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EXECUTIVE SUMMARY
The Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) was formed in 1955 to establish a public investment in the discovery and development of drugs for the treatment of cancer. At that time there was an urgent need to establish a focused national program for antineoplastic agents. In the ensuing years, the DTP has played a major role in discovery and development of chemotherapeutic agents for use in clinical settings.
In response to a pressing need to find new drugs to treat the growing number of AIDS patients, in 1986 NCI initiated within DTP a discovery program for AIDS therapeutics. The foundations for a large-scale, anti-HIV screening effort were already in place, based on progress made in the development of microculture assays for DTP's large-scale, in vitro, anti-cancer screening effort. The central focus of the program was a mechanistically non-selective, anti-HIV, cell-based screen, designed to discover synthetic compounds and natural products that inhibited the replication of HIV. In addition, DTP had in place the necessary capabilities for the development of selected anti-HIV compounds as a result of its cancer program. Such competencies include purification and identification capabilities, and the ability to conduct mechanism of action and pre-clinical toxicology and pharmacology studies sufficient to support an Investigational New Drug (IND) filing.
Earlier reviews of NCI's AIDS and cancer drug development efforts resulted in a series of recommendations for improving DTP's efforts. The Levine Committee (1996) concluded that the productivity of the program over the years 1988 to 1996 had been limited, and the overall program needed to be reorganized with a new focus.
In 1998 , the Horwitz Committee recommended four activities related to cancer drug screening in which the DTP role is appropriate and relevant: 1) a focused screening program for active compounds using assays for which it has developed expertise and capacity; 2) providing public access to its repository of compounds, research tools, and information databases; 3) working with the government, academic, and industrial communities to develop, evaluate, and deploy new assays in both the internal and external scientific communities; and 4) fostering a more collaborative approach to screening by serving as a matchmaker between chemists and biologists for the analysis of novel agents.
In 1998, NCI formed the DTP AIDS Review Group and charged it with the tasks of 1) reviewing changes in DTP that resulted from the Levine Committee's recommendations, and 2) defining the future role of NCI in the discovery and development of therapeutic agents for HIV/AIDS, opportunistic infections, and AIDS-related malignancies. The Review Group worked over the course of several months to develop a series of recommendations that would enhance the ability to discover new and useful therapeutics for AIDS. In developing these recommendations the Review Group heard presentations from representatives of large and small pharmaceutical and biotechnology companies, scientists and administrators from NCI and the National Institute of Allergy and Infectious Diseases, and extramural scientists.
The Review Group learned that discovery and development of anti-HIV agents against the well characterized targets is actively being pursued by industry and academia. Large pharmaceutical companies cannot, however, accommodate all the potential candidate drugs that academics and small biotechnology companies may have for testing and preclinical development. These groups could therefore benefit from having available to them the screening and preclinical developmental capabilities of DTP.
In addition, the Review Group concluded that a mechanism similar to the Rapid Access to Intervention Development (RAID) mechanism for cancer should be established by DTP for AIDS. Such a mechanism, which supports rapid movement of novel molecules and concepts from laboratory to clinic for proof-of-principle trials, could support the development of select compounds from academics and small biotechnology companies. In essence, the committee determined that there is an important role for DTP in the development of AIDS therapeutics.
As much as possible, duplication of efforts with private industry should be avoided. In this regard, the Review Group heard from pharmaceutical representatives of the Inter-Company Collaboration for AIDS Drug Development (ICC). This organization, begun 5 years ago, is a joint effort of 15 large and small pharmaceutical companies that shares drug development information related to AIDS. The companies meet regularly to increase awareness of available resources and activities and provide a forum for rapid exchange of information. The Review Group thought it important that DTP be a part of the ICC, as a means of sharing resources and learning about AIDS research and development activities in the private sector.
Finally, in order to integrate the activities of DTP in HIV/AIDS, and AIDS malignancy related research with the central mission of DTP in cancer therapeutics, the Review Group thought DTP would benefit greatly from a single Scientific Advisory Board that would meet on a regular basis to provide oversight and advice on cancer and AIDS activities. This group of experts would consist of scientists from academia and industry as well as the intramural program. In addition to providing advice on the selection and prioritization of screening strategies, targets and compound libraries, it would provide advice on interactions with other NIH Institutes and extramural entities and on areas academia and industry may neglect that, or where duplication may exist. Such an advisory group with suitable expertise in drug discovery and a working knowledge of DTP is needed to advise the NCI Director about the appropriate work scope and budget for DTP as well as the specific issues addressed in this report.
Many of the recommendations in the report are consistent with those of the Levine and Horwitz Committees. In particular, the Review Group agreed with the Horwitz Committee recommendation that many discovery and developmental activities could be performed in collaboration with or by supporting extramural scientists nationwide where relevant expertise may exist. Basic research into the discovery of drug targets for HIV/AIDS, opportunistic infections, and AIDS-related malignancies should continue to be supported by grants and intramural researchers. Detailed recommendations appear in the full report; the major recommendations are as follows.
Recommendations:
- NCI should establish a single Scientific Advisory Board consisting of both extramural scientists from academia and industry and leaders in the intramural program to review and provide oversight of DTP activities on a quarterly basis.
- The focus of AIDS drug discovery within the DTP should be in the development of non-cell-based, high-throughput, new target-based assays, grounded in research performed within NCI and in collaboration with academia with emphasis on targets that are not being actively pursued by industry.
- Cell-based assays should be used primarily as secondary assays to confirm hits or leads from molecular and biochemical assays.
- Use of synthetic compound libraries and purified discrete natural product libraries for primary screening in cell-based assays should be continued on a limited basis.
- NCI should continue to maintain, replenish and expand its existing repository of natural product extracts for drug discovery.
NCI should acquire and build combinatorial small molecule chemical libraries for intramural and extramural use in mechanism- and cell-based-screening for AIDS therapeutics.
- NCI should seek advice in the form of an external advisory group of experts to address issues of chemical diversity, new target-based assays, development of methods for the selection and prioritization of compounds for screening, and supervision of the natural products library and libraries constructed using combinatorial chemistry approaches.
- NCI should implement state-of-the-art methods for data management of its libraries of compounds and of results derived from use of these libraries in various screens. Methods to improve access by the extramural community to DTP resources should be implemented.
- DTP should have the medicinal chemistry capability required to optimize leads generated by screening or structure-based design strategies against novel HIV or opportunistic infections targets.
- DTP should play a translational role in identifying industrial partners to optimize and move forward lead structures identified in its screens.
- The lead optimization and pre-clinical activities supported by DTP should be available to both intramural and extramural researchers and should be utilized and prioritized based on the quality of the science and overall probability of success in generating a relevant therapeutic agent.
- An NCI Office of HIV-AIDS Research should be established as an efficient mechanism for coordination of all NCI activities related to HIV-AIDS.
- DTP should become a part of the Inter-Company Collaboration for AIDS Drug Development (ICC) to share drug development information related to HIV/AIDS and to avoid duplication of efforts.
- Given the extensive recommendations presented in this report, it would be appropriate for NCI to allocate resources to a level compatible with meeting the currently perceived needs for development of therapeutic agents for the treatment of AIDS.
I. INTRODUCTION
The Developmental Therapeutics Program AIDS Review Group (hereafter referred to as the DTP AIDS Review Group) was formed in 1998 to examine the National Cancer Institute's (NCI) research in HIV/AIDS drug discovery and development and to assist NCI in considering the future direction of efforts in this area and the related fields of opportunistic infections and AIDS malignancies. The DTP AIDS Review Group examined the scope and relevance of the Institute's DTP HIV/AIDS programs and developed specific recommendations regarding NCI's administrative and organizational structure, and the appropriate focus and direction of its research programs. This review is one of a series of critical examinations of NCI's major programs by outside experts. It follows on reviews conducted by prior NIH and NCI committees, the conclusions and recommendations of which were considered carefully by the DTP AIDS Review Group.
- Background
The history of DTP's involvement in AIDS drug discovery and development began in 1986 with a series of discussions within the NCI Division of Cancer Treatment. It was apparent at that time that there was an urgent need for new drugs to treat the growing number of AIDS patients and that no concerted effort was underway elsewhere to address this need. Investigators within the Division, notably Dr. Samuel Broder's group, had already taken a lead role in this area with their work on the drug AZT.
Progress in development of microculture assays for DTP's large-scale in vitro anticancer drug screening project at the NCI-Fredrick Cancer Research and Development Center provided a foundation for development of a complementary large-scale screen for anti-HIV drugs. Subsequent discussions between staff of NCI and the National Institute of Allergy and Infectious Diseases (NIAID) led to an agreement that NCI would take the lead in new drug discovery and development efforts and that NIAID would pursue establishment of clinical testing capabilities. In February of 1987 the Division of Cancer Treatment Board of Scientific Counselors gave concept approval to initiation of an antiviral drug discovery and development program within DTP. Anti-HIV drug screening began in the late summer of 1988 and within the first few months, carbovir (the active form of Ziagen) and 3TC were defined as active in the in vitro screen, and that information was returned to the originating suppliers. The U.S. Food and Drug Administration (FDA) has approved these drugs for use in treatment of patients with AIDS.
Until a few years ago, DTP focused on drug development for both cancer and AIDS, attributing approximately 52 percent of its budget to AIDS-related projects. The central focus of the program was a mechanistically nonselective, anti-HIV, cell-based screen designed to assess the potential of synthetic compounds or natural products to inhibit the replication and spread of HIV in a human T-lymphoid cell line. Compounds and natural products tested in the assay were actively acquired from a variety of sources, including industry. Data from the assay were reviewed by an oversight committee, the NCI Decision Network. This committee selected test substances for possible further evaluation. This evaluation included purification and identification in the case of natural products, as well as studies to determine biological and molecular mechanism of action for all substances exhibiting sufficient antiviral activity. The program had capabilities to move interesting compounds or their derivatives through formal toxicology and pharmacology studies sufficient to support an investigational new drug (IND) filing. A compound of sufficient interest would eventually lead to phase I clinical studies.
In 1996 the National Institutes of Health (NIH) Research Program Evaluation Working Group of the Office of AIDS Research Advisory Council, also known as the "Levine Committee" after its chair Arnold Levine of Princeton University, issued a series of recommendations regarding AIDS research activities across NIH. The Levine Committee was charged with reviewing and making recommendations regarding the $1.4 billion, NIH AIDS- related programs, including treatment, education, and clinical and basic research. A Drug Discovery Review Panel was formed as a subcommittee of the Levine Committee and charged with: 1) assessing NIH's drug discovery and preclinical drug development portfolio; 2) developing goals and priorities for the next phase of AIDS research in these areas; and 3) making recommendations to ensure that these goals and priorities will be met. One of the programs evaluated by the panel was NCI's HIV/AIDS drug discovery program.
- Recommendations of the Levine Committee
Because of the relevancy of these three-year-old recommendations today, a summary of the Levine Committee's evaluation of the NCI program and their subsequent recommendations bear repeating. The Committee was impressed with the logistical scope of NCI's DTP effort and with the highly interactive process by which anti-HIV compounds are evaluated. However, the heavy dependence of the NCI drug discovery program on the nonselective, cell-based, antiviral screen was considered problematic. Since the screen is not aimed at specific molecular targets, wrote the Committee, the entire system is driven solely by agents that yield positive activity in this assay, irrespective of the specific target that is inhibited. Many compounds that have the same target as agents already well studied in the clinic have been identified and pursued to varying degrees.
The Levine Committee also concluded that of the many thousands of defined compounds and natural products that have been screened by DTP, the few that have advanced to further study represent a restricted number of antiviral mechanisms. Most of the compounds that were initially identified by the screen are nonnucleoside RT inhibitors, and one is a putative inhibitor of the viral nucleocapsid protein. Several compounds were introduced into the DTP development process at later stages following their initial identification as antiviral agents elsewhere. Much of the basic research that has gone into elucidating the mode of action of these compounds has been of good quality, concluded the Committee, as has been the research required to establish the mechanism-based assays needed for these studies. Yet, they resolved, undertakings have not been used in a way that enhances the ability of the program to discover and study truly novel inhibitors of HIV. As a result, the Levine Committee deduced that the productivity of the program over the years 1988 to 1996 had been limited, and the overall program needed to be improved and a clear focus determined.
Finally, the Levine Committee concluded that the development of new treatment modalities for AIDS-associated malignancies appeared to have received relatively scant attention from DTP efforts, and made the following recommendations:
- DTP should no longer focus primarily on the nonselective antiviral screen.
- The DTP management structure should be reviewed, given its apparent inability to enhance the productivity of the AIDS drug discovery effort.
- DTP should use its core resources to support NIH-wide antiretroviral discovery efforts by providing compounds and natural products for various screening endeavors as well as medicinal chemistry, pharmacologic, and toxicologic support as needed. Ongoing review of the DTP AIDS drug discovery program should include assessment of its ability to support the overall NIH drug discovery effort.
- DTP resources also should be used to support the efforts of other Institutes and Centers (ICs) to develop treatments for opportunistic infections (OIs).
- An external scientific advisory board should be constituted to provide guidance regarding appropriate DTP support for NIH drug discovery programs. It is not cost-effective to reproduce the considerable DTP infrastructure in other ICs.
- The operational logistics of DTP require review and should be restructured. Given these recommendations, a substantial decrease in the size and funding of the DTP's current HIV/AIDS drug discovery effort may be appropriate.
- Research on developmental therapeutics for AIDS-associated malignancies should be pursued.
Given the new AIDS research directions NCI was asked to take, and the ongoing AIDS research efforts of other Institutes within NIH, NCI met with representatives from the NIH Office of AIDS Research and NIAID. Based on these discussions, it was decided that a small review group of outside advisors with diverse backgrounds should be convened to meet with NCI and other NIH staff to: 1) provide a comprehensive review of the response to the Levine Committee report; 2) review the existing programs in HIV/AIDS drug discovery and development; and 3) make recommendations to NCI in the specific areas of opportunistic infections with its obvious implications for AIDS and cancer, and for AIDS-related malignancies.
Since 1996 NCI has enacted a rapid down-scaling of the in vitro, cell-based screen of natural products and synthetic compounds, with the plan to terminate all primary HIV drug in vitro, cell-based screening, except for a low level of activity to accommodate academic research needs. The proportion of AIDS-related expenditures in the total DTP budget has dropped dramatically since FY 1996-from 49 percent ($20 million of $41 million) to 6 percent in FY 1999 ($2 million out of $36 million)-and is expected to decline even further to 4 percent by FY 2000.
- Recommendations of the Horwitz Committee
In 1997, the Director of NCI formed the DTP Review Group, and charged it with the task of defining the future of NCI with respect to the discovery and development of new chemical and biological therapies for the treatment of cancer.
Over the course of a year, this group, called the Horwitz Committee after its chair Susan Horwitz of Albert Einstein College of Medicine, worked to develop a series of recommendations to enhance NCI's ability to discover new and useful antitumor drugs during the next decade. The focus of the recommendations is to foster the discovery of drugs which are not simply antiproliferative agents, but rather have unique and novel mechanisms of action. Among its many recommendations, the following are of relevance to the DTP AIDS Review Group.
The Horwitz Committee was enthusiastic about adopting a plan that would enhance dramatically the ability of DTP to make decisions concerning its resource allocations through the development of a mechanism, such as oversight group, to continuously monitor DTP activities. A major goal of this plan would be to create a discovery and development process for any drug target or drug candidate by bringing together and coordinating distinct proposals from different laboratories or institutions nationwide.
In addition, the Horwitz Committee concluded that the NCI Decision Network Committee, responsible for prioritizing drugs for clinical development, was not functioning properly. They recommended that the membership of this committee be expanded to include representatives of academia, including cancer centers, and industry, as well as NCI staff.
The Horwitz Committee recommended four activities related to drug screening in which the DTP role is appropriate and relevant: 1) a focused screening program for active compounds using assays for which it has developed expertise and capacity; 2) providing public access to its repository of compounds, research tools, and information databases; 3) working with the government, academic, and industrial communities to develop, evaluate, and deploy new assays in both the internal and external scientific communities; and 4) fostering a more collaborative approach to screening by serving as a matchmaker between chemists and biologists for the analysis of novel agents.
Because the Horwitz Committee reported to the NCI Director in late 1998 it is not clear to what extent its recommendations will be implemented. The DTP AIDS Review Group, although charged with reviewing the HIV/AIDS aspects of DTP, as compared to the Horwitz Committee review of the cancer aspects of its program, found itself in much of the same territory as the Horwitz Committee and benefited from its prior review.
- Focus of this Review
In its charge, the DTP AIDS Review Group was asked to consider and provide advice on the following series of questions for drug discovery efforts relevant to AIDS malignancies, opportunistic infections (OIs), and anti-HIV:
- Given the rapid advances in the fields of biology and chemistry and the growth of a large and active biotechnology and pharmaceutical industry, what are the gaps that currently exist on a national level in drug discovery efforts in AIDS?
- In what way should NCI move to fill these gaps? Specifically, should NCI/NIH be involved in the discovery of new targets and screening of anti-HIV agents?
- What are the state-of-the-art screens?
- What should be the nature and extent of this involvement (e.g., scientific expertise,
The full DTP AIDS Review Group met five times in 1998 and 1999 to discuss these and other issues (see Appendix). The Review Group devoted one full day to receiving information and input from biotechnology and pharmaceutical company representatives about private sector interests in this area of research. In addition, the Review Group met for two days and heard presentations from NCI and NIAID scientists and administrators about relevant research portfolios currently supported with NIH funds.
This report is organized around the three areas of research considered by the Review Group, HIV/AIDS, AIDS-related malignancies, and opportunistic infections. In addition, a separate section focuses on organizational issues that must be addressed if NCI is to continue its support of high-quality research in these areas. In general, the Review Group discussed whether NCI should continue to be involved in AIDS drug discovery and development, and if so, to what extent and how. More specifically, the Review Group considered how NCI might appropriately interact with industry in such efforts, as well as components of NIH.
II. ANTI-HIV RESEARCH AT THE NATIONAL CANCER INSTITUTE
The primary aim of DTP has been to acquire, discover, and develop novel strategies, including small molecules and biologic constructs, for the treatment of cancer. Approximately ten years ago, at a time during which new cases of HIV infection and AIDS were rising rapidly, NCI appropriately expanded the mission of DTP to include drug development directed against HIV/AIDS. This included strategies to combat HIV, opportunistic infections, and AIDS-related malignancies, but in fact most AIDS-related work was devoted to identifying inhibitors of virus replication.
Until 1995, the program relied heavily on a colorimetric assay using human host cells and live virus, technology which grew out of the cancer drug discovery effort. Over 80,000 compounds have been screened to date with 1,500 demonstrating antiviral activity. The Division of Cancer Treatment Decision Network Committee formally approved a total of 25 compounds for preclinical development and 6 were advanced to clinical development. These discoveries have emerged from both intramural and extramural activities. DTP maintains its own basic research program along with screening of the natural product repository within the program, and it fosters collaborations with both academia and the industrial sectors. The 6 compounds advanced to clinical development include racemic 3TC, carbovir, a guanosine analogue that is chemically related to abacavir, and calanolide, a non-nucleoside reverse transcriptase inhibitor.
An example of DTP's interaction with academia is the development of carbovir. Dr. Robert Vince of the University of Minnesota synthesized numerous carbocyclic nucleoside analogs, which were submitted to DTP for antiviral testing. A guanosine analog, carbocyclic dideoxyguanosine, showed anti-HIV activity and was the first compound identified by the DTP anti-HIV drug screen. Although the lead compound carbovir was selected by NCI for formal pre-clinical development in 1988, the University of Minnesota licensed carbovir and its synthetic pathway to Glaxo for subsequent development. Carbovir proved toxic in animal studies, however a close structural analog, abacavir, emerged from this development effort. Abacavir, has proven to be an extremely potent orally bioavailable nucleoside reverse transcriptase inhibitor (NRTI) and has been recently approved by the FDA to treat HIV infection.
DTP has also established productive interactions with industry. The collaboration with the Agricultural Division of Uniroyal Chemical Company is most illustrative. In 1988 Uniroyal submitted NSC 615985 to DTP for screening. This compound was the first non-nucleoside reverse transcriptase inhibitor (NNRTI) identified. Problems with metabolic inactivation were overcome in a collaborative effort between the medicinal chemists at Uniroyal and DTP. However, as the rapid development of resistance to NNRTIs was demonstrated in vitro and in clinical trials of non-related compounds (nevirapine, delavirdine), the NNRTI development effort was redirected to the characterization of NNRTI-resistant viruses and screening compounds for activity against these resistant isolates. From this effort, a collaboration with Uniroyal and the Rega Institute in Belgium, an orally bioavailable compound UC781 was selected from more than 1,500 analogs synthesized by Uniroyal for subsequent clinical development. Uniroyal subsequently licensed the rights to UC781 and related compounds.
The discovery and development of cyanovirin-N (CV-N) is the result of DTP's natural product research effort. CV-N is a highly potent anti-HIV protein isolated from extracts of a cyanobacterium. The compound shows broad antiviral activity in vitro and aborts cell-cell fusion and spread of HIV infection in vitro. The mechanism of action of this agent has not been completely elucidated but does appear to inhibit virus-cell fusion and entry by high affinity interactions with a highly conserved binding site(s) on the viral glycoprotein envelope gp120. CV-N is an extremely heat-stable 101 amino acid polypeptide without homology to known proteins. It is presently undergoing pre-clinical development jointly by NCI and NIAID. It must be emphasized that CV-N might not have been identified as a potent antiviral in screening assays based on molecular targeting of virus or cellular constituents as opposed to cell-based assays were it not for DTP's efforts.
The Science Applications International Corp. (SAIC) Laboratory of Antiviral Drug Mechanisms, formerly headed by Dr. William Rice, has also conducted basic research in identifying mechanisms of antiviral activity. From this laboratory emerged interesting discoveries, such as inhibitors of zinc fingers, novel non-nucleoside RT inhibitors, and fusion inhibitors. The discovery of the conserved retroviral nucleocapsid (NC) zinc finger domains has established a potentially unique anti-HIV target. NC contains the most highly conserved sequence motif in the Gag structural protein, three cysteine and one histidine residues at a defined spacing. All retroviruses except for the spumavirus genus have one or two zinc fingers in NC, and hence it is unlikely that resistant viruses would readily emerge if drugs could be targeted to this motif. Numerous chemicals have been identified as having zinc finger reactivity, and they act by binding to and oxidizing sulfur atoms within cysteine residues, ejecting the zinc atom. Some of these compounds are relatively selective for the retrovirus-type zinc finger, and one was advanced to clinical trials but proved toxic. However, it remains to be established that any of these compounds can be developed into useful anti-HIV drugs. Nevertheless, judged on this work and similar efforts on other novel agents, the Laboratory of Antiviral Drug Mechanisms has been one of the most innovative and successful units associated with DTP.
The recent advances in HIV therapeutics have resulted in dramatic reductions in HIV-related mortality and morbidity. This is encouraging, however it should not be taken as a permanent trend. HIV infection is chronic and the emerging problems of resistance to combination therapy or inability to continue therapy due to drug toxicities may be accompanied by resurgence in HIV-related mortality and morbidity. Given this scenario, it is important to identify the critical areas of drug development needed to address these future challenges.
It is currently estimated that anywhere from 30 to 50 percent of individuals being treated with combination antiretroviral therapy are failing, due to the emergence of drug-resistant variants. Factors promoting the emergence of drug resistance include poor adherence to complex and toxic regimens, advanced disease, and pretreatment with non-suppressive antiretroviral regimens. In addition, alarming anecdotes of the sexual transmission of multi-drug resistant virus have appeared. Because of the rapid emergence of resistance, new targets should be pursued as a high priority.
To address this urgent need, the NCI has taken a lead in addressing resistance issues by creating a new program in retroviruses, an appropriate and necessary activity for NCI. The goals of the HIV Drug Resistance Program are: 1) to focus basic research in NCI on retroviruses by promoting collaboration and communication from within; 2) to recruit key investigators in existing NCI laboratories and extramurally; 3) to create a strong focus on basic and translational research related to genetic diversity and drug resistance; and 4) to provide a central resource for international investigators both within and outside NCI. In addition, NCI's collaborative efforts in molecular screens, medicinal chemistry, and structural biochemistry are important and appropriate to address the future priorities of HIV/AIDS research, such as identification of novel targets and HIV drug resistance.
- Anti-HIV Drug Discovery Process and Current Focus
In contrast to the discovery and development of anti-neoplastic agents, HIV/AIDS drug discovery has benefited in large part from the more simple task of understanding a 9kB viral genome and a significantly simpler life cycle as compared with the complex cellular and molecular events surrounding neoplastic transformation of human cells. Therefore, molecular screens, as opposed to cell-based assays, have allowed for rapid screening of large libraries of compounds with the identification of numerous lead compounds that have been translated into viable anti-HIV compounds. Furthermore, the identification of the crystal structure of HIV-1 protease has provided the first real example of rational drug design.
Figure 1 depicts the general process of molecular target-based drug discovery for HIV anti-viral agents. The HIV targets, which have shown success to date, include the reverse transcriptase (RT) and the viral protease (PR). In both cases, rational design strategies complemented by structural studies and compound screening, have led to the currently approved arsenal of anti-HIV therapeutics. Assays have been devised for other viral targets (e.g., Rev, gp120) and, at least in some cases, screening leads identified. However, either the insufficiency of the lead, its inability to be optimized, or the relevance of the screening assay to identify true viral inhibitors has stymied the exploitation of these targets to date. Finally, there remain other potential viral targets for which function and relevant assays remain obscure and thus, these have been inaccessible to the drug discovery process.
An alternative to the molecular-target-driven process is the cell-based, anti-viral assay shown in Figure II. In this case, a direct anti-viral assay (used in Figure I only as a secondary confirmatory screen) is configured as the primary screen for identifying leads. This screen is relatively low-throughput and particularly difficult for handling complex mixtures such as natural product extracts. The mixtures that score positive can require significant resources to de-replicate into true leads and high false-positive hit rates are not uncommon. Cell-based, anti-viral assays are best run against pure compound banks and require validated secondary assays in order to delineate leads that are working via a selective anti-viral effect. Of course, the advantage of this strategy is that any leads discovered already demonstrate anti-viral activity and, thus may provide an immediate platform for lead optimization and/or target identification analysis. However, it should be emphasized that the low throughput and inhe
rent difficulties with cell-based, anti-viral screening make this strategy resource intensive and problematic to run as a primary screen, thus necessitating changes in strategy and/or alterations and improvements in the cell-based screen itself.
The two strategies depicted are not mutually exclusive and can, when properly implemented and controlled, identify valid lead structures and/or tool compounds, which can be optimized by additional chemistry to possess the pharmacologic properties necessary to become potential clinical drug candidates. A major criticism of DTP's anti-neoplastics effort is the continued reliance on cell-based assays. This reliance on cell-based assays to identify hits/leads does not lend itself readily to HIV drug discovery given the development of molecular targets, particularly those that screen for inhibitors of protease and reverse transcriptase. Nevertheless, cell-based screens are indeed relevant to discover agents that are active at targets that are either unknown or have not been fitted to a molecular or biochemical screen adapted for rapid through-put.
Despite past efforts and successes of DTP, in general the program has had limited impact on the development of antiviral agents. It is this lack of impact and relative ineffectiveness that led to reductions in the NCI-HIV/AIDS budget and recommendations that the projects relying on the cell-based assay be sharply curtailed. With a budget of only $2 million, however, it becomes difficult to comprehend how DTP can be expected to accomplish any drug discovery mission within the field of HIV/AIDS therapeutics.
Furthermore, the current administrative configuration within DTP is problematic. There exist both intramural and extramural HIV/AIDS activities, which appear fragmented. In addition, there appears to be a lack of interactive collaborations, which seems to exist organizationally within NCI. Programs involving clinical sciences, HIV drug discovery, and basic science do not appear to be complementary. Thus, in addition to severe financial restraints on the relevant DTP research budget, there are organizational challenges to be addressed. (See Section V for further discussion.)
- Chemical Diversity and Repositories
Discovery of new drug leads for AIDS chemotherapy at NCI historically has been driven primarily by access to a large repository of discrete synthetic compounds and natural product extracts acquired, processed, and replenished by DTP. The primary AIDS drug screen has been a cell-cased assay in which synthetic compounds, purified natural products, and crude extracts of biological material are tested for their ability to inhibit the replication of HIV in a human T-lymphoid cell line. This mechanistically non-selective, anti-HIV screen was criticized in the 1996 Levine Committee review of drug discovery at NIH because of its poor overall productivity as judged by the restricted number of antiviral mechanisms through which active compounds were found to exert their influence on virus replication. In response to this review, DTP initiated a reduction in cell-based antiviral screening so that screening of natural product extracts ceased as of January 1, 1997. Currently there is some limited cell-based screening ongoing (~2,500 tests per year) using synthetic compounds.
Presentations heard by the Review Group from scientists in the commercial sector delivered the clear message that with few exceptions, industry is still focused on HIV protease, reverse transcriptase, and integrase as its primary targets. There is an urgent need to identify new targets against which novel classes of anti-HIV drugs can be directed. The DTP pure chemical and natural products repositories, if expanded and used efficiently with improved screening methodology, both targeted and non-mode-of-action, can be important tools for studying the basic biology of virus replication and identifying and validating new targets important in the life cycle of HIV.
While the Review Group concurs with the conclusion of the Levine Committee that improved screening methods are needed to identify lead compounds, it is crucial that the phasing down of the current cell-based screen as a primary assay for natural product extracts not affect the fundamental integrity or compromise the existence of DTP's unique and important natural product repository. DTP has excelled in collecting, cataloging, and processing natural products while safeguarding the intellectual property rights of countries from which the biological samples are obtained. The natural products repository should be maintained and even enhanced with further acquisitions for subsequent use in conjunction with new assays.
Because of their inherent stereochemical complexity, natural products represent a source of chemical diversity not found in current chemical libraries generated by combinatorial synthesis. Moreover, since many natural products are large, relatively rigid molecules, they may represent an especially useful source of drug lead candidates that can affect the HIV viral life cycle by interfering with crucial macromolecular interactions between the HIV genome, HIV proteins, and host cellular proteins. Insights gained from knowledge of how these natural products exert their anti-HIV effect could be used in the design of small molecule combinatorial libraries or other low molecular weight discrete compounds likely to have improved pharmacological properties.
An examination of DTP budgets (real and anticipated) for FY1995 through FY2001 indicate that the projected AIDS-coded spending for all acquisitions of natural products and discrete compounds will decrease from $4.3 million in 1995 to zero in 2000. A portion of this reduction in AIDS-related DTP spending for acquisitions is not actually lost but rather simply recoded as a cancer-related activity. Nevertheless, the total DTP budget (AIDS + cancer) for acquisition is expected to be reduced from $6.5 million in 1995 to $4.2 million in 2000. At a time when the biodiversity of plants, marine organisms, fungi, and other microorganisms is in decline world-wide as a result of environmental degradation, DTP should be increasing its collection and processing efforts (not reducing them) and at the same time expanding into new geographical areas and ecological niches to ensure that this unique source of biological and chemical diversity will be available for screening by extramural and intramural investigators.
In addition to maintaining and enhancing its natural products repository for drug discovery, DTP should continue to acquire and build small molecule chemical libraries for intramural and extramural use in mechanism and cell-based screening for AIDS therapeutics. In the interest of maximizing drug discovery possibilities, construction and acquisition of combinatorial libraries and their use in screening should be carried out based on information that may be available or can be inferred about the structure of the target protein and known antagonists or inhibitors. For example, compounds in existing libraries could be prioritized computationally for high throughput screening based on pharmacaphore matching to known antagonists or inhibitors. Individual compounds in all libraries should be scored computationally for chemical diversity. In the absence of any information about the structure of the target or known effector molecules, a subset of compounds that best captures the diversity resident in each library could be used for initial screening. Hits from this diversity set should then be expanded upon by parallel (focused) combinatorial synthesis in an effort to identify even more potent drug candidates. Where possible this parallel synthesis approach should be guided by co-crystal structures of the diversity set leads with the target macromolecule.
The important point is that there needs to be a much stronger connection between synthesis, computational chemistry, screening, and structure than currently exists at NCI in order to streamline the drug discovery process. It is recognized that achieving this goal is becoming more difficult within the current NCI/DTP organizational structure since a number of former DTP labs that could participate in such a multidisciplinary drug discovery effort are migrating as DTP apparently becomes more service oriented.
Use of the synthetic compound library and purified discrete natural product library for screening in the cell-based, antiviral assay is encouraged. Library compounds should first be prioritized for chemical diversity and these diversity plates used in high-throughput, mechanism-based screens to test for inhibition of HIV protease, reverse transcriptase, and integrase. Diversity compounds showing no inhibition in these mechanism- based assays can then progress to the cell based screen. This approach will reduce the number of hits in the whole cell assay and more importantly, will greatly increase the probability that compounds active in this assay exert their anti-HIV effect through novel mechanisms of action. Such hits should be vigorously pursued by NIH scientists to identify the relevant biological targets. When new targets are identified, appropriate high-throughput, mechanism-based assays should be developed to facilitate additional screening with synthetic compound and natural product libraries.
The anticipated increase in size and complexity of the DTP database of natural products and discrete chemical compounds poses problems for management, organization, and distribution of the libraries as well as for documenting results of their use in various screens. Based on its discussions with industry and academic representatives, it is clear to the Review Group that NCI significantly under advertises its resources. Improved data management and public relations regarding DTP databases, repositories, and screening results, both within NIH and extramurally, are needed to foster more efficient use of DTP resources and to attract the attention of potential collaborators and partners in both the academic and commercial sectors.
Recommendations
- NCI should continue to maintain, replenish, and expand its existing repository of natural product extracts. Moreover, the collection of additional biological material from underrepresented geographical areas and ecological niches is strongly encouraged as a means of further enhancing the repository's biological and chemical diversity.
- NCI should acquire and build combinatorial small-molecule chemical libraries for intramural and extramural use in mechanism and cell based screening for AIDS therapeutics. The libraries must emphasize chemical diversity for lead generation. Lead refinement must be closely coordinated with generation of focused libraries using parallel synthesis methods and drawing, where possible, on structural information about the macromolecular target. Efforts should be coordinated so as not to duplicate work being performed by industry.
- Use of synthetic compound libraries and purified discrete natural product libraries for primary screening in cell-based assays should be continued on a limited basis. Pre- screening of such libraries to eliminate compounds active against HIV protease, RT, and integrase prior to use in the whole cell assay is encouraged in order to focus attention on "hits" that exert their anti-HIV effect through novel mechanisms of action. This service should continue to be made available to investigators within academia.
- NCI should seek expert advice in the form of an advisory group to address issues of chemical diversity, to develop methods for the selection and prioritization of compounds for screening, and to supervise the natural products library and libraries constructed by using combinatorial chemistry approaches.
- NCI should implement state-of-the-art methods for data management of its libraries of cmpounds and of results derived from use of these libraries in various screens. Methods to improve access by the external community to DTP resources and data should be implemented.
- Targeting and Screening
The DTP-HIV/AIDS drug discovery effort was founded out of need for the discovery of effective antiviral agents at a time when there were minimally effective agents available. Much has changed since that time and in 1999 approximately 13 compounds have been approved for the treatment of HIV infection. Nevertheless, due to drug resistance and problems with drug adherence and toxicity, the need for new compounds directed at both resistant and wild-type virus remains. Yet discussion with representatives of major pharmaceutical corporations have made clear that in the near future already established targets, such as protease and reverse transcriptase, will continue to be the main focus of drug discovery and development. Therefore, there exists a need for the DTP-HIV/AIDS program to maintain its function, that is, to develop new tools to facilitate drug discovery.
In contrast to previous efforts by DTP in which the cell-based assays were used as primary screens to identify new anti-HIV compounds, it appears that a more productive approach would be to promote research and development of novel molecular-based assays. Potential targets not being pursued by industry include accessory proteins such as Tat, Rev, or Nef; other constitutive enzymes such as RNase H and integrase; structural proteins, such as Gag, or those with nuclear import functions such as nucleocapsid-p7; envelope proteins (Env); and inhibitors of cell entry and fusion. Of equal importance is the targeting of resistant viruses by the use of molecular assays directed at reverse transcriptase and protease, containing drug resistance-associated amino acid substitutions.
However, the use of cell-based assays should continue on a limited basis. Clearly it serves a critical role as a secondary assay to confirm hits or leads in molecular assays. However, cell-based assays, if streamlined, may serve as primary assays in special circumstances. This is a role that DTP should serve, given its expertise.
Recommendations:
- The focus of drug discovery within the DTP should be in the development of non-cell-based, high-throughput, new target-based assays, grounded in research performed within NCI and in collaboration with academia.
- Emphasis should be placed on targets that are not being actively pursued by industry.
- Cell-based assays should be used primarily as secondary assays to confirm hits or leads from molecular and biochemical assays; cell based assays should be streamlined to take advantage of current technology and advances in HIV molecular biology.
- Optimization and Pre-clinical Development
Continued research into the HIV infection process and associated opportunistic infections, as well as further functional characterization of various HIV gene products and their cellular interfaces, will provide the information needed to exploit new molecular targets for therapeutic interventions. As molecular and cellular reagents and the corresponding relevant assay systems are developed, these novel targets will be utilized in screening formats and rational design strategies for identifying active lead structures which have the potential to evolve into drug candidates. The Review Group recommendations supporting concerted efforts by DTP to develop screening expertise and increase the chemical diversity that can be brought to bear on the lead selection process are designed to help DTP serve in a translational capacity with collaborating intramural and extramural researchers for identifying the "best" possible leads active against novel HIV targets.
It is important to emphasize that screening or structure-based leads rarely possess the appropriate intrinsic properties required to become viable pharmaceutical agents. It remains the norm that substantial medicinal chemistry resources and often years of effort must be applied to an optimization process which ultimately may lead to a clinical drug candidate. Perhaps continued expansion of the available chemical diversity platform and the implementation of ultra high-throughput screening technologies will eventually reduce this resource-intensive lead optimization process, but this is not the case today or in the near future.
Thus, in order to bridge the gap between (1) the early discovery processes of target identification, assay development and lead identification, and (2) the later-stage discovery processes of lead optimization into a viable clinical candidate (see Fig. I), it is essential to have the capability to perform iterative chemistry on the lead and to have all the biological measurement systems in place in order to provide feedback to the synthetic process. Key biological parameters, which must be monitored and utilized during the optimization process, include:
- potency (SAR)
- formulation properties
- metabolism/pK/pD
- bioavailability
- toxicity
Expertise in each of these areas is essential for providing the information required to produce an appropriate clinical candidate structure. Clearly, the optimization process-which achieves this goal-must be well coordinated. The efficient operation of this complex matrix process is at the very heart of drug discovery. It provides the critical bridge between early discovery efforts and achieving sufficient assurance that a drug candidate will meet appropriate criteria to allow clinical testing for safety and efficacy in humans.
Whenever possible these late-stage discovery optimization and pre-clinical efforts should be carried out by an experienced industrial partner. Thus, DTP's translational role should extend well beyond providing screening capability and chemical diversity to research collaborators but must also provide key interfaces with industry so that the lead compounds identified are efficiently moved through the optimization and pre-clinical process.
However, it is too often the case that industry cannot be convinced at the lead generation stage (either in HIV infection or opportunistic infections) to take the initiative. This is apparently also the case for certain cancer therapeutic opportunities. For these reasons, DTP has been empowered to provide some capability to carry out pre-clinical pharmacology, toxicology, and formulation research on potential drug candidates. Moreover, the recent report of the Horwitz Committee supports this strategy and provides a series of recommendations aimed to enhance NCI capabilities in these important pre-clinical areas for cancer therapeutics. The Horwitz Committee recommendations support establishment of Centers of Excellence comprised of core facilities capable of doing , for example, state-of-the-art drug metabolism, pK, drug absorption, toxicology, and formulation. The report also addresses the critical component of a medicinal chemistry resource required to perform the chemical optimization needed to advance a screening or structure-based lead to a clinical candidate.
In addition, it will be important to leverage the preclinical capabilities being supported for cancer drug discovery to also encompass HIV and opportunistic infections drug discovery efforts. If implemented properly, NIH would have a single dedicated resource that could be used by NCI and NIAID to advance chemical leads in cancer, HIV and opportunistic infections drug discovery arising from basic research efforts nationwide. DTP would serve as the critical translational capability for providing chemical diversity, drug screening, optimization chemistry, and the pre-clinical analyses that must be aligned to create a viable clinical candidate. The value and attractiveness provided by this process might for certain candidate molecules allow hand-off to industry prior to implementation of clinical trials. Alternatively, if industry continues to remain uninterested, it would provide the bridge needed to get appropriate drug candidates from early discovery lead identification into clinical investigation.
Recommendations:
- NCI should provide DTP with the medicinal chemistry capability required to optimize leads generated by screening or structure-based design strategies against novel HIV or opportunistic infections targets.
- DTP should play a translational role in identifying industrial partners to optimize and move forward lead structures identified in its screens. Whenever possible, DTP should proactively shift lead optimization and pre-clinical testing to an industrial partner.
- NCI should implement the recommendations made in the Report of the NCI DTP Review Group (in Section V: Pharmacology, Toxicology and Formulation) with the goal of creating a single, rationalized capability for advancing anti-cancer, anti-HIV and anti-opportunistic infections drug candidates into clinical trials. This resource should be restricted to those candidates that cannot be transferred to an industrial partner.
- NCI needs to coordinate its activities with NIAID such that (1) duplication of effort in lead optimization and pre-clinical testing is minimized, and (2) a management structure is established to prioritize and set appropriate criteria for gaining access to this DTP resource for anti-cancer, anti-HIV and anti- opportunistic infections therapeutic candidates.
- An effective DTP management system will be required to run the complex matrix interactions needed to optimize leads through pre-clinical testing so that appropriate clinical candidates emerge.
- NCI should seek input from industry via an advisory mechanism in developing, implementing, reviewing, and managing these later-stage lead optimization and pre-clinical activities.
- A DTP system will be needed to coordinate the different pharmacologic/ biologic testing paradigms required to advance anti-cancer, anti-HIV and anti- opportunistic infections drug candidates, especially as concerns the use of animal models.
- The lead optimization and pre-clinical activities supported by DTP should be available to both intramural and extramural researchers and should be utilized and prioritized based on the quality of the science and overall probability of success in generating a relevant theraapeutic agent.
III. AIDS-RELATED MALIGNANCIES
AIDS malignancies contribute substantially to the morbidity and mortality of patients with HIV infection. In 1994 the discovery of a new gamma herpesvirus, human herpesvirus 8 (HHV8) or Kaposi's sarcoma herpesvirus (KSHV), led to a rapid series of investigations strengthening links of this virus in the pathogenesis of all forms of Kaposi's sarcoma as well as to a rare type of B cell tumor called primary effusion lymphoma, and to multicentric Castleman's disease. Other DNA herpesviruses have also been linked to other malignancies in AIDS, such as EBV with primary central nervous system and systemic lymphomas, and HPV with anogenital dysplasia and cancer.
HIV-1 infection is known to increase the incidence of Kaposis' sarcoma (KS) and non-Hodgkin's lymphoma (NHL). It recently has been shown that KS is associated with Human Herpes Virus-8 (HHV-8) infection. The incidence of KS has fallen dramatically over the past 5 to 7 years, perhaps due to changes in sexual behavior among homosexual men, and likely as a result of improved therapies, which target HIV directly.
The NHL's are of high-grade histology and generally present at extra-nodal sites, with particular predilection for the central nervous system. These tumors are associated with severe immunodeficiency, although they may occur at earlier stages of HIV-mediated immune suppression. The tumors, a result of B-cell monoclonal proliferation, are classified into Burkitts lymphoma (BL), Burkitts-like lymphoma (BLL), and diffuse large-cell lymphoma (DLCL). Therapies for NHL associated with HIV have followed more traditional routes, with anti-neoplastic chemotherapy the mainstay for systemic disease, whereas radiation has been the preferred treatment modality for primary central nervous system lymphoma.
However, it has not been established that HIV-1 infection is related to increased risk of other cancers, including squamous cell carcinoma of the anus and Hodgkin's disease. Thus it appears that the etiologies of the opportunistic malignancies are quite different from other neoplastic processes. NCI should commit resources, both financial and intellectual, to the support of research concerning HIV-related malignancies via the DTP-HIV/AIDS program.
The identification of HHV-8 as the etiologic agent of Kaposi's sarcoma is a clear opportunity for drug discovery. Despite the decreasing incidence of KS, the identification of a new virus creates new targets and new opportunities for basic research. These are being pursued by academic investigators. Given the vastness of the DTP's library of potential anti-HHV-8 compounds, this area is a previously unexplored area for collaboration with academia. It is clear that HHV-8 and specifically HIV-related KS is not a priority established by industry, given the reduced incidence of HIV-associated KS, and descriptions of response to anti-HIV therapy (particularly PR- containing regimens).
Another unexplored issue, which is somewhat compelling, is the role of antineoplastic agents and immune-modulating agents in designing effective antiviral regimens. Hydroxyurea, an inhibitor of ribonucleotide reductase, has been used to potentiate the effects of didexoyinosine (ddI). However, anecdotal reports have suggested that the drug may reduce the pool of latently infected CD4 positive T cells by limiting the number of "activated cells" during periods of active virus replication. This observation as well as the issues surrounding the obstacle of "latency" merit furthers exploration. Such investigation again lends itself to the DTP effort as it is unlikely to be embraced by larger pharmaceutical companies given the emphasis on drug discovery against known targets, RT, and protease.
NCI currently is not involved in the discovery and development of new agents in AIDS malignancies and the involvement of industry appear to be limited. The Levine Committee suggested that NCI take a leadership role in developing therapeutic approaches to AIDS-related malignancies. The DTP-HIV/AIDS program has been more or less exclusively devoted to the identification and development of antiviral agents with inhibitory effects on HIV replication. It has not made AIDS-related malignancy a target for drug discovery. In summary, given the advances made over the past five years in drug development directed at inhibiting HIV-replication, it is clear that new and exciting opportunities exist that fall outside this area. A commitment to novel non-HIV targets such as HHV-8 and cellular targets is likely to have an impact on HIV related malignancy as well as having potential to effect issues surrounding HIV infection and latency.
Recommendation:
- DTP resources should be available to develop assays intramurally or extramurally that can identify potential therapeutics for AIDS-related malignancies.
IV. AIDS-RELATED OPPORTUNISTIC INFECTIONS
AIDS-related opportunistic infections have declined in incidence in a dramatic fashion since 1996. Since the introduction of more effective antiretroviral therapy, most studies have reported at least a 66 percent and, in some cases, an 80-percent reduction in the incidence of new opportunistic infection. Although this is to be welcomed, and indeed emphasizes the critical role of antiretroviral therapy in restoring the immune system, it has had the unintended consequence of decreasing attention to the development of new therapies for opportunistic infection. This decrease is in spite of the fact that immediately prior to the advent of these therapies there was a clear need for new treatments for virtually all of the major opportunists that complicate HIV infection. Resistance to standard therapy was emerging among Candida and other fungi, and in Mycobacterium avium infections. Second line therapy for PCP (i.e. for patients allergic or intolerant of trimethoprim-sulfamethoxazole) was often ineffective. Therapy for cytomegalovirus infection was inadequate with all available options. There was no available therapy for some less common but often lethal infections such as cryptosporidiosis and PML. Despite this unmet medical need, industry-sponsored drug development for these opportunistic pathogens has essentially been halted because of the perception that there will be no market for new drugs. The sole major exception to this is for antifungal therapy because of the need for new treatments for candida infection in other areas of medicine.
It is critical therefore to attempt to predict whether the current reduction in AIDS-related opportunistic infection will be sustained. A number of observations make it unlikely. First, antiretroviral therapy is not durably effective in a substantial number of patients, and although immunological improvement is seen in the majority, it is likely that the immune system will eventually deteriorate again if viral replication is resumed. Second, as survival from HIV increases, the at-risk population will increase and thus more patients will eventually develop opportunistic infections. Third, this population is aging and it is possible that, with age, residual defects in immune function will become more clinically relevant. Thus, it is reasonable to conclude that although the proportions of opportunistic infections seen from 1994-1996 may not be reached again, there will be more patients with opportunistic infection as a consequence of HIV infection.
However, AIDS is not the only setting in which opportunistic infections occur. The risk of these infections has not diminished and, indeed, may be increasing in other settings. Iatrogenic immunosuppression occurs in organ transplants, inflammatory diseases, and, with particular relevance to NCI, with cancer chemotherapy. Therefore, it is imperative that NIH continue to maintain a research agenda in opportunistic infection that includes the capability for drug development, particularly since all available evidence suggests that the private sector will not maintain such an infrastructure. NIAID has a well-developed program for research in opportunistic infections. In particular, through the NCDDG-OI program, NIAID has a focused, funded research effort targeting important opportunistic pathogens, especially mycobacteria, cryptosporidia, and PCP. Important exceptions to the NIAID program include the fungi (which remains a priority for industry) and CMV (which appears to have assumed considerably less importance in the private sector). Areas of strength for the NIAID program are in animal models and in screening using in vitro targets. Areas that are not currently supported by NIAID (or supported to a minimal degree) are formulation, toxicologic and pharmacologic studies of new agents, and re-synthesis. Recent initiatives in opportunistic infections have been jointly sponsored by both NIAID and NCI, a development that is to be encouraged.
Recommendations:
- It is critical that a research infrastructure be maintained within NIH to address the problems of opportunistic infections. NCI's DTP program has clear expertise in, toxicology, pharmacology, and medicinal chemistry. It appears that this expertise directly complements the perceived weaknesses of the current NIAID NCDDG-OI program. Thus it would appear to be in the best interest of NIH that the efforts of NIAID and NCI in the area of drug development for opportunistic infections be coordinated. NCI should not attempt to duplicate the current efforts of NIAID in the area of drug discovery and development; specifically NCI/DTP should not be involved in the discovery of new targets and screening of anti-opportunistic infection agents. However, NCI could play a major role in the subsequent development of novel agents by providing an infrastructure for the synthesis, toxicology, and pharmacology testing of such agents.
- NCI should work with NIAID (and perhaps OAR leadership) to develop a coordinated plan for NIH-sponsored drug development for opportunistic infections.
- NCI should work in conjunction with NIAID and other federal agencies to track the changing epidemiology of HIV infection and assure that if certain pathogens emerge as major problems, priorities for drug development can be changed. At this point, it is difficult to predict which of the opportunistic pathogens will warrant most attention (although currently mycobacteria, cryptosporidium parvum and cytomegalovirus deserve the greatest attention). Decisions with regard to potential drug development may be better made on scientific merit rather than by prioritizing specific pathogens.
V. ORGANIZATIONAL AND ADMINISTRATIVE ISSUES
In many ways, AIDS research programs are anomalous within NCI; they exist because of historical events and funding patterns. The Review Group carefully considered whether it continues to make sense to maintain the programs as they currently exist. The Review Group concluded that because the infrastructure for cancer drug discovery and development exists currently within the NCI DTP, and because of the critical importance of such a presence within NIH, it makes sense to maintain an AIDS program within NCI. However, its continued operation requires some reorganization, less insularity and a better system of external review and oversight. In addition, because HIV/AIDS research does not always mesh well with similar and parallel efforts in cancer research (the predominant paradigm at NCI) special efforts are required to coordinate activities and ensure that program elements are in communication with relevant HIV/AIDS programs across NIH.
- Coordination of HIV/AIDS Research within NCI
NIH continues to have a substantial commitment to intramural and extramural HIV/AIDS related research: there are many other institutes besides NCI and NIAID pursuing basic and translational research in HIV/AIDS drug discovery.
It is highly desirable to establish an efficient mechanism for coordination of all NCI activities related to HIV/AIDS. Therefore, the Review Group recommends the creation of an NCI Office of HIV/AIDS Research. A suggested integrated organizational diagram for this office is shown in the accompanying figure.
The duties of this office would be to coordinate all activities related to HIV/AIDS within NCI and with other NIH Institutes. In addition, it should coordinate intramural NCI activities with extramural entities including both universities and industry. It is expected that certain costs will be incurred with the development of this office. Consolidation of existing administrative activities may lessen these costs. This office should be empowered with the ability to influence and track resource allocations.
- Oversight of NCI's DTP-AIDS Activities
Because knowledge in the field of AIDS is rapidly changing it is imperative that research and discovery activities at NCI and within DTP exploit the latest developments in basic AIDS research. NCI should establish a single Scientific Advisory Board consisting of both extramural scientists from academia and industry and leaders in the intramural program to review activities on a quarterly basis. The Scientific Advisory Board should have the ability to provide advice on designing molecular, mechanism-based screening strategies for novel targets, and for developing more sophisticated methods of screening and evaluating "non-mode-of-action," cell-based antiviral assays. The Board should also provide advice regarding interactions with other NIH Institutes and on areas of research that may be neglected by academia and industry or where duplication may exist.
The Scientific Advisory Board should work closely with NCI and DTP administration. The group should have the capability to form working subgroups (with outside consultation). The Board should have staggered appointments to facilitate continuity.
Additionally, metrics should be developed for measuring scientific accomplishments, for on-going evaluation of the NCI DTP-AIDS program by users, and for evaluating the quality of on-going assistance in decision making regarding priorities and resource commitments to various screening projects.
Recommendations:
- NCI should establish a single Scientific Advisory Board consisting of both extramural scientists from academia and industry and leaders in the intramural program to review and provide oversight of DTP activities on a quarterly basis.
- The NCI DTP Decision Network Committee should be expanded and broadened to include extramural representatives.
APPENDIX: MEETING DATES/ACKNOWLEDGMENTS
Meeting Dates of the DTP AIDS Review Group
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| May 7-8, 1998
July 13, 1998
September 1, 1998
October 2, 1998
January 22, 1999 | Rockville, Maryland
Bethesda, Maryland
Rockville, Maryland
Rockville, Maryland
Rockville, Maryland |
Acknowledgments
The Review Group requested and received detailed data on the history, budget, and operations of AIDS-related efforts; and heard testimony and received comments from a variety of NCI and NIAID personnel, and heard presentations from members of the extramural scientific community and private industry. The Review Group wishes to acknowledge the following individuals for their contributions to the review process. Their contributions are greatly appreciated.
Norbert Bishofberger, Gilead Sciences, Inc.
Michael Boyd, National Cancer Institute
David Clanton, Science Applications International Corporation
John Coffin, National Cancer Institute
Dan Cook, ISIS Pharmaceuticals
David Covell, National Cancer Institute
Susan Dillon, SmithKline Beecham Pharmaceuticals, Co.
Dennis Dixon, National Institute of Allergy and Infectious Diseases
Michael Eissenstatt, Science Applications International Corporation
John Erickson, Science Applications International Corporation
Ellen Feigal, National Cancer Institute
Robert Fisher, Science Applications International Corporation
Steve Heyse, National Institute of Allergy and Infectious Diseases
Melinda Hollingshead, National Cancer Institute
Jon Kagan, National Institute of Allergy and Infectious Diseases
Charles Knirsch, Pfizer Pharmaceuticals, Co.
Barbara Laughon, National Institute of Allergy and Infectious Diseases
Gregory Petsko, Brandeis University
William Rice, Science Applications International Corporation
Vicki Sato, Vertex Pharmaceuticals, Co.
Edward Sausville, National Cancer Institute
Shizuko Sei, Science Applications International Corporation
Robert Shoemaker, National Cancer Institute
Lynn Smiley, Glaxo Wellcome, Inc.
Sherman Stinson, National Cancer Institute
George VandeWoude, National Cancer Institute
Susan E. Viitanen, Dupont Merck Pharmaceuticals, Co.
Robert Wittes, National Cancer Institute
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