Notice of Intent to Publish a Funding Opportunity Announcement for Facilitating Preclinical and Early Phase Human Studies for New Therapeutics (UG3/UH3 Clinical Trial Optional)

Key Dates

None.

National Institute on Aging (NIA)

This Notice informs that the National Institute on Aging (NIA) intends to publish a Notice of Funding Opportunity (NOFO) inviting applications on T1 translational aging research (i.e., bench to bedside) which focus on advancing new therapeutics from preclinical stages to first-in-human (FIH) trials for aging-related conditions such as sarcopenia, physical functional impairments, heart failure with preserved ejection fraction (HFpEF), and deficits such as immunosenescence.  Biologics or stem/progenitor cell therapies for improving injury repair in older adults (e.g., fractures, wound healing) may be proposed. This may include treatments with cytokines, trophic factors, etc., to improve stem/progenitor cell function to promote more efficient repair of injuries or wounds, as well as homeostasis of the damaged tissues.  Proposed projects should clearly state the relationship between candidate compound or therapeutic target of interest for preclinical development to the clinical indication (i.e., aging-related condition of interest).

Applications focusing on neurodegenerative diseases and Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) will be outside the scope of the NOFO.

The NOFO is expected to utilize the Exploratory/Developmental Phased Award Cooperative Agreement UG3/UH3 activity code, which is a milestone-driven, phased innovation mechanism. The UG3/UH3 application must be submitted as a single application. Investigators must propose annual milestones with timelines for the UG3 and UH3 phases. The specified milestones should be quantifiable goals (or deliverables) which can be used to monitor progress at each phase, and for go/no-go decision-making at the UG3/UH3 transition point.

This notice is provided to enable advance planning by potential applicants to identify potential collaborators, coordinate and obtain approvals (if needed) for required research resources, and prepare a well-developed research plan for advancing a therapeutic through the stages of preclinical drug development and early phase human studies. The NOFO is expected to be published summer 2024 with an anticipated application due date in fall 2024. These are estimated time frames, and they may change.

It is anticipated that the NOFO will support the following two categories of milestone-driven projects:

1. Traditional de novo drug development (i.e., new chemical/molecular entities) with one of the following entry points to the translational pipeline:
   • Screening through preclinical validation, or
   • Hit to lead through Investigational New Drug Application (IND), or
   • Late-stage preclinical development through FIH studies
2. Data-driven computational drug repurposing strategies with subsequent validation of predictions and generation of proof-of-concept data in pertinent animal models and/or in human in vitro studies. For the purposes of the NOFO, drug repurposing refers to approaches for identifying alternative uses for drugs approved by the United States Food and Drug Administration (FDA) or investigational therapeutics which are beyond the scope of the original intended clinical indication

UG3/UH3 Exploratory/Developmental Phased Award Activities

The UG3 phase will be the first phase. This phase will be devoted to planning and preliminary studies. Depending on the entry point of the proposed projects, pilot activities may include the following:

• Development and testing of new computational approaches
• Screening of candidate compounds (including virtual methods)
• Identification of a lead compound
• Studies of structure activity relationship (SAR)
• Characterizing and optimizing promising hit compounds
• Target identification and engagement studies (characterization of on-target and off-target effects)
• Generation of preliminary efficacy data using animal models (e.g., in vivo and in vitro) and/or human in vitro studies including investigation of potential differences due to age and sex
• Pilot absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies, including in silico prediction
• For candidate therapeutics at more advanced stages of preclinical development, the UG3 phase may be used for pre-IND protocol development

Progression to the UH3 phase will be based on an administrative review/approval by NIA staff and dependent on achieving UG3 milestones established by the investigators.

The UH3 phase will be the second phase. The UH3 phase will enable more comprehensive pharmacology and/or toxicology evaluations (including experimental validation of in silico predictions) of the proposed therapeutics, as well as replication studies to confirm preliminary findings. Possible activities to be conducted during the UH3 phase include the following:

• Testing of analogs in ADMET assays
• Scale-up synthesis
• Efficacy and/or target engagement studies
• Multiple dose pharmacokinetics (PK) testing with pharmacodynamic (PD) correlations, if possible
• Dose-ranging finding toxicology studies
• Initial IND-enabling toxicology/toxicokinetics
• Early phase FIH trials of safety/tolerability, dose-ranging, and PK/PD

Assay and methodological development, including new computational approaches or tools may be included in both the UG3 and UH3 phases, depending on the needs of the project.

It is expected that the NOFO will include the following requirements and/or instructions:

• Investigative teams of UG3/UH3 projects must be multidisciplinary and can involve collaborations with academic, nonprofit, or commercial entities to achieve the requisite expertise, experience, and research resources. At a minimum, the investigative teams should include basic, clinical, translational/pharma expertise, biostatistics, and a multi-Principal Investigator (PI) arrangement to ensure necessary leadership as the project progresses through translational pipeline stages. Projects involving data-driven computational approaches for drug development should include additional expertise in data science, bioinformatics, computational chemists, and computational biologists, as needed.
• Provide a Target Product Profile (TPP) which states the ultimate goals of the proposed therapy development effort such as stages of the age-related condition proposed for the project, patient population, mode of administration, dosing regimen, duration of treatment, biomarkers and/or outcome measures, and criteria for determining clinical efficacy.
• For projects proposing early phase FIH trials, discuss the rationale behind the selected clinical population and provide evidence in support of feasibility for evaluation of clinical efficacy should the proposed therapy be tested (for example, describe strategies for gaining access to appropriate patient population, the selection of clinical endpoints).  Describe the group clinical expertise used to determine the goals of the therapeutics development program and the proposed FIH trial.
• For a multiple-Program Director(s)/PI(s) (PD(s)/PI(s)), multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing intellectual property) among the institutions consistent with achieving the goals of the program. Applicants should clarify how intellectual property will be shared or otherwise managed if there are multiple PDs/PIs and institutions involved.

Funding Information

Public/State Controlled Institution of Higher Education
Private Institution of Higher Education
Nonprofit with 501(c)(3) IRS Status (Other than Institution of Higher Education)
Small Business
For-Profit Organization (Other than Small Business)
State Government
Indian/Native American Tribal Government (Federally Recognized)
County governments
Independent school districts
Public housing authorities/Indian housing authorities
Indian/Native American Tribally Designated Organization (Native American tribal organizations (other than Federally recognized tribal governments)
U.S. Territory or Possession
Indian/Native American Tribal Government (Other than Federally Recognized)
Regional Organization
Eligible Agencies of the Federal Government

Applications are not being solicited at this time. 

Inquiries

Please direct all inquiries to the following NIA contacts:

Chhanda Dutta, Ph.D.
Division of Geriatrics and Clinical Gerontology (DGCG)
Email: Chhanda.Dutta@nih.gov

Jennifer Fox, Ph.D.
Division of Aging Biology (DAB)
Email: Jennifer.Fox@nih.gov

Lorenzo M. Refolo, Ph.D.
Division of Neuroscience (DN)
Email: Larry.Refolo@nih.gov