DP Tool Club 15/CD_ASCQ_15_070894.iso/vrac/atn199.zip/ATN199.TXT

Text File | 1994-06-04 | 26KB | 608 lines

___________________________________________________________

          J O H N   J A M E S  writes  on  A I D S
___________________________________________________________

[Electronically distributed for GENA by AEGIS/San Juan Capistrano. 714.248.2836]

AIDS TREATMENT NEWS Issue #199, May 20, 1994
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:

AIDS Research Direction: New Scientific Approach?
San Francisco, Other Cities: Protease Inhibitor Combination
Trial

Resources

   New Directory of Federal Biomedical Research
   Antiviral Agents Bulletin Newsletter
   Gene Therapy Review

Announcements

   "Poppers" Meeting, May 23-24, Gaithersburg, Maryland


***** AIDS Research Direction: New Scientific Approach?

by John S. James

The future of AIDS research was the focus of two articles
which appeared on May 12: "AIDS: Time to Turn to Basic
Science," by Bernard N. Fields, M.D., in the scientific
journal NATURE, and "Scientists Say U.S. Research on AIDS
Needs Redirection," by Gina Kolata in THE NEW YORK TIMES. The
TIMES article underlined the importance of the one in NATURE,
by quoting leading scientists -- especially Harold Varmus,
M.D., the new director of the U.S. National Institutes of
Health ("Everyone agrees with Bernie's basic precept"), and
William Paul, M.D., head of the newly strengthened and
centralized Office of AIDS Research ("We take that [the ideas
expressed in the NATURE piece] as our marching orders"). The
impact of the new thinking is likely to be gradual, however,
because of (1) the momentum behind the existing system, and
(2) the fact that the budget for Fiscal 1995 (the year which
begins in October 1994) is already largely completed.

Clearly the NATURE article reflects the views of a number of
leading basic-research scientists -- including the two
officials (Dr. Varmus and Dr. Paul) who will have the most
influence on the future of the U.S. government AIDS research
effort, which is by far the world's largest.

Among AIDS treatment activists, most (but not all) who have
been following this changing emphasis seem to be viewing it
favorably -- especially in welcoming the new involvement in
AIDS research by leading scientists. But few if any believe
that this new thinking is the whole answer. And some fear
that certain problems could be made worse.

What Is Proposed?

Dr. Fields, the author of the NATURE article, is a leading
virologist, and chairman of the Department of Microbiology
and Molecular Genetics of Harvard Medical School; until this
year he was editor of the JOURNAL OF VIROLOGY. The commentary
in NATURE is his first publication on AIDS.

How could an article by someone new to the field have so much
influence? The process may have started on February 17 of
this year, when Dr. Paul's appointment as head of the Office
of AIDS Research was announced. Dr. Paul, a leading
immunologist who had been chief of the Laboratory of
Immunology at the U.S. Institute of Allergy and Infectious
Diseases, was also new to AIDS. (This was neither surprising
nor unwelcome. A number of people, including this writer,
have felt that Federal AIDS research should be led by a well-
regarded scientist from outside the AIDS field.) After being
appointed, Dr. Paul sought the advice of top scientists in
virology and other relevant fields -- many of whom were also
new to AIDS -- about how research and treatment development
could be improved.

Before publishing his article, Dr. Fields showed drafts to
Dr. Varmus, Dr. Paul, and others in the informal group of Dr.
Paul's advisors, and found general agreement with the major
points. Not everyone agreed totally, however.

It is hard to summarize this two-page article, but a quote
from the second paragraph gives a sense of its direction and
tone:

"It is my view that we need to bring fresh scientific thought
to the problem of AIDS. We need change, but what kind? We
need to put increased emphasis on basic science and broaden
our definition of AIDS-related research. In addition, we need
to look critically at the time, effort, and money spent on
many aspects of drug development and vaccine programmes that
have little or no scientific rationale, and are thus unlikely
to lead to effective therapies or prevention. The focus on
drugs and vaccines made sense a decade ago, but it is time to
acknowledge that our best hunches have not paid off and are
not likely to do so."

Dr. Fields mentions a few of a long list of largely
unanswered scientific questions, such as how HIV spreads from
a primary site of infection on mucosal surfaces, and how it
kills cells. He points out that HIV is very different from
other viruses, such as polio. With polio, the critical steps
were the isolation and culturing of the virus; with AIDS this
has already been achieved, but that has not solved the
problem.

Dr. Fields suggests four points to guide future research:

(1) Broaden the definition of AIDS research. For example, he
suggests that a particular virus in mice "provides an
excellent model for studying viral persistence and the host
response." Such studies could be funded as AIDS research,
even though the virus is not HIV.

(2) "Emphasize the basics of the science directly relevant to
HIV and AIDS" -- for example, through studies of AIDS
pathogenesis, and the immune response to HIV.

(3) Expand studies of opportunistic infections, and increase
"longer-term support for high-quality proposals in this
area."

(4) "Continue to look directly for a new drug or effective
vaccine" -- but "concentrate on studies that offer a real
possibility of working... In our zeal to control AIDS, we
have invested enormous resources in the search for drugs and
vaccines. This may have been reasonable 10 years ago, but is
no longer."

Comment

When AIDS research began, the leading, established scientists
in the various relevant fields, such as virology and
immunology, did not choose to work in AIDS. This is
understandable; they already had a full plate of projects
going, and in the early days there was much fear for the
safety of laboratory workers, because no one knew what
precautions were necessary for working with the new disease.
Later, it seems to have been difficult for new people to
enter AIDS work, because funding has been short, and already
spoken for. We believe that as a result, AIDS research never
recovered from the early lack of senior people.

Now Dr. Paul has brought in leading researchers. Dr. Fields'
article outlines his assessment (with which many others
agree) of the research so far, and proposes directions for
reform. It is asking for a more rational research program,
with clinical trials based on scientific knowledge. (This
would replace a system in which the trials that actually
happen are determined partly by accident, but largely by
which drugs have the commercial clout to push through the
random obstacles in their way.) The high-level attention
reflected in Dr. Fields' article opens the door to new
scientific leadership to address the major problems in AIDS
treatment and vaccine research and development.

But this new thinking has not fully addressed what we believe
is the biggest single problem in AIDS research -- the nearly
complete lack of movement of potential new treatments from
the stage of academic papers to the earliest test for
antiviral or other activity in humans. Ideally, scientific
consensus could provide the missing momentum, leading to
early development and small human trials which, if
successful, will generate enough industry or other interest
to assure further development. But it may take years to
understand the basic science; in the beginning, there may be
only a scientific hunch.

In this case, we believe that there is another legitimate
criterion, besides conclusive science, for picking candidate
drugs for further development -- namely, practical
feasibility. If the potential drug or combination is already
in human use, and well known to be safe; if a small trial
could be run safely, quickly, inexpensively, and easily; and
if the treatment, if successful, could quickly be brought
into wide use -- then a pilot, screening trial may make
excellent human and public-health sense, even if the
scientific mechanism is not fully understood -- and even if
the probability of success is small.

Why has AIDS treatment development been so disappointing?
Some of the thinking behind current AIDS trials was based on
the relative success of treatment development in certain
leukemias and some other cancers. What worked there was to
keep comparing different drug combinations, looking for small
differences in effectiveness; eventually these small
treatment improvements added up to major advances. For this
trial-and-error process, it was not necessary to understand
why a combination worked.

But cancer research has much better procedures than AIDS
research for getting new treatments into testing, and into
combination testing -- whether or not a pharmaceutical
company is interested at the early stages. In AIDS, each
potential new agent is usually just dropped, and never
developed or seriously evaluated. And no wonder; usually the
only available path in AIDS is that first a company must
become interested enough to foresee taking a drug through the
whole process -- on the basis of no human data. Cancer
research has much more flexible ways of getting new agents to
physician-researchers earlier; this allows rational planning
of further research, based on actual human experience.

In AIDS this has not worked because it has not been tried.
New agents are not allowed to begin development. And early
combination experience has been inordinately difficult to
arrange, because of the difficulty of getting competing
companies to work together, and because of FDA reluctance to
allow combination trials early in the development process.
This is why we are concerned with the conclusion that "our
best hunches have not paid off and are not likely to do so"
(quoted from Dr. Fields, above). Few hunches have failed or
been rejected; many have been blocked or dropped arbitrarily.
The solution is to unblock this process, to allow an orderly
flow of feasible ideas into small pilot trials -- not to
abandon this research until the science is perfected.

We agree that scientific understanding is the best basis for
designing clinical trials. We hope that the new basic-science
viewpoint will not make the mistake of considering it the
only legitimate basis.

[Note: Before going to press, AIDS Treatment News discussed a
draft of this article with Dr. Fields. He emphasized that the
NATURE article represents his views, which a number of people
agree with, but that there was no total agreement or formal
consensus process.

[Dr. Fields was a candidate to be the director of the Office
of AIDS Research, but removed himself for health reasons. He
wrote the NATURE article because, as a general virologist who
has closely followed AIDS, he thought that some points needed
to be stressed -- and since he is not conducting AIDS
research himself, he could speak from a certain distance.

[Dr. Fields emphasized that basic science is not a substitute
for the clinical research now going on -- that we must do
everything we can to find new drugs and vaccines. The
question is how to get there fastest. We must balance the
total resources available, to cover areas we are now missing.
He gave the example of whether we should spend $20 million to
$30 million on a vaccine trial when the data strongly suggest
that it will not work -- instead of using the resources to
learn what is critical about immunity to HIV.]


***** San Francisco, Other Cities: Protease Inhibitor
      Combination Trial

A critically important trial of the Merck protease inhibitor
(L-524) needs 60 volunteers who have never taken AZT or ddI
for more than two weeks, and who have a T-helper count of
under 500. The trial will take place in San Francisco and at
several other U.S. sites; we do not know the other cities at
press time. In San Francisco, the trial is planned to begin
in June.

Volunteers will be randomly assigned to receive three
different treatments: L-524 plus AZT plus ddI, L-524 alone,
and AZT plus ddI. (Merck has increased the dose of L-524 to
600 mg, from the 400 mg used in some earlier studies.) The
trial will last for 24 weeks; and if the therapy is well
tolerated and appears to have satisfactory antiviral effects,
patients who complete the 24 weeks will be offered continued
treatment through extensions of the study. The purpose is to
compare changes in HIV RNA and changes in T-helper count, and
to see if resistance to L-524 develops differently when that
drug is used alone or in combination.

The major entry criteria are:

* HIV positive, between 18 and 65 years of age;

* No AZT or ddI ever for over two weeks;

* T-helper count below 500 (there is no lower limit);

* Volunteers will be tested and must have HIV RNA levels of
at least 50,000 copies per milliliter (as determined by the
Roche Biomedical Laboratories quantitative PCR test);

* If on ddC, patients must be willing to discontinue at least
two weeks before the study treatment begins; if on d4T or
other investigational drugs, they must be willing to
discontinue 30 days before;

* No prior treatment with a protease inhibitor;

* No history of pancreatitis or peripheral neuropathy;

* Not positive for HBsAg (hepatitis B surface antigen,
indicating chronic active hepatitis B).

The ideal volunteer for this study would be someone with a
low T-helper count who has never had antiretroviral
treatment.

For more information about volunteering at the San Francisco
site, contact Christopher King, assistant director of
research, Conant Medical Group, through the trials
information line, 415/923-0555 (or by fax at 923-0337). Leave
your name, complete address, and phone number, and he will
call within five working days.

Comment

The reason this trial is important is that the Merck protease
inhibitor has shown good results temporarily, even in persons
with very low T-helper counts, in the very few cases tested
so far. But the drug stops working well, because HIV develops
resistance to it. In other diseases, such as tuberculosis or
cancer, combination therapy is used to overcome drug
resistance. The purpose of this trial is to make sure that
the combination of L-524 with AZT and ddI is safe, and to see
if it delays the development of resistance to the protease
inhibitor.

The reason for the exclusion of prior AZT and ddI is that if
these drugs have been used, virus resistant to them may have
already developed. In that case, the full benefit of the
combination would probably not be seen. It is important that
this trial get clean data, so that the future development of
L-524 (and other protease inhibitors) in combination
treatment can be planned correctly.


***** Resources


** New Directory of Federal Biomedical Research

The FEDERAL BIO-TECHNOLOGY TRANSFER DIRECTORY is a unique
reference book on biomedical research which is available for
commercial development from the federal government. It
includes over 2,800 abstracts -- mostly on patents,
licensing, and government-industry development agreements --
many of which are relevant to AIDS. The information is
recent; the directory was published in April 1994, and
correctly reflects current AIDS developments. (The principal
author, Ronald A. Rader of the Biotechnology Information
Institute in Rockville, Maryland, is very familiar with AIDS,
as he has edited the monthly newsletter Antiviral Agents
Bulletin, from its beginning in 1988 to the present.)

The following technical description is from the Biotechnology
Information Institute:

The book is the largest directory of biotechnology and
pharmaceutical inventions available for licensing, and is a
unique source for information and competitive intelligence
concerning federal research, development and
commercialization activities. The book provides information
about invention licenses and Collaborative Research and
Development Agreements (CRADAs); related research and
development, strategic partnerships and commercialization
activities; and the status of products and technologies in
development and in the marketplace. Much of this information
has never before been published.

The FEDERAL BIO-TECHNOLOGY TRANSFER DIRECTORY contains over
2,800 abstracts describing: 2,100 federal inventions (900
patent applications and 1,200 U.S. patents); over 500 CRADAs;
nearly 1,000 invention licenses/transfers (including 270
exclusive and 640 nonexclusive patent licenses); and 140
biological materials transfers. Most of this information is
recent with over 60% of inventions (45% of patents and 80% of
patent applications) since 1990 and about 80% of CRADAs
presumed active in late 1993. The book has over 400 pages of
abstracts/text organized by agency/laboratory and over 250
pages of subject and other indexes. Inventions and CRADAs are
abstracted, cross-referenced and indexed in-depth with over
36,000 subject index entries. The book also includes:
organization, inventor/investigator, patent/application
number, license number and culture collection deposit
indexes; federal laboratory and agency contacts; sources and
methods for obtaining further information; a detailed users
guide; and an overview of federal technology transfer
mechanisms.

The directory is organized by Federal agency, with AIDS-
related abstracts scattered throughout. A very extensive
subject index (over 200 pages, with more than five pages on
HIV alone) allows researchers to look up particular
treatments. This directory does not cover all Federal
biomedical research, however; instead, it focuses on work
which is relevant to intellectual property.

The FEDERAL BIO-TECHNOLOGY TRANSFER DIRECTORY, by Ronald A.
Rader and Sally A. Young, is available for $150 (includes
shipping and handling; $175 outside North America) from:
Biotechnology Information Institute, 1700 Rockville Pike,
Suite 400, Rockville, MD 20852-1631, 301/424-0255, fax
301/424-0257.


** ANTIVIRAL AGENTS BULLETIN Newsletter

ANTIVIRAL AGENTS BULLETIN, a 32-page newsletter published 12
times a year by the Biotechnology Information Institute,
covers "commercial and scientific developments, federal and
regulatory activities, information resources, treatment
advances and trends, patents, and technology transfers.
Abstracts of all antiviral and virus-related U.S. patents,
announcements of international patent disclosures, and
abstracts of recent journal articles are also included. An
annual review issue describes the year's developments and
indexes articles by agent, virus/disease, and organization.
U.S. patents are indexed in another issue." The newsletter
has a strong HIV focus, "reflecting the dominance of HIV in
antiviral research and development."

Each issue includes abstracts of several dozen U.S. patents,
and also lists of several dozen international patents:

Non-U.S. patent disclosures are important because they are
often the first public disclosure of commercially-significant
developments, and may be the only public disclosure of
unpublished work. Most non-U.S. patent applications become
available at a certain point after filing, usually 18 months.
U.S. patents are only publicly disclosed after granting,
which usually requires at least 2-3 years from filing of the
application.

Emphasis is on early pre-issuance disclosures from major
patenting countries and international bodies including the
European Patent Office (EPO), World Intellectual Property
Organization (WIPO), major European countries, and Japan.

Full copies of international patents may be requested through
your in-house library, local research libraries, or
commercial document delivery services.

The international listings include only the title, country,
application number, date of disclosure, inventors, and patent
owner. It is not difficult to obtain the full copy, however,
given the application number. [Note that in many cases
companies are eager to publish their AIDS-related
developments, and information appears in journals before the
patent application is released.]

The April issue includes the following news stories:

* HHV-6 Further Linked to AIDS;

* Antigen-Coated Diamond Particle HIV Vaccines;

* Thalidomide Enters Phase II Trials;

* Oral Hypericin Trials Begin/Blood Disinfection
Demonstrated; and

* Anti-HIV Calanolides and Costatolides Available for
Licensing.

Recent U.S. patents abstracted include:

* An antiviral antibiotic complex, BU-3889V and its
components, useful for treatment of HIV, herpesvirus and
influenza virus infections, patented by Bristol-Myers Squibb
Co. (U.S. patent #5,286,649);

* Antisense phosphorothioate oligonucleotides for treatment
of retroviral infections, patented by the U.S. Public Health
Service/NIH (5,286,717);

* Use of antioxidant or anti-inflammatory thiol-repleting
methionine or methionine derivatives for treatment of HIV
infection (5,292,773);

* Pyridazinamines for treatment of viral infections, patented
by Janssen Pharmaceutica NV, subsidiary of Johnson & Johnson
(5,292,738);

Some international patents to be listed in the May issue:

* Retroviral protease inhibitors, SmithKline Beecham Corp.
(EPO 538366);

* Peptides that induce antibodies which neutralize
genetically divergent HIV-1 isolates (EPO 570357);

* Therapeutic anti-HIV oligonucleotide and pharmaceutical
(Hybridon Inc.) (WIPO 9408004); and

* Human neutralizing monoclonal antibodies to human
immunodeficiency virus, by Scripps Research Institute (WIPO
9407922);

ANTIVIRAL AGENTS BULLETIN is available for $350 per year
($410 per year outside of North America, including air mail
delivery) from the Biotechnology Information Institute, 1700
Rockville Pike, Suite 400, Rockville, MD 20852, phone
301/424-0255, fax [phone]. A sample issue is available
free -- or perhaps your university or research library could
subscribe.


** Gene Therapy Review

A readable but in-depth review of the current status of gene
therapy appears in the current JOURNAL OF THE PHYSICIANS
ASSOCIATION FOR AIDS CARE (formerly PAACNOTES), dated March
1994. It summarizes the work of the nine U.S. biotechnology
companies currently developing one or more gene-therapy
products for treatment or prevention of HIV infection or
AIDS. The author is Henry E. Chang, Director of Research and
Development at Shared Medical Research Foundation, Tarzana,
California.

The companies are: * Applied Immune Sciences, Inc.; * Avigen;
* Cell Genesys, Inc.; * CellPro, Inc.; * Genetic Therapy,
Inc.; * Immusol, Inc.; * Targeted Genetics Corporation; *
Viagene, Inc.; and * Vical, Inc. Sixteen different potential
products are listed; about a third of them are now in human
trials.

A copy of the March 1994 JOURNAL OF THE PHYSICIANS
ASSOCIATION FOR AIDS CARE, which also has major articles on
interleukins (such as IL-2 and IL-12), and on the testing and
treatment of syphilis, is available for $10 from: PAAC
Publishing, Inc., 101 West Grand Avenue, Suite 200, Chicago,
IL 60610, phone [phone].


***** Announcements


** "Poppers" Meeting, May 23-24, Gaithersburg, Maryland

The National Institute of Drug Abuse is sponsoring a two-day
"Nitrite Inhalant Review Meeting," which will examine
technical evidence relating to nitrite use and HIV disease.
Three sessions, "Epidemiology of nitrite use," "Do nitrites
lead to increased risky sexual behavior and HIV
transmission?" and "Do nitrites suppress the immune system?"
will be held on May 23. The next day there are two morning
sessions "Do nitrites act as a cofactor in Kaposi's sarcoma?"
and "General discussion -- Objective: To identify research
needed to implicate or exclude nitrite inhalants as
significant factors promoting HIV infection and/or disease
development."

There is no fee to attend, but space is limited. Those
planning to come should notify Mrs. Jean Bennet at 301/443-
6697, or by fax at 301/443-2317.


***** AIDS TREATMENT NEWS
      Published twice monthly

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   Internet: aidsnews.igc.apc.org
Editor and Publisher:
   John S. James
Reader Services and Business:
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   Tadd Tobias
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Statement of Purpose:
AIDS Treatment News reports on experimental and
standard treatments, especially those available now. We
interview physicians, scientists, other health
professionals, and persons with AIDS or HIV; we also
collect information from meetings and conferences,
medical journals, and computer databases. 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.

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ISSN # 1052-4207

Copyright 1994 by John S. James.  Permission granted for
noncommercial reproduction, provided that our address
and phone number are included if more than short
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