Date: 20 May 94 17:35 PDT From: "John S. James" Lines: 605 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 301/424-0257. 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 312/222-1326. ***** 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 Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews.igc.apc.org Editor and Publisher: John S. James Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha 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. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. 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 quotations are used.