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T-20 (also knows as pentafuside) a "fusion inhibitor," is an
entirely new kind of HIV treatment being developed by
Trimeris, Inc., a small biotechnology company in Durham,
North Carolina. Because of its complex and unique mechanism
of action, this drug and its development have not been widely
understood; they have been "off the radar" of Wall Street and
the media, even the AIDS press. We think this work is as
important as anything now happening in AIDS research, for
several reasons:
- T-20 has successfully shown "proof of principle" in
patients, with a clear dose response and, at the highest
dose, antiviral activity at least equivalent to a protease
inhibitor in all four patients receiving that dose. No human
toxicity has been seen. A larger trial is about to begin.
- T-20 works differently than any retroviral now in use
(meaning that it targets a different step in the viral life
cycle). Therefore, it is unlikely to have any cross
resistance with existing treatments, and should work equally
well no matter what treatment history a patient has.
- Both theory and laboratory tests suggest that resistance to
T-20 will be slow to develop, although it can exist. None has
been seen in people so far. In the laboratory, resistant
virus has been produced -- but then that virus was used to
design a new drug like T-20 which was effective against it.
- T-20 is active only against HIV-1; however, the same
mechanism may lead to the development of similar drugs active
against other enveloped viruses -- a group which includes
influenza, hepatitis B, hepatitis C, and Ebola fever.
- T-20 is active against all strains of HIV-1 tested so far.
Since the co-receptor used by the virus does not matter, the
compound is equally active against both SI (syncytium
inducing) and NSI (non syncytium inducing) viruses.
(Incidentally there is a little activity against HIV-2, but
not enough to be clinically useful. A different drug like T-20 has been developed against HIV-2.)
- Trimeris has two technologies for finding other drugs in
the same class as T-20 (that is, which exploit the same viral
target), either against HIV or other viruses. One analyzes
viral sequences to find similar compounds which might work
better than T-20 itself -- for example, against resistant
viruses. The other technology uses laboratory procedures to
screen chemical libraries to look for small-molecule
compounds which are chemically unrelated to T-20, but have
equivalent antiviral action.
T-20 Disadvantages
The main disadvantage of this potential treatment is that it
must be given by injection. It will probably be delivered
subcutaneously by a portable infusion pump, which is worn
like a pager -- probably the pump made by MiniMed, Inc., which
is currently used by tens of thousands of diabetics to inject
insulin. Eventually, orally bioavailable compounds with the
same mechanism of action may be developed.
Meanwhile, an injectable drug does have compensating
advantages, especially for patients with advanced illness.
Much greater control of blood levels is possible, because the
pump can be programmed to deliver whatever amount is needed,
continuously or on any schedule required. There are no daily
peak and trough blood levels unless those are wanted, and no
drug variation due to delay or forgetting to take pills.
Also, all problems of drug absorption go away, along with
this source of unknown variation between patients. Diarrhea
or other gastrointestinal problems will not affect blood
levels. And there is never a need to have a full or empty
stomach for this drug.
Instead, a needle is changed every three days. It is a small
needle, since T-20 is given continuously, so a very low flow
rate is required. The pump can be detached for activities
like showers or swimming -- and programmed to give a bolus dose
first, which can maintain an effective blood level with the
pump detached for up to several hours. The pump can be worn
during sleep.
What Is T-20 and How Does It Work?
T-20 was discovered several years ago at Duke University by
Thomas Matthews, Ph.D., in the Laboratory of Dani P.
Bolognesi, Ph.D. Dr. Bolognesi's team, working to develop
candidates for an HIV vaccine, compared viral sequences from
different strains of HIV, looking for a part of the virus
which changed very little from strain to strain. The idea was
to use this piece of the virus for a vaccine which could
provide immunity against many different variants of HIV from
around the world. This search for a conserved sequence in the
virus led to a part of gp41, the HIV protein which penetrates
uninfected cells as the first step in viral entry. This 36-amino acid piece of gp41 was manufactured for further tests.
It failed to work for a vaccine, however.
But before moving on, Dr. Matthews tested this piece of the
virus against live HIV, and found that it was highly
effective in stopping the virus from infecting new cells.1
The potential drug which is code-named T-20 is therefore a
piece of the HIV virus itself.
Exactly how T-20 works involves complex protein
biochemistry.2 But basically, at one step in the entry
process, the T-20 portion of gp41 must bind with a
complementary sequence which is also in gp41; this binding
changes the shape of gp41 and exposes the portion which first
penetrates the membrane of the cell. The binding is part of
an elaborate process which recognizes the cell's receptors, a
process HIV and other enveloped viruses have evolved in order
to be selective. Otherwise these viruses would be likely to
enter cells where they could not reproduce, or try to enter
debris which was not a cell at all.
T-20 is believed to interfere with this cell entry process by
binding to its target first, displacing the T-20 sequence
within HIV. Therefore the gp41 cannot change its shape into
that which is required to enter the cell.
Viral Resistance to T-20
HIV resistant to T-20 has been created in laboratory tests.
This resistance may be slow to develop, however, because the
sequence which T-20 binds to in gp41 is highly conserved
among different strains of HIV. When part of a virus stays
much the same from strain to strain, it usually means that
the region is critical, and changes there could produce a
defective virus which is not viable. The T-20 sequence can
vary somewhat, but HIV seems to have less freedom here than
it does elsewhere.
When HIV resistant to T-20 does occur, it appears
straightforward to develop a new inhibitor like T-20 against
it. Since there may be few options for resistance to this
drug, due to the T-20 sequence being highly conserved, it
might be possible to make T-20 drug variants to block any
resistant virus which becomes a problem in practice. Much
more research is needed, however, to find out to what extent
T-20 resistance will occur in people, and to what extent this
problem can be overcome.
Manufacturing and Supply
T-20 is a 36-mer peptide (a sequence of 36 amino acids). It
is relatively easy to manufacture small amounts, enough for
the initial clinical trials, by a technology called solid
phase synthesis. Large quantities for major trials or for
marketing will require a more difficult manufacturing
process -- either solution phase synthesis, or genetic
engineering (creation of a genetically modified cell which
produces the drug). Development is now proceeding on both of
these approaches.
Use of an infusion pump to inject the drug continuously will
greatly reduce the amount of T-20 needed. It is estimated
that using the pump instead of twice-daily injections will
allow the same amount of drug to treat up to 14 times as many
patients, while maintaining the same minimum (trough) blood
level. This is because T-20 has a relatively short half life
in the blood, about 2.0 hours; if it is administered twice a
day, a large excess must be given so that the required
minimum blood level will still be present just before the
next shot.
Toxicity
No toxicity of T-20 has been seen in human trials so far. In
the laboratory, the drug inhibits HIV at concentrations
10,000 to 100,000 lower than those harmful to cells.
T-20 does not enter cells, which further reduces the
likelihood of toxicity. This is because drugs which get into
cells have many more opportunities to create mischief than
those which do not.
Clinical Trial Results
The only human results so far are from a phase I trial
reported at the IDSA (Infectious Diseases Society of America)
meeting September 1997 in San Francisco.3 In this study, T-
20 was injected intravenously twice a day, for 14 days. Four
different doses were tested: 3 mg, 10 mg, 30 mg, and 100 mg
every 12 hours -- and four volunteers received each dose. There
was a clear dose response, with little viral load change at
the two lower levels, a half log drop at the 30 mg dose, and
at 100 mg, all patients became undetectable (a mean change of
1.5 logs, but since the viral load became undetectable in
every case, this number was the maximum possible in the
design of this experiment; the drug clearly produced a larger
change, but it could not be measured here). The average CD4
count increased by 52 cells at the high dose, increased by 21
cells at the 30 mg dose, and decreased at the two smaller
doses.
In this trial the cutoff for undetectable viral load was 500
copies. Later analysis with a more sensitive test found that
none of the volunteers went as low as 50 copies. But since
they started with an average viral load over 10,000, they
probably could not have reached 50 copies in 14 days even if
new infection was completely shut off, because of the time
required to clear the virus from the body.
According to Trimeris, outside experts looked at the data and
agreed that the speed of viral decline may be greater than
any published results with combinations of RT (reverse
transcriptase) and protease inhibitors. Of course this
conclusion is tentative, since only four patients have yet
been treated with the most active dose.
One factor that may have contributed to these results is that
T-20 gets into the lymphatic system very well. This is where
most of the virus is and most of its replication occurs. A
second factor could be that T-20 blocks both mechanisms by
which HIV enters a cell -- virus to cell infection, and fusion
of an infected cell with uninfected cells.
Clinical Trial Plans
Trimeris is about to start a larger trial at several sites.
Forty patients who have failed at least one protease
inhibitor combination will receive different doses of T-20,
all of which are calculated to be effective. For 10 days they
will use T-20 alone, so that the effect on the virus can be
seen; then they will combine it with a new protease-inhibitor
combination. After the first 10 days, the combination phase
of this trial will last for 24 weeks -- and after that, no one
will be denied the drug if they want to continue it.
The first goal of this trial -- in the first 10 days -- will be
to confirm the dose of T-20 when given subcutaneously with an
infusion pump (the previous trial gave it intravenously twice
a day). While the drug is likely to get into the serum and
lymphatic fluid regardless of how it is injected, the dose
must be checked because the twice-daily injections had huge
peak levels of the drug. The available information for this
and other antiretrovirals suggests that it is the trough
level -- the minimum blood level -- which is important for
controlling HIV, and that the extra drug in the peaks is not
required. But with some antibiotics, the peak level, or the
total amount of drug, does matter; therefore it is important
to confirm quickly that a proper T-20 dose has been selected
for continuous use.
Later trials being planned include a large phase II with 360
patients, pediatric trials for children who have failed
protease inhibitors, another large phase II trial in adults
beginning HIV therapy, and a test of using T-20 for induction
of combination treatment in patients with a very high viral
load (to lower the viral load quickly in order to help avoid
resistance to the protease inhibitors and other conventional
treatments being started). There are also plans to test T-20
as a topical microbicide for prevention of HIV transmission
in discordant couples.
A number of possible short-course uses of T-20 have been
discussed; these would be most important in the hopefully
unlikely case that long-term use is not feasible, either
because of side effects, development of antibodies which
could make the drug ineffective, or manufacturing
difficulties which delay production of an adequate supply.
Such short-course uses could be for patients who have to go
off all oral medications, for example due to surgery, or when
oral medications cannot be absorbed temporarily because of
other gastrointestinal problems; when a drug holiday from
conventional treatments is necessary due to their toxicity;
when viral load increases greatly due to an opportunistic or
other infection; for prevention of maternal transmission,
possibly in the first trimester if the inability of T-20 to
get into cells reduces its risk to the fetus; and for post-exposure prophylaxis (reducing the chance of HIV infection by
short-term antiretroviral treatment shortly after accidental
exposure).
Because the clinical research on T-20 is still in such an
early stage, Trimeris does not expect to be able to file for
marketing approval at least until the first quarter of 2000.
Technologies for Developing New Drugs Like T-20
Trimeris has two different technologies for creating or
discovering new drugs with the same mechanism of action.
One uses a computer analysis of viral sequences to suggest
new peptides which may be effective; these peptides can
easily be manufactured in small quantities for initial tests.
This methodology (called C.A.S.T. -- Computerized Anti-Fusion
Searching Technology4) has already been used to develop a
drug which in the laboratory was 100 to 1000 times more
powerful than T-20 against HIV. This particular compound,
called T-1052, failed in animal studies, however, probably
because it was inactivated by something in the blood. But
even though this drug did not work, it illustrates the power
of the methodology to design new sequences which are much
better than the natural one found in the target virus -- not
surprising, since in the virus the binding must be weak
enough to be reversible, while in a drug, the stronger it is,
the better. T-20 may be the first example of a new area of
drug development which is only now coming into view.
The other drug-development technology consists of laboratory
tests to screen existing chemicals -- usually small molecules,
not peptides -- to find any which happen to work like T-20.
This screening procedure sets up a laboratory situation where
T-20 binds to its target -- a process which must happen
naturally in HIV, aside from any treatment -- and then
determines if the chemical being tested can block this
binding. Trimeris is beginning to screen chemical libraries,
looking for potential drugs which could substitute for T-20,
and might be orally available so that they would not need to
be injected.
The Company
Trimeris currently employs about 45 people. It's scientific
advisors include: Dani P. Bolognesi, Ph.D., whose laboratory
at Duke University discovered T-20; Michael S. Saag, M.D., of
the University of Alabama, who ran the phase I clinical
trial; Joe Pagono, M.D., Chairman of the University of North
Carolina Lineberger Comprehensive Cancer Center; Thomas
Matthews, Ph.D., who discovered T-20; and Eric Hunter, Ph.D.,
chairman of the University of Alabama Center for AIDS
Research. The president and CEO of Trimeris, M. Ross Johnson,
has 25 years experience in major pharmaceutical companies.
Wall Street, however, has not been enthusiastic so far.
Trimeris first issued stock last October, priced at 12.00.
The price went up as high as 17, then down as low as 7, and
at this writing is 8.
What seems to have happened is that the financial community
has not understood what the company is doing. The only human
data so far -- the results of the phase I study -- were presented
at the IDSA conference last September; this happened during
the SEC-mandated "quiet period," so the company was unable to
explain these results or tell its story. Since then there has
been no significant news about Trimeris or T-20, and no in-depth background article about the company or its technology.
Publication of the phase I trial is expected in the next few
weeks.
References
Wild CT, Shugars DC, Greenwell TK, McDanal, CB, and
Matthews TJ. Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41
are potent inhibitors of virus infection. Proceedings of the
National Academy of Sciences, USA October 1994; volume 91,
pages 9770-9774.
Lawless MK, Barney S, Guthrie KI, Bucy TB, Petteway SR,
and Merutka G. HIV-1 membrane fusion mechanism: Structural
studies of the interactions between biologically-active
peptides from gp41. Biochemistry. 1996; volume 35, number 42,
pages 13697-13708.
Saag M, Alldredge L, Kilby M, Venetta T, DiMassimo B,
Lambert D, Johnson MR, and Hopkins S. A short-term assessment
of the safety, pharmacokinetics, and antiviral activity of T-20, an inhibitor of gp41 mediated membrane fusion. Infectious
Diseases Society of America 35th Annual Meeting, San
Francisco, September 13-16, 1997 [abstract #771].
Lambert DM, Barney S, Lambert AL and others. Peptides from
conserved regions of paramyxovirus fusion (F) proteins are
potent inhibitors of viral fusion. Proceedings of the
National Academy of Sciences, USA March 1996; volume 93,
pages 2186-2191.
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