Preclinical Development of Novel Therapeutics Targeting Aging Mechanisms (SBIR U44 Clinical Trial Not Allowed)

Background Recent health statistics indicate that the prevalence of multiple chronic conditions (two or more) in the United States is 50% among individuals age 45-64 years and 81% among individuals age 65 years and older. Examples of chronic conditions include diabetes, arthritis, chronic obstructive pulmonary disease (COPD), heart disease, cancer, stroke, and dementia and other cognitive impairments. Individuals with multiple morbidities experience more functional limitations and usually have worse health outcomes than those affected by a single disease. This public health burden is expected to increase,as the over-65 population is projected to triple by 2030. In addition, there are age-related conditions, such as sarcopenia/skeletal muscle function deficit, heart failure with preserved ejection fraction (HFpEF), and mobility disabilities, for which effective therapies remain to be identified. Thus, there is substantial interest in the identification of new compounds and the repurposing of FDA-approved drugs which can modulate fundamental mechanisms of aging (e.g., cell senescence, autophagy, mitochondrial dysfunction, etc.). Not only would such therapies be applicable to a wide variety of aging-related conditions, but they also have the potential to prevent multiple chronic conditions. Ultimately, the goal of translational aging research is to promote health span--the maintenance of good health as we age. Investigators involved in translational aging research continue to generate proof-of-concept data in model organisms and/or in vitro experimental systems for a variety of compounds which have been found to either extend life span, modulate various aging mechanisms, or alleviate specific age-related deficits in physiological functions (e.g., endothelial cell dysfunction, impaired wound healing, alterations in cardiomyocyte function). Yet only a small fraction of these geroscience-based discoveries enters preclinical drug development pathways. Consequently, the prospects for taking potentially novel therapies for aging conditions to first-in human (FIH) studies and clinical trials continue to remain low. While efforts are underway to address the current methodological and regulatory challenges faced by investigators involved in geroscience-based drug development, the lack of funding sources to support the range of studies required for the preclinical development activities represents a major hurdle. Such studies are usually expensive, resource intensive, and time consuming, but crucial to the design and implementation of initial human testing of promising new therapeutics. It is important, therefore, to engage small business concerns (SBCs) in translational aging research since they possess the necessaryinfrastructure and research resources and follow standard operating procedures (i.e., Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP)) that will meet regulatory requirements and increase the likelihood of a successful filing of an Investigational New Drug (IND) application. The National Institute on Aging (NIA) is thus establishing a cooperative agreement SBIR (U44) program to facilitate the preclinical development of new, repositioned, and repurposed drugs and other types of therapeutics targeting fundamental aging mechanisms for the prevention and treatment of aging-related conditions. Research Objectives This Funding Opportunity Announcement (FOA) utilizes the SBIR cooperative agreement (U44) activity code to support key phases of the preclinical development of emerging therapeutics targeting fundamental mechanisms of aging (e.g., inflammation, cell senescence, proteostasis). This includes the translation of a broad range of potential geroscience-based therapies, such as new classes of compounds (e.g., senolytics), biologics, stem/progenitor cell-based therapies, repositioning of existing investigational drugs, and repurposing of FDA-approved drugs for the treatment and prevention of clinical conditions related to aging and common in the aged. NIA encourages the submission of applications which involve translational research activities across all stages of preclinical drug development. It is anticipated that the type and amount of data to be included in the U44 applications will vary in accordance with the stage of preclinical development of an investigational compound and with drug repositioning and repurposing. Applicants with promising in vivo data on a lead compound being proposed for further development are encouraged to consider the Direct-to-Phase II mechanism, while earlier stage applicants are encouraged to consider the Fast-Track mechanism. All applicants are encouraged to contact the scientific contacts listed in this RFA to discuss their application and the most appropriate funding mechanism. Applications must present a strong scientific rationale for the intended clinical application of the proposed therapeutics based on the aging mechanism(s) of interest and, at the very least, include high-quality proof-of-concept data obtained in aging-relevant experimental models and human in vitro systems. Moreover, because the effects of targeting a fundamental aging mechanism may differ between organs/tissues and thereby influence the outcomes (beneficial and adverse), applicants should consider possible tissue- or organ-specific effects in their rationale. Applications involving the repositioning of an existing investigational drug or repurposing of an existing FDA-approved therapeutic should include information on the feasibility of an IND submission. In addition to any other information the applicant feels is pertinent, applications should include documentation to show access to existing pharmacokinetics/pharmacodynamics (PK/PD) data, toxicology data, and any relevant clinical data required by the FDA. Applicants must include a Target Product Profile (TPP) based on FDA guidance in their applications. In addition, U44 awardees will be required to convene periodic meetings with the FDA to discuss any necessary modifications to the TPP based on research progress or to meet specific regulatory requirements (e.g., pre-IND meeting). These requirements are intended to increase the probability of a successful IND submission (if the preclinical results are sufficiently promising to support an IND submission). The range of translational research activities appropriate for this FOA include, but are not limited to, the following: Further characterization of candidate compounds/proposed therapy, such as molecular size, bioactivity, and bioavailability, including the development of assay methodologies or research tools to conduct the characterization. Collection of limited additional data regarding target validation. Validation of target engagement assays, including experiments using human biospecimens. Development of stage-appropriate bioanalytical assays and optimization in compliance with regulatory requirements. Generation of pilot data to help design IND-enabling toxicology studies (dose-range determination, routes of administration to be tested, selection of appropriate animal models, etc.). Pilot studies of potential age and/or gender differences in PK/PD characteristics which may influence design of IND-enabling studies. Chemistry, Manufacturing, and Control (CMC)-related activities such as purification, final formulation development, GMP manufacturing/scale-up for IND-enabling pharm/tox testing. Testing to confirm the identity, quality/purity, and potency of lots of the investigational compound that will be used for toxicology studies and intended for the proposed human study. Refinement and validation of assay methodologies to further test pharmacokinetic (PK) properties, or for in vitro studies intended to evaluate drug toxicity. Replication studies if required to establish feasibility of further translation of proposed therapeutics, including assessment of efficacy in additional animal models and testing of the impact of age-related changes (e.g., use of aged animals). For proposed stem/progenitor cell replacement therapies, additional characterization of aging changes in the systemic milieu and/or tissue microenvironment, phenotypic properties, or aspects of cell sorting/isolation which may impact regenerative potential. Assessment of in vivo pharmacology such as determination of dose range, frequency of dosing, route(s) of administration, etc., in appropriate animal models and in different age groups (based on anticipated age range of target clinical population). This includes studies of potential age-related differences in pharmacodynamic (PD) properties and Absorption/Distribution/Metabolism/Excretion (ADME). Studies of the relationships between PK and PD properties with target engagement measurements, correlations between in vitro and in vivo activities, and bioavailability at site of action. Testing of different formulations, optimization of delivery systems, or special formulations (e.g., controlled release, extended delivery). Refinement of manufacturing processes (e.g., purification yield, purity, yield of cells from isolation process) and establishment of scale-up procedures. IND-enabling pharmacology and toxicology studies (acute, subacute, chronic, reproduction studies, mutagenicity and tumorigenicity studies). Any special toxicity studies related to the drug's mode of administration or conditions of use (e.g., intranasal, extended release formulation). Immunogenicity evaluation, as appropriate. Biodistribution studies, as needed. Studies of potential drug interactions, if needed. Translation and validation of assay methodologies used in animal studies for monitoring efficacy or safety outcomes for use in clinical studies. Preparation and submission of an IND package to the FDA. At the end of the U44 funding period, it is expected that a successful project would be poised to enter the phase of IND-enabling studies or, for projects at more advanced stages of translation, result in the submission of an IND application to the FDA. Investigators who receive U44 awards under this FOA will also have the option of subsequently applying to the NIH SBIR/STTR Commercialization Readiness Pilot (CRP) Program Technical Assistance and Late Stage Development FOA to accelerate the pace of their translational research activities. For example, U44 projects could obtain additional funding through the CRP program to conduct additional drug development activities such as IND-enabling studies or for manufacturing costs, regulatory assistance, or a combination of services, including planning for FIH studies or early-phase clinical trials (e.g., Phase I and II). Applicants should include travel funds for staff to participa ein annual meetings in Bethesda, MD. The first annual meeting should occur within the first four months of the project period. Non-Responsive Applications Projects which primarily focus on basic science mechanistic studies or the early phases of target discovery are outside the scope of this FOA. Preclinical development of new drugs for Alzheimer’s disease and related dementias (AD/ADRD) are also outside the scope of this FOA, as several other NIA FOAs are available for this purpose. Information on current NIA FOAs on AD/ADRD is available at https://www.nia.nih.gov/ad-foas. Milestones Milestones are quantifiable goals that are used to monitor the progress made by a research project and serve as a basis for go/no-go decision making between NIA program staff and the project research team. Prior to the issuance of an award, NIA program staff will contact the applicant to discuss any modifications to the proposed milestones, as recommended by the review committee or NIA program staff. A final set of approved milestones will be specified in the Notice of Award. Progress towards achievement of the established milestones, including transition from U44 Phase I to II, will be evaluated by an NIA oversight committee composed of NIA program staff. NIA staff may seek advice from staff at other NIH Institutes and Centers (ICs) with relevant expertise, as necessary. If warranted, the milestones for future years may be revised based on data and research progress during the preceding year. Funding for the project may be restricted or discontinued if there are delays in meeting milestones or if milestones are not met. Continuation of funding will also be based on the overall robustness of the data generated and their interpretability (independently of achieved milestones), overall progress, competitive landscape, and availability of funds. Intellectual Property (IP) Applicants are encouraged to prepare this section in consultation with their institutions' technology transfer officials. NIA strongly encourages the awardees and/or their collaborators to obtain and retain any IP developed during the project period (refer to instructions on attachment of letters to address IP issues in Section IV). In compliance with the Bayh-Dole Act, this cooperative agreement U44 research program is structured so that the awardee institution can elect to retain title to inventions; notwithstanding the rights reserved by the U.S. Government if title is elected by awardee institution, NIA/NIH does not intend to hold any additional IP rights for therapeutics developed under this U44 program. NIH policy requires invention reporting in I Edison. Patents should also include a reference to NIH funding support by including the grant/cooperative agreement number in the patent. The awardee institution will take responsibility for patent filings, implementation, maintenance, and licensing efforts toward eventual commercialization. PDs/PIs are expected to work closely with their institutional technology transfer/business development officials to ensure that appropriate technology transfer agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated, as required, over the course of the project period. Awardees are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the therapeutics development process. Pre-Application Webinar A webinar is planned to provide prospective applicants the opportunity to receive information and ask questions about the scientific scope of this FOA and technical details for applying. The webinar will be open to all prospective applicants. Participation in the webinar is not a prerequisite to applying to this FOA, but prospective applicants will need to register in order to participate. Prospective applicants are also encouraged to submit their questions regarding the FOA in advance of the webinar; further details on where to submit the questions will be provided once the webinar has been scheduled. Please refer to www.nia.nih.gov/RFA-AG-21-026 for further details on the pre-application webinar, including the time and date and registration information.