AIDS Treatment News #164, December 4, 1992
John S. James

In our last issue we outlined the problem of the empty pipeline of AIDS drug development ("Call to Activists: Focus Needed on Early Human Research," AIDS TREATMENT NEWS #163, November 20, 1992). Here we show that there is no lack of promising HIV treatment leads, by listing some of those which appeared in just one issue of one journal -- ANTIVIRAL RESEARCH, March 1992, which published the abstracts of the Fifth International Conference on Antiviral Research, held this year in Vancouver from March 8 to 13. We include this list to show that the lack of promising treatments for HIV infection reflects a management problem, more than the scientific difficulty of the task; very few of the existing leads are effectively followed up, because there is no one in a position to find the most promising potential new treatments, wherever they may be, and work together with industry or anyone else involved to make sure that they are handled appropriately and that unnecessary obstacles do not block progress.

Drugs late in the development pipeline can easily develop a constituency, because researchers are paid to study them, data exists about them, and the public wants them. But each early drug is likely to have a constituency of at most a handful of people, and they do not have nearly the clout to get the drug into human development. (The decision to proceed seriously toward human testing is a very expensive one for a company -- and the rules usually require a huge investment before there is any information on how well the drug works in practice in people.) Sometimes there are underground efforts to get a new drug tried, but without mainstream support, these projects usually move slowly. The U. S. drug-development system is set up in such a way that only large companies can expect to operate it successfully (see "Clinical Trials: Asking the Right Questions -- Interview with Lewis Sheiner, M. D.," AIDS TREATMENT NEWS #142, January 3, 1992).

We highlight these issues now because the incoming Clinton administration may signal that the nation is at last willing to take on the responsibility of addressing the AIDS epidemic effectively, instead of denying the problems and leaving them for someone else. As a result, there is now a chance that the real obstacles to more effective AIDS research and treatment development can be addressed. But the problems and proposed solutions must be on the table, discussed and analyzed by professionals and the public. Even activists have often failed to realize how many early leads are available; researchers could get the information, but their incentives have pushed them to emphasize drugs already marketed or close to marketing, and they could do little about the systemic misallocation of resources without public awareness and support.

One approach to a solution would be using small teams of experts, with no conflict of interest, to pick perhaps ten to 20 of the most promising potential drugs, contract them out for the FDA-required animal studies, then contract them to medical centers for the first human tests on HIV-positive volunteers. If these tests were successful, a drug could easily get the attention necessary for rapid further development by pharmaceutical companies or by other institutions. (Such an approach has been used very effectively to develop certain key military technologies, by the Defense Advanced Research Projects Agency [DARPA], despite ideological resistance by the Bush administration, which objected to similar government involvement in civilian technology. The Clinton administration is likely to apply such approaches to support long-term U. S. economic competitiveness. Biomedical research would have the two-for- one advantage of developing the economy while saving lives through the same effort.)

Examples: Potential Antivirals

In each entry below, we give the title of the abstract, the first author, the institution(s) where the work was done, and the abstract number. For more information about these potential drugs, see the abstract (which is usually one paragraph in length) in the March 1992 ANTIVIRAL RESEARCH, Supplement I.

This list omits studies of drugs which are generally familiar to the AIDS research community (such as ribavirin, hypericin, and the Roche tat inhibitor), as well as other studies which were more oriented to basic research or otherwise did not focus on new HIV treatment leads. Also, the conference had many presentations on other viruses which are relevant to AIDS treatment, including CMV and herpes simplex; we omitted those here, to focus on HIV.

Some of the drugs listed below may already be getting all appropriate research attention. We do not intend to imply otherwise, only to give a sense of how many interesting leads are available, how much laboratory drug-development work is going on, and which institutions are most productive in developing leads for new antivirals.

Many other new antivirals, not included here, are published elsewhere each year. In addition, there are many proposed "alternative" treatments which also are not included, as the collection below is mostly chemistry oriented, and weak on natural products. For these reasons, this list of potential AIDS treatments could be greatly expanded.

* * *

* New approaches for synthesizing antiviral nucleosides. Dennis C. Liotta. Emory University, Atlanta. Abstract 1.

* Optically active isodideoxynucleosides: a new family of potential anti-HIV agents. V. Nair and others. University of Iowa, Iowa City. Abstract 3.

* Potent and selective inhibition of HIV-1 and HIV-2 replication by a novel class of bicyclams targeted at viral uncoating. E. De Clercq and others. Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium; Johnson Matthey Technology Centre, Reading, Great Britain; and Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania. Abstract 4.

* HIV-1 specific phenylacetamide derivatives: A novel class of reverse transcriptase inhibitors with potent and selective antiviral activity in vitro. R. Pauwels and others. Rega Institute for Medical Research, Leuven, Belgium; and Janssen Research Foundation, Beerse, Belgium. Abstract 5. [Note: One drug of this class, code-named R89439, was covered in more detail in "Alpha-APA: New Anti-HIV Compound," AIDS TREATMENT NEWS #159, September 18, 1992.]

* Cooperativity of a HIV-1 Protease Inhibitor (SKF 108922) with AZT in acute and chronic HIV-1 infections in vitro. D. M. Lambert and others. SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania. Abstract 8.

* Synthesis and antiviral properties of Carbocyclic 3'-Oxa- 2',3'-dideoxyguanosine. S. W. Schneller and others. University of South Florida, Tampa; and Rega Institute for Medical Research, Belgium. Abstract 20.

* Synthesis and structure-activity relationships in a novel class of polyamines that inhibit HIV-1 and HIV-2 replication. G. Bridger and others. Johnson Matthey Technology Center, Reading, Great Britain; Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania; and Rega Institute for Medical Research, Leuven, Belgium. Abstract 21.

* Synthesis and in vitro anti-HIV activity of 2',3'-dideoxy- 2',3'-methanonucleosides and of 3'-deoxy-2',3'- (difluoromethano)thymidine. H. Maag and others. Syntex Research, Palo Alto, California. Abstract 22. * N-3 derivatives of azido- or fluoro-dideoxythymidine: synthesis and biological activities. D. Grierson and others. CNRS, Gif-sur-Yvette, France; Institut Curie, Paris; Rhone- Poulenc-Rorer Central Research, Vitry, France; Hopital Saint- Louis, Paris. Abstract 23.

* Synthesis, anti-HIV activity and cytotoxicity of derivatives of 5-hydroxymethyldeoxyuridine. S. V. P. Kumar and others. University of Saskatchewan, Saskatoon, Canada; supported by MRC Canada. Abstract 24.

* Antiviral activity of 9-{2-(phosphonomethoxy)- ethoxy}purines against HIV, FIV and visna virus. R. M. Perkins and others. SmithKline Beecham Pharmaceuticals, Gt. Burgh, UK, and Diagen GmbH, Dusseldorf, Germany. Abstract 29.

* Differential inhibitory effects of the (S)- and (R)- Enantiomers of 9-(3-fluoro-2-phosphonylmethoxypropyl)purine derivatives on retrovirus replication in vitro and in vivo. J Balzarini and others. Katholieke Universiteit Leuven, Belgium; and Czechoslovak Academy of Sciences, Prague. Abstract 31.

* Selenoorganic compounds useful as anti-HIV inhibitors. M Lemaitre and others, Rhone-Poulenc Rorer Central Research, Vitry, France. Abstract 32.

* New potential anti-HIV prodrugs in the d4T series. M. Lematre and others, Rhone-Poulenc Rorer, Vitry, France, and Institut Pasteur de Lille, Lille, France. Abstract 33.

* Combination studies with antiviral compounds to prevent reactivation of latent HIV-1 in OM-10.1 cells. P. M. Feorina and others. Emory University, Atlanta; Veterans Affairs Medical Center, Decatur; and Centers for Disease Control, Atlanta. Abstract 35.

* Synthesis and anti-HIV activity of 2-substituted, 6- Benzyl- Pyrimidine Derivatives. P. La Colla and others, Universita di Cagliari, Italy; and Universita di Roma, Italy. Abstract 36.

* Anti-HIV-1 activity of rev and gag phosphorothioate oligo- Deoxynucleotides in chronically and acutely infected cells. P. La Colla and others. Universita di Cagliari, Italy; and Universita di Napoli, Italy. Abstract 37.

* Broad-spectrum antiviral activity of polyoxometalates against human immunodeficiency virus and other enveloped viruses. N. Yamamoto and others. Rega Institute for Medical Researach, Leuven, Belgium; Johnson Matthey Technology Centre, Reading, Great Britain; and Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania. Abstract 42.

* Novel polyanionic albumin derivatives are potent and selective in vitro inhibitors of HIV, FIV, and SIV cell fusion and giant cell formtion. R. W. Jansen and others. University Center for Pharmacy, Groningen, Netherlands; and University of Leuven, Belgium. Abstract 43.

* Metabolism of carbovir in CEM cells. W. B. Parker and others. Southern Research Institute, Birmingham, Alabama. Abstract 47.

* Cell membranes, cell fusion and phospholipids: new targets and novel inhibitors of HIV-1. D. Kinchington and others. Medical College of St. Bartholomew's Hospital, London; University of Southampton, Southampton, UK. Abstract 49.

* Anti-human immunodeficiency virus activity of a novel synthetic peptide, T22 ( [tyr5,12,Lys7]polyphemusin II ) -- a possible inhibitor for virus-cell fusion. H. Nakashima and others. Tokyo Medical and Dental University School of Medicine, Tokyo; Kyoto University, Kyoto; Seikagaku Corporation, Tokyo. Abstract 53.

* Quinobene, a new synthetic sulfonated dye with potent anti- HIV activity. D. J. Clanton and others. National Cancer Institute, Bethesda, Maryland. Abstract 57.

* Non-nucleoside inhibitors of an early stage of HIV reproduction [oxathiin carboxanilide, diaryl sulfone, and thiazolobenzimidazole]. J. P. Bader. National Cancer Institute, Bethesda, Maryland. Abstract 58.

* Retroviral vectors expressing antisense and ribozyme RNA directed against HIV-1 tat can inhibit HIV-1 replication. K. M. S. Lo and others. Dana Farber Cancer Institute, Boston. Abstract 61.

* Antiviral efficacy of 9-(2-phosphonylmethoxyethyl)-2,6- diaminopurine (PMEDAP) upon oral administration to moloney murine sarcoma virus (MSV)-infected mice. L. Naesens and others, Rega Institute for Medical Rsearch, Leuven, Belgium. Abstract 63.

* Anti-HIV activity of 5-hydroxymethyldeoxyuridine in vitro and in vivo. V. S. Gupta and others. University of Saskatchewan, Saskatoon, Canada; CIBA-GEIGY Ltd, Basle, Switzeland; Rega Institute, Leuven, Belgium. Supported by MRC Canada. Abstract 64.

* Didox and an analog are effective against retrovirus in a murine model (FeLV). D. L. Mills and othrs. Virginia Commonwealth University, Richmond, Virginia; Molecules for Health, Richmond, Virginia. Abstract 65.

* Reversal of established FeLV-FAIDS infection after adoptive transfer of activated lymphocytes in combination with AZT and alpha interferon. NS Zeidner and others. Colorado State University, Fort Collins, Colorado. Abstract 82.

* Experimental therapy of immunodeficiency-inducing feline retroviruses with phosphonylmethoxyethyl adenine (PMEA) E. A. Hoover and others. Colorado State University, Fort Collins, Colorado. Abstract 165.

* * *

Probably none of the potential new drugs listed above is ready for use today as an AIDS treatment. But a number of them should be candidates for emergency research and development. Instead, they are largely ignored.

Very few of the AIDS clinical trials running today could possibly produce a major treatment advance. Researchers will sometimes admit that they are testing unlikely drugs or theories, saying that they have no better ones to try. Often they will say that the AIDS virus is very difficult to control, or imply that better treatments must wait for a better understanding of the disease process of AIDS (which may take years).

The list above shows that many important leads are available. But they are almost always overlooked unless some pharmaceutical company makes the big decision to prepare for human testing. Individual researchers cannot carry out or sponsor the animal and other work required to get these drugs ready for the first human test.

It is the responsibility of the Federal AIDS program to develop a coordinated response to this bottleneck, which no one person or company can overcome on their own.

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