ANTI-ORTHOPOXVIRUS DRUG DISCOVERY AND DEVELOPMENT Release Date: October 20, 1999 RFA: AI-00-002 National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: December 15, 1999 Application Receipt Date: January 19, 2000 PURPOSE As part of DHHS-wide efforts for civilian defense from possible bioterrorism, the Division of Microbiology and Infectious Diseases (DMID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), invites research applications to (1) discover and design drugs against orthopoxvirus and (2) provide sufficient quantities of promising compounds for evaluation in animals. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), ANTI-ORTHOPOXVIRUS DRUG DISCOVERY AND DEVELOPMENT, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations; public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments; and eligible agencies of the Federal government. Foreign institutions are not eligible to apply however foreign investigators may participate as collaborators, consultants or subcontractors. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the Cooperative Agreement (U01), an "assistance" mechanism, rather than an "acquisition" mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed later in this document under the section Terms and Conditions of Award. The total project period for applications submitted in response to this RFA may not exceed five years. At present, the NIAID is administratively limiting the duration of U01 cooperative agreements to four years; this administrative limitation may change in the future. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. FUNDS AVAILABLE The estimated total funds (direct and facilities and Administrative (F&A) costs) available for the first year of support for all awards made under this RFA will be $1.5 million. However, depending on Fiscal Year 2000 budget appropriations, this amount may increase. In Fiscal Year 2000 the NIAID plans to fund 1 to 4 awards. In Fiscal Year 2001, with the addition of the scale-up synthesis, the estimated total funds will be $1.75 million. The usual NIH policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. RESEARCH OBJECTIVES Background In recent years, there has been a significant change in both the nature and degree of the threat posed by the use of weapons of biological warfare. The risk of using such weapons once appeared to be restricted to international conflicts involving small numbers of industrialized nations. However, an increasing number of developing countries, as well as terrorist groups, and rogue individuals now view the use of biological weapons as agents of terror, rather than as instruments of warfare. Recent events, such as disclosures of international biological weapons programs, the bacterial contamination of restaurant food by cultists, and the delivery of a putative anthrax bacterial culture to a DC office, have dramatized both the possibility of bioterrorist attack and the vulnerability of the U.S. population to such an event. Although the DoD has developed some defenses for biological warfare to protect military personnel, comparable and additional defenses need to be developed to protect the civilian population. One is that the populations to be protected are different as civilians include people of all ages and physical conditions. Thus, the important research goals for biological agents with the potential terrorist use include; 1) rapid, accurate diagnosis; 2) effective therapy for those infected; 3) protective vaccination for those at risk of exposure; and 4) basic research, which provides the essential underpinning of the other areas. Of the organisms that might be used in bioterrorism, smallpox would likely have the most horrific impact on the health of the U.S. population. As the result of a successful immunization program, smallpox disease was eliminated in the U.S. by the 1960s. Routine immunization against smallpox was terminated. Americans today either have never been immunized or were vaccinated more that 30 years ago and those have little, if any, remaining protection. Smallpox is highly contagious and mortality is in the range of 30%. There is no available antiviral therapy. As a result of the eradication of the disease, antiviral research on smallpox and related orthopoxviruses has largely been abandoned. This Request for Applications (RFA) will support broad, innovative, multidisciplinary approaches to the design and discovery of drugs for prophylactic and/or therapeutic use in the event of an outbreak of smallpox. The NIAID has already initiated some activities in this area. Current contractors engaging in antiviral screening and animal models of viral infections have been supplemented to establish cell-based in vitro anti-vaccinia virus screens and murine animal models of vaccinia and cowpox. Any investigators who have novel compounds can request services of our contractors to evaluate their compounds with the approval of NIAID’s project officer. Further, an orthopoxvirus genomics facility will be established under a separate RFA to assist with the identification of gene targets for intervention. Some genomic information will be available through this research facility. In addition, the NIAID has entered into an agreement with the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) to perform in-depth preclinical evaluation of candidate drugs in animal models, primarily the infection of non-human primates with monkeypoxvirus. Although compounds with activity against vaccinia virus in cultured cells have repeatedly been reported in the literature, a drug that meets the requirements of efficacy, safety and ease of delivery, qualities essential for response to a potential terrorist event, has not been identified. This RFA will support the design and discovery of such new agents. Through studies of antivirals developed for other infections, scientists at USAMRIID have recently identified a potential anti-orthopoxvirus drug: cidofovir, an FDA-approved drug for retinitis caused by human cytomegalovirus (HCMV) in AIDS patients. Cidofovir demonstrated significant efficacy for the treatments of cowpox infection in mice and monkeypox in cynomolgus monkeys. However, this drug has several disadvantages - including the need to be given intravenously and serious potential toxicity problems that make it impractical for emergency use. Viruses are intracellular pathogens sharing many of the nutritional requirements and synthetic pathways with the host cells they infect. Therefore, an ideal antiviral agent will be one that effectively interdicts viral infection as a consequence of interaction with a target that is unique to the virus, and hence has little or no impact on uninfected host tissues. In principle, such selective antiviral activity is best achieved by directing drugs toward virus- specific genes, enzymes, or cellular receptors, or other cellular gene that contributes to pathogenesis. Recent developments in chemistry and biology suggest that one can logically apply such information for rational design and discover selective antiviral drugs. A recent dramatic example is the design of clinically effective inhibitors based on the crystal structures of the HIV protease and influenza neuraminidase. Recent preliminary clinical trials have also shown encouraging results with inhibitors of the picornavirus receptor-binding interaction. Antisense oligonucleotides targeting specific viral mRNA sequences of HIV, HCMV, or human papillomavirus (HPV) are also now in clinical trials. Advances in the science of molecular diversity generated from combinatorial libraries, natural products, and chemical databases present a series of rich sources of novel diversified chemical entities ready for drug discovery. Knowledge-based searches of such sources could lead to the discovery of active compounds with unanticipated structures. These advanced knowledge and technologies have provided unprecedented opportunities for identifying novel therapeutics, and for hastening the drug discovery process. Research Objectives and Scope This Request for Applications (RFA) will support research to design and discover pharmaceuticals suitable for the mass treatment of smallpox virus infection. The objective is to stimulate preclinical research in the design, synthesis, discovery, and in vitro evaluation of novel compounds aimed at the effective prophylaxis and/or therapy of smallpox virus infection for the purpose of civilian defense against bioterrorism. Viral-specific or virus-induced events in viral replication, pathogenesis, and host interaction pathways might provide appropriate targets for selective antiviral agents. Important or new targets would then be utilized for new lead generation and optimization. Possible strategies may include, but are not limited to: o Structural determination of viral gene targets, molecular modeling and de novo design, quantitative structure-activity relationships, computer-assisted structural searching, mechanism-based design, and/or transport and receptor-based design; o Exploitation of molecular diversity generated from structure-based combinatorial libraries (chemical or biological) and natural products coupled with functional/target-based high-throughput screening strategies; o Optimization of lead compounds by the principles of medicinal chemistry. Investigators should have the capability of scale-up synthesis of up to five compounds per year to supply sufficient amounts for animal model evaluations. Funds will be added to this initiative in the second year for this purpose. It is assumed that there will not be any compounds ready for animal evaluation in the first year. The areas outlined above are not intended to be all- inclusive. Collaborations between different scientific disciplines, such as chemistry and virology, as well as collaborations between industrial and academic investigators are encouraged. The following areas of investigation, some of which are supported by different initiatives, will be considered not responsive to this RFA: o Pharmacological agents such as therapeutic vaccines, cytokines, antibodies, and biological response modifiers. o Large-scale random screening of compounds. o Development of alternative synthetic methods for cost effective re-synthesis of currently existing compounds. o Development of prodrugs for currently existing compounds. o Development of animal models. o Extensive studies required for the clinical development of identified potential drugs, such as toxicological testing and formulation development. NIAID-supported contractors who engage in preclinical evaluation of potential antiviral compounds can be available to further evaluate the antiviral agents designed and discovered by investigators supported by this RFA. The contractors provide NIAID-supported animal models, which examine compounds' in vivo efficacy and toxicity and limited pharmacokinetics. The models currently available are murine models of vaccinia and cowpox. Highly promising candidate drugs can be further studied in monkeypox model by the investigators of USAMRIID. It is anticipated that this RFA will lead to the identification and optimization of lead structures. TERMS AND CONDITIONS OF AWARD The administrative and funding instrument used for this program is the cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the research will be shared among the awardees and the NIAID Scientific Coordinator. Cooperative agreements are subject to the administrative requirements outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on PHS regulations at 42 CFR part 52 and HHS regulations at CFR 45 Part74, are applicable. These special terms and conditions pertaining to the scope and nature of the interaction between the NIAID and the investigators will be incorporated in the Notice of Grant Award. However, these terms will be in addition to, not in lieu of,the customary programmatic and financial negotiations that occur in the administration of cooperative agreements. 1. AWARDEE RIGHTS AND RESPONSIBILITIES Awardees will have primary responsibility for defining the research objectives, approaches and details of the projects within the guidelines of the RFA and for performing the scientific activity. Specifically, awardees have primary responsibility as described below. a. The Principal Investigator defines the details for the project within the guidelines of the RFA, retains primary responsibility for the performance of the scientific activity, and agrees to accept close assistance of NIAID staff in aspects of scientific and technical management of the project in accordance with the terms mutually agreed upon prior to the award. b. The awardee is to plan and conduct the research stipulated in the application and to ensure that the results obtained are analyzed and published in a timely manner. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. c. The awardee is to participate in an annual meeting of investigators funded under this and related RFAs to discuss progress and strategies for future research. 2. NIAID STAFF RESPONSIBILITIES Assistance via Cooperative Agreement differs from the traditional research grant in that, in addition to the normal programmatic and administrative stewardship responsibilities, the component awarding the Cooperative Agreement anticipates substantial programmatic involvement during performance of the project. NIAID staff assistance is to participate in, but not direct, the research to ensure that important disease targets are addressed. The Antiviral Research and Antimicrobial Chemistry Program Officer, Virology Branch, DMID will serve as Scientific Coordinator and will participate as a member of the research team. The Scientific Coordinator will interact with the Principal Investigators and Co-investigators in the overall research planning and in data analysis. During performance of the award, the NIAID Scientific Coordinator may provide appropriate assistance by participating in the design of research group activities; advising in the selection of sources or resources; coordinating or participating in collection and/or analysis of data; and, advising in management and technical performance. The Scientific Coordinator may assist with arrangements for the further evaluation, both in vitro and in animal models, of agents resulting from this research. However, the role of NIAID will be to facilitate and not to direct the activities. Specifically, it is presently envisioned that the NIAID will be actively engaged in the facilitation of components including assisting the awardees in: a. Collaborative participation in overall research planning and data analysis. Specifically, the NIAID Scientific Coordinator may suggest studies within the scope of the award's objectives and research activities; may present to the investigators experimental findings from published sources or from contract projects in support of these suggestions; may participate in the design of experiments; and may participate in the analysis of results. b. Provision of needed resources and information that may not be otherwise available to the investigator. This may include the provision of data from testing conducted in resource contract laboratories subject to the terms of confidentiality agreements with drug sponsors. NIAID staff will coordinate collaboration between this activity and other components of the orthopoxvirus research program, such as the genomics facility and animal model evaluation. c. In the event that an awardee's research results in a procedure or a product that requires testing of a nature beyond the awardee's capabilities, the NIAID Scientific Coordinator may provide resources available to the Institute for comprehensive preclinical efficacy evaluations. d. The NIAID Scientific Coordinator will organize an annual symposium in Bethesda, Maryland at which the principal investigators will discuss their progress. This will facilitate overall program planning and development, the evaluation of the feasibility of the attempted approaches, and will promote productive interactions among the successful applicants. The NIAID Scientific Coordinator will also ensure the participation in this symposium of investigators from other NIAID preclinical and clinical programs to provide the most relevant antiviral expertise possible to facilitate planning for future research and expedite the design and development of novel antiviral agents. 3. Arbitration Any disagreement that may arise on scientific or programmatic matters (within the scope of the award) between award recipients and the NIAID may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the individual awardee in the event of an individual disagreement, a second member selected by the NIAID, and the third member with expertise in the relevant area and selected by the two prior members will be formed to review any scientific or programmatic issue that is significantly restricting progress. While the decisions of the Arbitration Panel are binding, these special arbitration procedures will in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR Part 16. LETTER OF INTENT Prospective applicants are asked to submit, by December 15, 1999, a letter of intent that includes a descriptive title of the overall proposed research; the name, address and telephone number of the Principal Investigator; and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Madelon Halula at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available: (1) at most institutional offices of sponsored research; (2) from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov; and (3) on the internet at http://grants.nih.gov/grants/funding/phs398/phs398.html. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and on the RFA label and the YES box must be marked. The sample RFA label at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Applications must be received by the application receipt date of January 19, 2000. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Applicants are strongly encouraged to call NIAID program staff with any questions regarding the responsiveness of their proposed project to the goals of this RFA. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single- sided photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express mail or courier service) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to Dr. Halula at the address listed under INQUIRIES. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. REVIEW CONSIDERATIONS Review Considerations Upon receipt, applications will be reviewed for completeness and adherence to the Special Instructions above by the NIH Center for Scientific Review and for responsiveness by NIAID staff; those judged to be incomplete will be returned to the applicant without review. Those considered to be non- responsive will be returned without review. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID. As part of the initial merit review, a process will be used by the initial review group in which all applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Allergy and Infectious Diseases Advisory Council. Review Criteria The criteria to be used in the evaluation of grant applications are listed below. To put those criteria in context, the following information is contained in instructions to the peer reviewers. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address the goal of the RFA? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. The earliest anticipated date of award is September 2000. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic (research scope and eligibility) issues to: Dr. Christopher Tseng Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Room 3134 6700-B Rockledge Dr. MSC 7630 Bethesda, MD 20892-7630 Telephone: (301) 496-7453 FAX: (301) 496-8030 E-Mail: ctseng@niaid.nih.gov Direct inquiries regarding review issues; address the letter of intent to; and mail two copies of the application and all five sets of appendices to: Madelon Halula, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6700-B Rockledge Dr. MSC 7616, Room 2150 Bethesda, MD 20892-7616 Telephone: (301) 496-2550 FAX: (301) 496-2638 E-Mail: mhalula@niaid.nih.gov Direct inquiries regarding fiscal matters to: Annette Hanopole Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive MSC 7614, Room 2122 Bethesda, MD 20892-7614 (zip for express mail is 20817) Telephone: (301) 496-7075 Fax: (301) 480-3780 E-mail: ahanopole@niaid.nih.gov Schedule Letter of intent receipt date: December 15, 1999 Application receipt date: January 19, 2000 Scientific review date: June 2000 Advisory Council date: September 2000 Earliest award date: September 2000 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.856, Microbiology and Infectious Diseases Research, and No. 93.855 - Immunology, Allergy, and Transplantation Research. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro- Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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