info-aids@apple.com (Info-AIDS Mailer) (10/03/89)
AIDS TREATMENT NEWS Issue # 84, July 28, 1989
Contents:
Overview
DDI and Parallel Track: Overview and Editorial
Congressional Hearing On Parallel Track, July 20
Parallel Track Access: How You Can Help
Community-Based Research Organizations -- AmFAR Will Coordinate
Peptide T
San Francisco: DHEA Study Is Recruiting
In Memoriam: Charlie Samson and Don Wright
*****
Overview
The most important news now concerns the antiviral DDI, and
the policies being developed about who will have access to it
before full marketing approval, which is probably over two years
away. This issue of AIDS TREATMENT NEWS will show how you can
have input into decisions being made this month about DDI, and
about the "parallel track" or other systems for early access
while formal trials continue.
The DDI situation is moving very rapidly, and there is much
confusion. We will bring out some hidden ethical issues concern-
ing treatment access. We will show what probably will happen,
what should happen, and why it makes sense to work on both at
this time.
DDI is not new, as many think. It has a history, with pub-
lished references back at least to 1981. In a later issue, we
will include a bibliography of published articles about DDI.
This issue of AIDS TREATMENT NEWS also includes a historical
overview of peptide T, by David Smyth of San Francisco. We first
reported on peptide T over two and a half years ago (issue #22,
January 16, 1987), after the drug had been given to four people
in Sweden. Since that time peptide T has been the subject of
unusually intense scientific controversy; the research in Sweden
was stopped, for unknown reasons; and despite general agreement
that the drug is safe, it is still in phase I (small dosage and
toxicity studies) over two years later, with trials in Los
Angeles and Boston. Although the evidence for peptide T appears
weak at this time, the drug may have some usefulness. In any
case its history illustrates a lack of practical judgment in the
management of AIDS clinical research. When it was clear that the
drug was safe, and that there were leading scientists on both
sides of the efficacy debate, rapid efficacy testing should have
been done. The scientific theories under dispute can serve only
as guidelines as to what might work, and cannot substitute for
experience.
The peptide T history is the first major article in 84
issues of AIDS TREATMENT NEWS not written by a member of our
staff. We first met the author about a year ago, and were
impressed by his knowledge of peptide T, and his determination to
research this treatment thoroughly and become an expert in the
drug and its history.
*****
DDI AND PARALLEL TRACK: OVERVIEW AND EDITORIAL
by John S. James
Both the medicine and the public policy around DDI are
developing rapidly. But the real progress should not obscure the
fact that we still have a serious problem.
The bottom line is that unless major toxicity is found with
DDI (which could still happen), the current plans, intentions,
and directions will lead to an unprecedented situation of a clear
medical consensus in favor of a treatment which is blocked by red
tape. There will be adequate supplies of the drug, and it will
not be especially expensive to produce. But treatment will be
denied because of scientists' fears that they will not get sub-
jects for trials of other drugs such as AZT or CD4 if patients
have viable options, because of regulators' fears that precedents
set with AIDS will damage their control over routine drugs in the
future, and because even if the drug is inexpensive there is no
way to charge for it, no one to pay for it, and reluctance to
provide a free alternative to high-priced AZT. In other words,
thousands of people will be denied lifesaving treatment because
the lives of persons with AIDS are still not valuable enough to
arouse the political will to treat this epidemic as an emergency.
Formal efficacy trials of DDI should start soon -- hopefully
within the next few weeks or months. There will probably be
three different double-blind trials: DDI vs AZT for those who
have never taken an antiviral before; low-dose DDI vs high-dose
DDI for those intolerant to AZT; and AZT vs DDI for those who
have already been on AZT for over a year. No one will get a pla-
cebo.
These trials appear to be ethical for those who can get into
them. The problem is that they will take two years or more to
get results -- the time needed to wait for statistically signifi-
cant numbers of deaths or serious infections to accumulate in the
control groups. Meanwhile, for each person who can get into
these trials, others who need DDI will be excluded, for various
reasons.
It now seems clear that some form of early access -- whether
called "parallel track", "treatment IND", or "compassionate use"
-- will be provided for certain people who cannot get into the
trials, during the two or more years it takes the trials to run,
and the additional time for paperwork before DDI is approved for
marketing. The issue then becomes what criteria are used to
select those eligible for early access. There is much concern
that the criteria will be narrow, in order to define away the
parallel track as much as possible. Patients and their physi-
cians benefit by early access, but other interests involved are
likely to see it as an expense and bother, if not a threat.
An advisory committee including persons with AIDS or AIDS
advocates is now being formed to advise Dr. James Mason, Assis-
tant Secretary of Health, about the parallel track on or before
August 21. You can write to Dr. Mason about the parallel track
and access to DDI; for more information, see below. Telling Dr.
Mason and the committee about your own situation, or that of your
patients, could be especially helpful, as committees often pro-
duce inappropriate rules or criteria because they did not think
of enough examples during their deliberations.
What will be done on DDI is haggling about the specific
rules and boundaries of access -- who will and who will not be
allowed the option of using this treatment, with decisions being
made primarily for institutional interests, not patients'
interests. Consequently there will also be increasing activity
around "underground" DDI. At this time it is hard to find, and
costs about $600 per month or more; but several early samples
have been tested and all were good quality. Further chemical
testing will be essential, however, in order to prevent fraudu-
lent and/or dangerously contaminated products.
What should be done is to move toward more control of treat-
ment decisions by patients and their physicians. But clinical
research will have to reform itself to work well in a more open
environment (or in any environment, for that matter). Today it
is argued that we must restrict patients' access to treatment
options, in order to balance the interests of the "few" (those
now ill with AIDS or HIV) against the interests of the "many"
(those who will become ill in the future). The fear is that if
patients have attractive treatment options, they will not
volunteer for scientific trials, and therefore we will not get
the answers needed. Even the more humane wing of the current
professional debate, Fauci's "parallel track" proposal, is based
on the idea that access must be denied those who could partici-
pate in trials, in order to force them to do so.
The cheap and easy way to get research subjects would seem
to be to deny patients other treatment options. This approach
not only is unethical, however, but also it has failed to produce
subjects for trials even when there is no access to alternatives.
The right way to get volunteers would be to reform what is
currently wrong in clinical trial design. Too often trials are
not designed for the real world. For example:
(1) If a trial asks a real, practical question, then if fol-
lows that all the treatment arms to which patients are randomized
must be viable, medically sound therapeutic choices. Why ask
patients to undergo a course of therapy which is known in advance
to be unattractive and not a viable option? What useful
knowledge is gained?
The answer is that commercial considerations often override
scientific and medical ones. The drugs which get studied tend to
be those with the most commercial and professional momentum
behind them, whether they are the best scientific prospects or
not. Or patients are forced to take single drugs only (when in
practice those drugs will be used in combination with others),
because each company wants its product to be approved by itself,
not in combination with a rival's product.
When patients are asked to undergo bad medicine for the sake
of "science", then naturally they will seek other options. But
if trials were redesigned to compare good therapies with other
good therapies, then few patients would object to the randomiza-
tion and blinding which the researchers want, and the conflict
would go away. An added bonus is that trials so designed would
produce more useful information, because they would focus
directly on obtaining the answers which physicians need.
It is finally being acknowledged that the information sought
by the FDA for the drug-approval process, and the information
sought by physicians for making treatment decisions, are not the
same. How odd it is that they should be different! Imagine how
much more efficient the system could be if clinical trials were
designed to answer the same questions that good physicians will
ask when they decide whether or not to use the drug. (One funda-
mental problem, however, is that the FDA is set up to approve
products, not to approve treatments, and clinical trials are
therefore designed accordingly.)
Some progress is being made. Trial design now is better
than it was two or three years ago. But progress is inherently
slow, because it means that academic researchers, who often look
down on clinicians, need to learn new ways of thinking, and learn
them well enough to be successful in using them.
(2) Another major problem in clinical trials is the discour-
tesy with which potential volunteers are often treated, the lack
of concern for their interests and practical needs. For example,
patients often must stop using other treatments which are impor-
tant for their health in order to qualify for trials. Too often
when they do so they are strung along, told that the trial is not
ready for them at the expected date, and left to wait indefin-
itely without their standard medication, with no clear answers
about when they can start the trial. (Notice that this problem
is not considered in the ethical review of the trial, or the
informed consent, because it occurs before the patient begins an
official relationship with the study.)
Better administration is part of the answer, but not all of
it. In addition, research on human beings must be recognized as
a special calling. It differs profoundly from testing drugs on
laboratory animals -- and not only because stricter ethical
guidelines are required. For human research to be successful,
the whole approach to the problem must be different.
The practical effect that such reforms could have on
recruitment is illustrated by community-based research organiza-
tions which have persons with AIDS or HIV on all their review
boards and decision-making bodies. Organizations such as New
York's Community Research Initiative have done far better than
academic medical centers in recruiting volunteers for trials.
The reason is that persons with AIDS and their physicians are
well represented on the scientific and ethical review boards
which approve these trials. Before studies begin, they are modi-
fied to take into account their medical and ethical impacts as
felt by those most affected.
In contrast, the academic centers have done so poorly that a
number of studies have gone through all the required steps of
approval, at considerable trouble and expense, and then failed to
recruit a single qualified volunteer. It is preposterous to
blame the patients for this situation, or to blame access to
"underground" treatment options, or sanctioned options such as
the proposed parallel track -- instead of analyzing the problem
case by case to find out why patients do not volunteer, and how
future trials could be improved so that they would.
*****
CONGRESSIONAL HEARING ON PARALLEL TRACK, JULY 20
On July 20, the U. S. House of Representatives Subcommittee
on Health and the Environment, chaired by Henry A. Waxman (D- Los
Angeles) held a public hearing on the "parallel track proposal
for clinical drug development." The first panel was James Mason,
Assistant Secretary for Health, testifying for the government,
with FDA Commissioner Frank Young, NIAID director Anthony Fauci,
and National Cancer Institute Director Samuel Broder available
for questions. The second panel was Jim Eigo of the Treatment
and Data Committee of ACT UP/New York, and Martin Delaney of Pro-
ject Inform, representing AIDS advocacy organizations. The third
panel was John Petricciani, vice president of the Pharmaceutical
Manufacturers' Association. We did not attend this hearing but
have received copies of the prepared text submitted in advance by
most of the speakers.
The opening statement by Congressman Waxman is an excellent
neutral summary of the issues as they are conventionally viewed,
so we reproduce it in full:
"Today's hearing is on the controversial and critical
issue of release of experimental drugs. The hearing is
specifically about recent proposals referred to as the
parallel track for drug development.
"Food and Drug Administration law does not allow drugs
to be sold until they are proven to be safe and effective.
The same law prohibits distribution in any manner of drugs
without permission of the FDA. This law was adopted to pro-
tect consumers from dangerous products and from snake-oil
remedies. It was intended to establish a straightforward
policy as to when manufacturers can profit from -- and when
consumers can take -- drugs whose effectiveness is unknown.
"Exceptions have been carved out of the general rule.
Drugs whose safety and effectiveness are unknown may be dis-
tributed for research purposes. Drugs whose safety is pro-
ven, but whose effectiveness is undemonstrated, may be dis-
tributed outside of strict medical trials under various
labels -- as Treatment Research or as Compassionate Use or
as Open Protocols.
"But the law and its exceptions have run head on into
the AIDS epidemic. Thousands of Americans find themselves
without useful approved treatment and with steadily declin-
ing health. A handful can get into controlled trials, but
most can just read about drugs they cannot get.
"During the course of the epidemic, this rationing has
been scientifically and morally justified as necessary to
the conduct of trials and appropriate for quickly meeting
the needs of future Americans with AIDS. We have lived with
a policy of limited distribution today so that we will have
adequate information for tomorrow.
"But now, many people -- patients, their families, and
researchers -- are questioning this policy. They argue that
scientific trials do not require that everyone else be
denied access to potential therapies; indeed, they say, the
trials are better conducted with willing volunteers rather
than desperate ones. And, they continue, it is, therefore,
morally wrong to withhold promising drugs from patients with
nothing else to turn to.
"From this questioning has grown the Parallel Track, a
proposal that drugs be available for some distribution when
they are known to be safe and when trials for effectiveness
are fully enrolled. Doctors treating patients who receive
such drugs would be asked to provide information back to
researchers, thus forming a source of information that is
parallel to the formal trials.
"This is an important proposal. It could change ground
rules on research, clinical care, markets, and insurance.
It could also provide access to drugs -- the good ones and
the worthless ones- -long before data are available. If it
works it could revolutionize drug development. If it fails
it could cripple AIDS research for some time.
"Today's hearing is to form a record of the proposal,
its reach and its limits as well as the questions that
remain unanswered. I hope that with this hearing we can
begin to form a consensus as to how AIDS drug development
will proceed."
Congresswoman Nancy Pelosi (D-San Francisco) gave specific
examples of problems with the current system:
"Each month, I hold an open meeting in my district for
people with symptomatic HIV infection and their advocates.
The group is very knowledgeable about HIV-related drugs and
their potential uses. Their top priority is access to
potentially lifesaving experimental drugs. Their stories
are compelling.
"One young man participated in a NIH-sponsored phase I
trial of DDC at Stanford. From his perspective, the drug
worked well. He felt subjectively much better and his
laboratory tests indicated a decline in p24 antigen level (a
measure of viral activity) and limited increases in T-cell
count (a measure of immune functioning). After 13 weeks, he
received a phone call telling him that his participation in
the study was no longer needed. Since then he has started
AZT several times but has had difficulty tolerating even
half of the standard dose. Although he has not yet received
a formal AIDS diagnosis, as of last month his T-cell count
dropped to 18. He is receiving no anti-retroviral therapy.
He and his treating physician want him to try DDI or to go
back on DDC. Given his history of prior use of AZT and DDC,
he is a poor candidate for other clinical trials. Why can't
this man and his physician be given access to either DDC or
DDI?
"Another man from this group has been on AZT for just
under two years. He did very well on this drug. However,
in the last two months, his T-cell level has declined from
over 300 to around 130. He is also beginning to experience
symptoms which he has not had in the last two years, includ-
ing disabling levels of fatigue. He and his physician
believe it is time for him to switch to another anti-
retroviral drug. Why can't this man and his physician be
given access to DDI? "
We have not seen Dr. Mason's testimony. But Jim Eigo of ACT
UP/New York's Treatment and Data Committee summarized the status
of the parallel track after the hearings. According to his sum-
mary:
* Dr. Mason's testimony showed that the Public Health Ser-
vice is committed to some form of parallel track -- but that what
parallel track means is so far undecided. The Public Health Ser-
vice asked that an FDA advisory committee, to include AIDS advo-
cates, report to Dr. Mason by August 21 and prepare recommenda-
tions on the parallel track.
* DDI will not be available under the "parallel track", at
least not immediately, but it will be available under the "treat-
ment IND" for people who are AZT-intolerant. However, FDA com-
missioner Frank Young admitted that Bristol-Myers has not yet
applied for a treatment IND.
* The day after the hearing, Jim Eigo "argued with Dr. Ellen
Cooper of FDA that DDI has to be made available under compas-
sionate use to at least two other groups of people: those too
sick to abide the rigors of the DDI clinical trials and those who
can't go off medication that the DDI trials forbid. She said she
believed that we could work that out."
* Parallel-track drugs will be open label (meaning that
patients will know what they are getting, instead of being ran-
domly assigned to two or more treatments and not told which).
* Parallel-track drugs will be judged individually -- prob-
ably by an FDA advisory committee with AIDS-community representa-
tion. Drugs must show "some indication of efficacy." Persons
receiving these drugs will sign informed-consent forms.
* There must be some way to prevent "secondary transfer"
(i.e. an underground market) of drugs obtained under the parallel
track.
On July 31 we spoke with Dr. Mason's office and learned:
* Dr. Mason wanted to emphasize that setting up the parallel
track must not interfere with or delay access to DDI.
* The committee to advise Dr. Mason by August 21 has not yet
been formed. However, it will probably consist of an FDA
antiviral advisory committee which already exists, plus AIDS
advocates brought in as consultants.
*****
PARALLEL TRACK ACCESS: HOW YOU CAN HELP
Patients and physicians who want to have input into the
definition of the parallel track should write to Dr. Mason at the
address below, as soon as possible. It is especially important
to let him and the advisory committee know the specifics of your
or your patients' situations, so that when the rules are
developed they can take your situation into account. We suggest
that letters be typed or printed, and be kept short if possible.
Tell about your experience in using treatments, attempting to get
treatments, or seeking, applying for, or participating in clini-
cal trials.
WARNING -- Dr. Mason's office may not be able to keep these
letters confidential; they may become public information. IF YOU
MUST KEEP YOUR HEALTH STATUS CONFIDENTIAL, THEN WRITE
ANONYMOUSLY, AND DO NOT INCLUDE IDENTIFYING INFORMATION.
If possible, send a copy of your letter to the Treatment and
Data Committee of ACT UP/New York; address it to: Jim Eigo, P.
O. Box 492, New York, NY 10009. It would also help if you would
send a copy to AIDS TREATMENT NEWS .
The address for Dr. Mason is:
The Hon. James O. Mason, M. D.
Assistant Secretary for Health
716-G Hubert H. Humphrey Building
200 Independence Avenue SW
Washington, DC 20201
*****
COMMUNITY-BASED RESEARCH ORGANIZATIONS -- AMFAR WILL COORDINATE
About 20 groups are organizing in cities around the country
to do community-based research. Recently the American Foundation
for AIDS Research (AmFAR) has hired a full-time coordinator to
put together a communication network for community-based organi-
zations doing clinical trials. The coordinator is Debbie Levine,
who also organized the Jul.y 1989 New York conference on
community-based trials.
AmFAR's community-based clinical trials program will set up
a series of conference calls to address major topics:
* Putting together multicenter trials;
* Standardizing data collection and data management;
* Communication, by conference calls, electronic mail, fax,
or voicemail;
* Examining the role of community-based organizations in the
parallel-track system;
* Working on the relationship of community-based clinical
trial organizations and NIAID's ACTG research centers;
* Fundraising for community-based research, including
government and pharmaceutical-industry support;
* How to set up Institutional Review Boards;
* Recruiting, including equal access for poor or minority
patients;
* How to work with the mass media;
* How to encourage community groups to have PWA representa-
tion on all decision-making bodies.
Immediate plans are for a conference call about once every
three weeks, with one representative from each group on the call.
There may also be a newsletter sent to each organization.
For more information, call Debbie Levine, Coordinator of
Community-Based Clinical Trials Programs, American Foundation for
AIDS Research, 212/719-0654.
*****
PEPTIDE T
by David Smyth
Peptide T first gained notoriety in late 1986 and early 1987
when researchers at the Karolinska Institute in Stockholm
reported in the Lancet improvements in lymphocyte counts,
psoriasis and neuropsychiatric functions in four patients who had
been given the drug on a compassionate basis (Wetterberg and oth-
ers, 1987). Since that time the drug has undergone further tests
in Sweden and the United States with scientists reporting some
positive results.
Although there was considerable evidence from the earliest
laboratory tests that peptide T is nontoxic, the drug has been
bogged down for nearly two years in a small phase I toxicity
trial in the U. S. Indeed, phase II efficacy studies have been
delayed in part because of the drug's lack of toxicity. The
questionable logic behind this policy dictates that phase II stu-
dies can not begin until a maximum tolerated dose is discovered
in phase I. Researchers had ample warning this might be the case,
because they could not find an LD50 dose (a dose potent enough to
kill half the animals to which it is administered) in studies
conducted before human trials began.
An application by the drug's sponsors for phase II studies
of peptide T in the National Institutes of Health extensive test-
ing system was denied in late July, 1989. And Bristol-Myers Co.
in May, 1989 withdrew from a federal license to market and
manufacture the drug.
Peptide T was discovered by Candace Pert, Ph.D., who was
chief of the brain biochemistry section at the National Institute
of Mental Health. The mechanism of action of the drug is dif-
ferent from most antivirals in that it does not act directly on
HIV or infected cells. Rather it is intended to block the virus
from entering cells (Pert and others, 1986).
Eight amino acids which constitute part of the viral
envelope called gp120 are thought by some scientists to be the
key by which HIV gains entry through the CD4 receptor. Indeed, a
common metaphor by which the drug's action is explained is the
lock and key.
Pert theorized that if HIV could enter the CD4 receptor, it
must mimic a chemical produced by the body that used the same
receptor (Pert, 1987). She found a sequence of eight amino acids
in a hormone called vasointestinal peptide (VIP) that duplicated
a section of gp120 and designed peptide T as a way of plugging
all the body's CD4 "locks" with artificial "keys". The drug's
lack of toxicity is thought to derive from its similarity to a
chemical produced by the body.
But the controversy swirling around the drug centers on its
efficacy, not its toxicity. And the fact that the drug is plod-
ding through a slow-moving toxicity study has done little to help
resolve the issue in a timely fashion.
Six months after Pert and others asserted in the Lancet that
peptide T helped Swedish AIDS patients, William Haseltine, Ph.D.,
of the Dana-Farber Cancer Institute in Boston reported that he
and several other researchers found peptide T did not inhibit the
virus in test tube experiments. Furthermore, the viral envelope
was constantly changing, thus the sequence of amino acids in pep-
tide T could not possibly duplicate a section of the viral
envelope (Sodroski and others, 1987).
Two years later, Joseph Sodroski, M. D., one of the drug's
critics, asserts, "There is no scientific basis for concluding
that peptide T will perform the (blocking) function. The first
work that said the peptide T region is not the region on gp120
that interacts with the receptor was from our lab (Kowalski and
others, 1987) and Larry Lasky's (Lasky and others, 1987) group at
Genentech, which pointed more to the carboxyl terminus on gp120.
Subsequently, Hans Wigsell (Nygren and others, 1988) at the Karo-
linska Institute has cleaved gp120 and they have a fragment that
has cleaved off peptide T-related sequences completely and that
still binds to CD4."
The drug's sponsors replied that Haseltine, Sodroski and
others had used high concentrations of virus in their experiments
(Ruff and others, 1987), and that no one knew what concentrations
were actually present in the bodies of AIDS patients.
Frederick Goodwin, M. D., then director of NIMH, called a
meeting where the opposing researchers could arrive at a con-
sensus about the drug's mechanism of action. However, no agree-
ment was reached (Barnes, 1987). Nevertheless the Food and Drug
Administration, which had a representative at the meeting,
granted permission to begin testing the drug in people, half a
year after the application was filed.
At about this time, a researcher at Oncogen, a small
Seattle- based company later acquired by Bristol-Myers Co. dev-
ised her own in vitro tests of peptide T and found the drug
worked against low and moderate viral concentrations, but not
against high concentrations (Barnes, 1987). This work helped
influence the pharmaceutical giant's decision to seek a license
for peptide T from NIMH, which has a patent pending on the com-
pound.
Douglas Brenneman, M. D., of the Laboratory of Developmental
Neurobiology at the National Institute of Child Health and Human
Development has asserted in articles in Nature (Brenneman and
others, 1988) and Drug Development Research (Brenneman and oth-
ers, 1988) that gp120 is associated with neuronal cell death and
that VIP and peptide T blocked the action of gp120 in the test
tube.
In an interview, Dr. Sodroski said, "That work is of dubious
significance. It's not clear what neuronal cell death in that
system really means....The neuronal cells in that system are
mouse cells. The problem is that gp120 does not bind to mouse
CD4."
Although FDA allowed phase I testing to begin, the National
Institutes of Health refused the sponsors' application for a
phase I study of the drug in the agency's drug trials network.
The agency wanted more documentation of the drug's mechanism of
action as well as more studies in animals. NIMH (which is part
of the Alcohol, Drug Abuse and Mental Health Administration, not
the NIH) searched for months for a medical center in which to
conduct its studies, finally contracting with the Los Angeles
County/University of Southern California Medical Center. Peter
Heseltine, M. D., was selected as principal investigator.
Intravenous administration of peptide T to the first group
of six patients in this trial began in November, 1987. NIMH
expanded this study in July, 1988 to include 24 patients. They
were given the drug by intravenous injection for twelve weeks,
followed by a four week "washout" period, during which no
antivirals (including peptide T) could be taken. The patients
were then given the option of continuing to take the drug
intranasally. This study focused on searching for toxic side
effects and determining a suitable dose for later trials of the
drug's effectiveness.
The first results of human trials came from the Karolinska
Institute, where seven patients were given the drug by
intravenous injection. Dr. Lennart Wetterberg and others
reported, "There was no evidence of clinical improvement in any
of the patients except in one case where a remarkable improvement
in the patient's psoriasis was observed. From all patients HIV
was isolated from peripheral blood mononuclear cells or plasma
before and after treatment. However, in three of the seven
patients there was a decline of HIV p24 antigen levels in serum.
"During treatment a transient rise in the CD4 (T4) cell
count was recorded in two patients. In four of the six treated
patients, which could be evaluated, the area of pathologically
altered brain white matter, as estimated by magnetic resonance
imaging, was reduced.
"These findings suggest that peptide T may have biological
effects in HIV-infected individuals. The results from this small
series of patients should be followed by further trials to evalu-
ate the possible therapeutic usefulness of peptide T" (Wetterberg
and others, 1988).
Dr. Wetterberg did not respond to requests to reconcile the
statement of "no evidence of clinical improvement" with the
assertions made in his next two paragraphs.
The Swedish researchers suspended a double-blind, placebo
controlled study in 36 patients when Bristol-Myers was granted
the federal license in August, 1988. The Karolinska team sought
financial assistance as well as clarification of their access to
the drug. The study was not resumed.
When Bristol-Myers acquired the license for peptide T some
people anticipated the pharmaceutical giant would speed up test-
ing of the drug and resolve the lingering questions about its
efficacy. However, the trial's pace was not increased. The com-
pany withdrew from the license in May, 1989. Susan Yarin,
manager of public affairs for pharmaceuticals at Bristol-Myers,
said, "We determined that peptide T's antiviral activity against
the HIV-1 virus is limited."
Some of the drug's supporters said the firm's decision had a
strong financial component, namely to concentrate the millions of
dollars necessary for large phase II trials on DDI. Integra
Institute, which had shared the license with Bristol-Myers,
recently notified the government it wishes to be the sole licen-
see, according to Pert, one of Integra's founders. Pert
responded to Bristol-Myers' announcement saying, "I think it's an
unwise decision. Integra is ready, willing and able to meet all
responsibilities of the license to the drug." Bristol-Myers will
continue to fund the Los Angeles trial and supply the drug to a
phase I trial at the Fenway Community Health Center in Boston
(see "Boston, Los Angeles: Peptide T Trials Recruiting," AIDS
TREATMENT NEWS # 78, May 5, 1989).
Reports from the Los Angeles study presented at the Fifth
International Conference on AIDS in Montreal concentrated on the
drug's ability to improve neuropsychiatric and neuromotor func-
tioning in HIV-impaired individuals. Peter Bridge, M. D., from
NIMH reported that peptide T reversed neuropsychiatric problems
in AIDS and ARC patients with HIV-related brain and central ner-
vous system impairment.
Dr. Heseltine asserted there were significant improvements
in brain function measured by tests of memory, motor speed,
attention and cognitive processing. The patients' test scores
declined when the drug was withdrawn after 12 weeks of treatment.
He said comparisons with other clinical trials that measured the
ability of AZT to improve brain function showed peptide T to be
twice as effective. Heseltine was associated with early studies
of AZT.
Responding to these assertions, Dr. Sodroski said, "It may
very well make people feel better or give them better appetites,
or do other things because it does have this homology (similar-
ity) with VIP, but in terms of stopping HIV infection in
patients, I think peptide T will do absolutely nothing."
Michael Ruff, Ph.D., Pert's associate, reported at Montreal
that cerebrospinal fluid "from 9 out of 18 HIV-infected individu-
als (in the Los Angeles trial) showed significant (>20% of con-
trol) in vitro neuronal killing activity which was always
blocked by peptide T. "
A draft of a letter submitted to The Lancet and expected to
be published in July, 1989 reports on results of administering
peptide T to six patients: "No toxicity was observed. Where
HIV-associated deficits (2 Standard Deviations below population
norm) had been present at baseline, cognitive neuromotor function
returned to normal during drug testing. Similarly, where HIV
constitutional symptoms had been present at baseline (weight
loss, watery diarrhea, fatigue, anergy, HIV- associated derma-
titis), improvement or resolution was observed. Two patients
were p24 antigen positive at baseline, becoming negative at
follow-up. T4 counts remained stable while T8 counts increased
50% on average (400 to 600). No changes were observed in natural
killer cell activity or in delayed hypersensitivity skin
testing....Constitutional/neuropsychiatric benefit, absent toxi-
city, and reduced p24 antigenemia in these patients is encourag-
ing" (Bridge and others, 1989).
A serious snafu at the Los Angeles study occurred this sum-
mer. Two volunteers who had gone off AZT for one month in compli-
ance with the protocol were told nine hours after they had
entered the hospital that there was no drug for them. They were
asked to return a month later. One volunteer came down with PCP
and the other was told one month later there still wasn't enough
drug. The volunteer said he had great difficulty getting infor-
mation from officials connected with the study and has decided
not to participate in the trial. He says his T4 count decreased
significantly while he was off AZT. "I feel helpless and victim-
ized, in addition to fearing for my life more than ever before,"
said Gordon McMahon, Ph.D., the volunteer.
The third study of the drug began in May, 1989 at the Fenway
Community Health Center in Boston. Sixty volunteers will receive
the drug intranasally for six months. Seventeen people have
enrolled in the trial so far, according to Kenneth Mayer, M. D.,
the study's research director and an assistant professor at Brown
University. "The jury is still out (on the drug's efficacy) and
these studies need to be done....We don't have enough data to
know the drug's efficacy," Dr. Mayer said.
[David Smyth is a free-lance reporter based in San Francisco, who
has participated in the Peptide T study in Los Angeles. He has
reported on AIDS treatments for the Bay Area Reporter, The San
Francisco Sentinel, Bay Windows, Frontiers, Health Week and other
publications.]
References
Barnes, D. Debate over potential AIDS drug. Science, 237(4811),
pages 128-130, July 10, 1987.
Brenneman, D. and others. Neuronal cell killing by the envelope
protein of HIV and its prevention by vasoactive intestinal pep-
tide. Nature, 335(6191), pages 639-642, October 13, 1988.
Brenneman, D. and others. Peptide T prevents gp120 induced neu-
ronal cell death in vitro: relevance to AIDS dementia. Drug
Development Research, volume 15, pages 361-369, 1988.
Bridge, P. and others. Peptide T: Improvements in phase I trial
of AIDS patients. Draft of letter submitted to Lancet, July
1989.
Kowalski, M. and others. Functional regions of the envelope
glycoprotein of human immunodeficiency virus type 1. Science,
237 (4820), pages 1351-1355, 1987.
Lasky and others. Delineation of a region of the human immunode-
ficiency virus type 1 gp120 glycoprotein critical for interaction
with the CD4 receptor. Cell, volume 50 number 6, pages 975-985,
1987.
Nygren and others. 95- and 25-kDa fragments of the human immuno-
deficiency virus envelope glycoprotein gp120 bind to the CD4
receptor. Proceedings of the National Academy of Sciences U. S.
A., volume 85 number 17, pages 6543-6546, 1988.
Pert, C., and others. Octapeptides deduced from the neuropeptide
receptor-like pattern of antigen T4 in brain potently inhibit
human immunodeficiency virus receptor binding and T-cell infec-
tivity. Proceedings of the National Academy of Sciences U. S.
A., volume 83, pages 9254-9258, December 1986.
Pert interview, Science Impact, pp. 6-7, June 1987.
Ruff, M., and others. Peptide T[4-8] is core HIV envelope
sequence required for CD4 receptor attachment.Lancet, 2(8561),
page 751, Sept. 26, 1987.
Sodroski, J., and others. HIV envelope-CD4 interaction not inhi-
bited by synthetic octapeptides. Lancet, 1(8547), pages 1428-
1429, June 20, 1987.
Wetterberg, L., and others. Treatment with peptide T in seven
immunodepressed HIV infected patients. Draft of paper submitted
to AIDS, Gower Academy Journal, London, June, 1988.
Wetterberg, L., and others. Peptide T in treatment of AIDS. The
Lancet, 1(8525), page 159, Jan. 17, 1987.
*****
SAN FRANCISCO: DHEA STUDY RECRUITING
In January 1988, AIDS TREATMENT NEWS reported on DHEA, a
hormone which is already present in the body and is closely
related to testosterone, and which was being tested as an AIDS
treatment in a small study in Paris (see issue #48, January 15,
1988). Recently, at the AIDS conference in Montreal, some DHEA
studies suggested that the drug might have a protective effect.
A phase I trial in San Francisco is now recruiting persons
who have some ARC symptoms (such as thrush, or hairy leukoplakia,
or chronic diarrhea, or fevers and sweats) and T-helper counts
between 250 and 600. Persons with an AIDS diagnosis are not eli-
gible for this study (because they meet the FDA criteria for AZT,
and therefore it would be considered unethical for researchers to
keep them off of that drug). Women also are not eligible,
because the drug is a male hormone which might be harmful to
them. (If the treatment is determined to be valuable it might be
usable by women, but researchers are reluctant to take the
increased risk before efficacy has been shown.) Patients cannot
use any antiviral with known or suspected anti- HIV activity
(such as AZT or dextran sulfate) during the study.
Volunteers will take DHEA by mouth for 16 weeks; there is no
placebo. Three different doses are being tested; 250 mg three
times a day, and 500 and 750 mg on the same schedule. Patients
cannot start on the next higher dose until all have completed
eight weeks on the lower dose without harm. (Even the lowest
dose in this study is higher than any we reported in the Paris
study in 1988.) After the study, the sponsor and the FDA have
agreed to provide maintenance of the drug, provided that it is
well tolerated and appears to be beneficial.
The trial is sponsored by Elan Corporation, which is based
in Ireland, and which also sponsored the Paris study. In San
Francisco, the principal investigators are Toby Dyner, M. D., and
Mark Jacobson, M. D.
Persons interested in joining this study should call Jaime
Geaga at the AIDS Clinical Research Project (ACRE) at Childrens'
Hospital; the phone number is 750-6529 or 750-6522. 24
volunteers are needed (eight for each dose level), and six are
already enrolled.
*****
IN MEMORIAM: CHARLIE SAMSON AND DON WRIGHT
AIDS TREATMENT NEWS recently lost two friends and former
staff members, Charlie Samson and Don Wright. They are remem-
bered for their strong fight to survive with AIDS and their good
work for the newsletter.
Charlie was responsible for the painstakingly thorough index
found at the end of the collected back issues of AIDS TREATMENT
NEWS #1 through #50. He was fluent in treatment information and
assisted many subscribers who called the newsletter with related
questions. Charlie also stood by very strong political convic-
tions. He fought for social justice before the epidemic, and
often protested the homophobic and xenophobic mishandling of the
AIDS crisis by the Reagan administration. When his friend Eric
died several years ago, Charlie contended that Eric and all peo-
ple who have died of AIDS were essentially murdered by the pur-
poseful neglect of their own government and a healthcare system
which puts profits ahead of people. Charlie was particularly
grateful for all the work women have done in the epidemic, and
often said so to his supporting circle of friends, which he
called his "Helper Cell". Charlie died on May 24th.
Don worked only briefly at AIDS TREATMENT NEWS but in that
time he developed a careful and useful method of archiving the
vast quantity of periodicals and correspondence we receive. Like
Charlie, Don viewed his life and his world through a political
perspective which challenged oppression of women, people of
color, gay people, and of course people with AIDS. He was fami-
liar with medical terminology and enjoyed discussing the newest
developments in AIDS treatments. Don died on July 23rd.
Charlie Samson and Don Wright will not be forgotten, and
their fight has brought us closer to the day when AIDS and the
injustices it exposed are defeated.
*****
STATEMENT OF PURPOSE
AIDS TREATMENT NEWS reports on experimental and complementary
treatments, especially those available now. It collects informa-
tion from medical journals, and from interviews with scientists
physicians, and other health practitioners, and persons with AIDS
or ARC.
Long-term survivors have usually tried many different treatments,
and found combinations which work for them. AIDS TREATMENT NEWS
does not recommend particular therapies, but seeks to increase
the options available.
We also examine the ethical and public-policy issues around AIDS
treatment research.
HOW TO SUBSCRIBE TO AIDS TREATMENT NEWS BY MAIL
Send $100.00 per year for 26 issues ($150.00 for businesses and
organizations), or $30.00 reduced rate for persons with AIDS or
ARC who cannot afford the regular rate, to: ATN Publications, P.
O. Box 411256, San Francisco, CA 94141. A six-month subscrip-
tion (13 issues) is $55.00 ($80.00 for businesses or organiza-
tions), or $16.00 reduced rate. For subscription information and
a sample issue, call (415) 255-0588.
For the complete set of over 70 back issues, send $75.00 ($18.00
for persons with AIDS or ARC) to the above address. The back
issues include information on hypericin, dextran sulfate, foscar-
net, passive immunotherapy, DTC (Imuthiol), naltrexone, DHEA,
lentinan, propolis, coenzyme Q, monolaurin, egg lecithin lipids,
fu zheng herbal therapy, DNCB, aerosol pentamidine, fluconazole,
ganciclovir (DHPG) and other experimental or complementary treat-
ments.
To protect your privacy, we mail first class without mentioning
AIDS on the envelope, and we keep our subscriber list confiden-
tial.
Outside North America, add $20.00 per year for airmail postage,
and $18.00 airmail for back issues. Outside U. S. A., send U. S.
funds by International Postal Money Order, or by travelers
checks, or by drafts or checks on U. S. banks.
Copyright 1989 by John S. James. Permission granted for non-
commercial reproduction.
-----------
Scotty
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