. This
drug is just entering human studies, so little is known to date.
This drug’s unique mechanism raises difficult questions about
how it will be studied and evaluated. It’s definitely research
to watch.
Bevirimat is a maturation inhibitor (MI) being developed
by Panacos Pharmaceuticals. It is currently in Phase II study. Maturation
inhibitors work near the same point in HIV’s replication cycle
as PIs. While PIs work by physically blocking the protease enzyme,
MIs like bevirimat, work by attaching to immature HIV proteins and
preventing the protease from cutting them up. Data from a Phase
II study showed that people taking 200mgs of bevirimat once a day
averaged about a 1 log reduction in HIV levels. A Phase II study
in treatment experienced people is enrolling now.
The phases of drug development
- Phase I studies are small and are designed to get
information about a new drug’s safety and how people
respond to different doses. These studies are generally the
first time a new drug is given to people, so they include
a small number of people (around 10–30), are short in
duration (around 1–8 weeks), and often will test a variety
of doses.
- Phase II studies involve more people (around 30–200
people) and last somewhat longer (12–48 weeks). Sometimes
Phase II studies examine different doses of a drug and look
for specific drug-drug interactions. In HIV, these studies
will often reveal early information about whether a drug is
active against HIV.
- Expanded Access Programs (sometimes called parallel
track) are programs that provide early access to drugs that
show promise in Phase II studies. They also help build a database
about a drug’s side effects, and therefore its safety.
While there aren’t hard and fast rules, these programs
will often open at the end of Phase II studies or during Phase
III studies once the Phase III study is fully recruited. In
HIV, they have typically been designed to provide access to
new drugs to people who have few options and who don’t
qualify for other ongoing studies.
- Phase III studies are larger (several hundred to
a thousand or more people) and last longer (minimally 24 weeks
to several years). In addition to looking at drug safety and
side effects, Phase III studies look for conclusive evidence
of a drug’s effectiveness. These are usually the pivotal
studies that determine whether a drug is approved.
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