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Twilight of NIH Drug Discovery Program Will Mean Even Slimmer Pickings for AIDS Therapeutic Pipeline

Farewell, ‘Fishing Expeditions’

In our national HIV/AIDS effort we must insure that all stages in the development of therapies are supported. These stages include basic science on HIV and HIV pathogenesis, drug development and clinical trials of potentially efficacious compounds. While the latter stage of drug development, clinical trials, receives considerable public attention, the earlier stages are often neglected completely. As treatment activists, TAG is committed to supporting a well rounded national effort to treat HIV infection.

The TAG sub-committee on Basic Science attempts to keep abreast of the needs of basic scientists and monitor issues related to public policy on funding and directions basic research on HIV infection. It has become apparent to both TAG and the research community at large that a gap in the development of potentially effective treatments for AIDS has developed.

While an elaborate mechanism to test the efficacy of potential AIDS therapies exists, the variety of different treatment compounds in testing is dangerously limited. When the present batch of protease and reverse transcriptase inhibitors completes clinical trials, the drug horizon is bleak. And if the early findings on these drugs are indicative of the final outcome, these drugs will not significantly alter the course of HIV infection.

Since the virus appears capable of escaping the effects of reverse transcriptase and protease inhibitors, drugs acting via different mechanisms are essential. But very few such drugs are in the later stages of clinical development, and this represents a serious situation for HIV-positive individuals. While clinical trials can be designed to test endless combinations of the mediocre durgs we have now, hope for a lasting significant treatment for HIV infection likely lies elsewhere.

The current dearth of therapies for HIV infection can be attributed to two factors: 1) Large investments in clinical testing of anti-HIV agents with little promise at the expense of basic research on the disease, and; 2) Lack of incentives to entice basic researchers to apply their work toward the development of new therapies for HIV infection.

The first problem was detailed in a recent commentary in the journal Nature by an eminent virologist, Dr. Bernard Fields. He expressed an opinion shared by many HIV/AIDS researchers in calling for a shift in the national effort on HIV back to more basic research, general viral pathogenesis and immune function. The past 10 years have seen the beginning of a new era in antiviral drug development. For the first time a very detailed picture of the life cycle of a virus (HIV) has emerged, and this information has been used in the “rational” design of anti-HIV medicines. By the application of recently developed molecular and cell biologic techniques and ideas, remarkable headway has been made in understanding the life-cycle of HIV. While our present scientific understanding of HIV has not been reflected in the development of HIV therapies, this scientific information is likely the only way a viable treatment will be realized.

The second problem entails the difficulties in getting these scientific observations made during “basic scientific investigations” translated into clinically testable agents. The first decade of scientific investigation into HIV produced among others, the reverse transcriptase and protease inhibitors. Unfortunately, we soon discovered that the virus undergoes rapid mutagenesis and essentially side-steps these compounds.

Undaunted, science forges ahead in its attempts to overcome these barriers and develop longer-lasting treatments. Modern scientific studies are daily opening new realms of understanding about HIV, within which lie renewed chances for therapeutic intervention. Unless the National Institutes of Health (NIH), however, which funds 80% of the our AIDS research, provides strong incentives to basic scientists, these opportunities often are missed. Herein lies the second roadblock to new AIDS therapies.

The mainstream NIH scientific funding mechanism (researcher initiated grants, i.e. RO1 and PO1) is not designed to support drug development. The NIH utilizes a very strict and conservative peer review process to determine which grants will receive funding. Grants are selected on the basis of scientific interest and sound experimental design. Proper experimental design requires that experiments produce, by and large positive results.

Unfortunately drug discovery, by nature, is a riskier endeavor. Drug discovery studies, often termed “fishing expeditions,” test hypotheses or ideas that, while scientifically sound, may and often do not yield useful drugs, and therefore are more prone to produce “negative results.” When these highly applied scientific studies compete with more basic research for the limited number of basic research grants, they tend to fare poorly.

Recognizing this limitation, in 1989 the NIH created the National Cooperative Drug Discovery Groups for HIV infection (NCDDG-HIV). The NCDDG-HIV program used “set-aside” funds to support only drug discovery research based on novel sound scientific ideas that showed some promise as therapy. This program also stimulated collaboration between drug companies and basic scientists. By requiring drug company collaboration, the program introduced the scientists to the constraints and problems of the “real world” development of human drugs.

It appears that, to a large extent, the NCDDG-HIV program was fulfilling its role in facilitating drug discovery. The program funded several highly successful groups, and in 1992 an ad hoc advisory committee commissioned by the NIH to evaluate the NCDDG-HIV program concluded that while fine tuning was necessary, the program should wholeheartedly be supported: “The panel unanimously agreed that both programs [NCDDG-HIV and NCDDG-HIV opportunistic infections] should be continued.” They felt that “investigator initiated, collaborative, consortium type research directed at drug discovery which truly synergized the efforts of diverse multi-institutional groups should be fostered.”

Coincidentally, the National Task Force on AIDS Drug Development, commissioned by the President, recently concluded that the NIH should make bridging the gap between basic and clinical drug development a top priority. Why has NIAID decided to discontinue the NCDDGs, a program set up to do just that? The NIAID has announced that present and potential NCDDG-HIV grantees should apply through the standard funding scheme to fund drug discovery studies. This defeats the purpose of setting up the NCDDG programs and represents an end to this highly successful initiative. Given the bleak outlook for promising new directions in AIDS therapy, this move seems particularly short-sighted.

In conclusion, TAG strongly supports the OAR’s effort to expand the basic science funding pool and encourages increased support for this aspect of the battle against AIDS. We also call on NIAID to fully support the NCDDG program per the recommendations of its own advisory committee and maintain set-aside funding for this essential component of the nation’s effort to develop therapies for AIDS.

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