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HHS STTR PA-14-054



Recent significant advances in genetics, the basic understanding of physiology, and the pathogenesis of disease coupled with technological advances in areas such as bioinformatics, chemical biology, synthetic chemistry, and protein engineering have provided a rich knowledge base and strong toolbox to identify and pursue new drug targets with the goal of generating new molecular therapies for the treatment of diseases. As part of its mission to reduce the burden of disease, NIDDK is committed to encouraging the translation of these discoveries into new treatments. The goal of this FOA is to support milestone-driven projects focused on the optimization and preclinical testing of candidate therapeutics for diseases within the mission of the NIDDK. All proposed studies must be directed at the most efficient route to regulatory submission, and therefore this program excludes basic research, studies of disease mechanism, or clinical studies. 

Prospective applicants are strongly encouraged to discuss the relevance of proposed projects to the mission of the NIDDK with program staff before preparing an application. The NIDDK is exclusively interested in disease-focused translational research relevant to its mission which includes obesity, diabetes, diabetic complications, endocrine diseases, liver and digestive diseases, nutrition, kidney and urological diseases, hematology, and inborn errors of metabolism. For additional information on disease areas of interest to the NIDDK, please see

Staging of Target Validation and Lead Advancement

The process of identifying and validating drug targets, small molecule chemical scaffolds, or biologics for the treatment of human disease begins with a hypothesis and can be viewed as progressing along a continuum of increasing confidence leading to widespread acceptance of its use in patient populations. This FOA is intended to support only later-stage efforts in lead optimization and pre-clinical development. For the purposes of this FOA, these stages are defined as:

Clinical target validation: Is defined as studies conducted in human patient populations to fully understand the efficacy and safety profiles of a compound and its associated target. True validation of a target may take decades of post-regulatory approval data accumulation.

Lead optimization and pre-clinical development: Are processes by which additional alterations to a pre-therapeutic lead may be made in conjunction with pre-clinical assessments of its in vivo pharmacokinetics, efficacy, and safety. The goal is to generate a lead clinical candidate and associated data packet which strongly supports regulatory approval for the initiation of clinical target validation.

Early-stage pharmacological target validation: Is a process of pre-clinical hypothesis testing to generate data that, over time, increases confidence that pharmacological manipulation of a target may be clinically efficacious and safe. This process occurs prior to clinical testing of a new compound but should include the use of human-derived data, tissues, cells, and systems.

Target identification: The generation of scientific evidence that a target is exploitable and involved in some significant way with a disease process.

This FOA is intended to stimulate research and development activities around lead optimization and pre-clinical development to a point where there is sufficient scientific evidence to justify filing of regulatory approval. It is not intended to support target identification or early-stage pharmacological or clinical target validation

Research Goals and Objectives

This funding opportunity announcement is intended to support lead optimization and pre-clinical development activities around agents with the potential to treat diseases within the mission of the NIDDK.

The following are types of applications that are not appropriate for this FOA:

  • Applications for which pre-therapeutic lead molecules or biologics have not yet been identified (e.g. assay development projects, screening of compound libraries, fractionation of natural products, target identification efforts);
  • The development of novel tools, models, or technologies without an integrated plan for their use in lead optimization or pre-clinical development;
  • Research focused primarily on understanding normal biology or disease processes;
  • Clinical studies or interventional clinical trials;
  • Agents for which the primary indication falls outside of the mission of the NIDDK.

The primary purpose of Phase I is to conduct key studies in support of Phase II applications, which are expected support projects that proceed through IND- or IDE-enabling studies.

Particular areas of interest appropriate for Phase I applications include, but are not limited to:

  • Generation of key proof-of-concept data for a pre-therapeutic lead agent in established models of pre-clinical efficacy to justify extensive pre-clinical development activities in Phase II;
  • Conducting a limited exploration of the structure activity/function relationship around a potential pre-clinical agent to demonstrate feasibility of an extensive lead optimization campaign in Phase II.

Phase I projects must result in one or more identified pre-clinical therapeutic leads with supporting efficacy data (e.g. animal models, ex vivo human tissues, iPSC-derived organoids, well justified in vitro target/pathway engagement) for a disease within the mission of the NIDDK to be considered for a Phase II award. Preliminary data should demonstrate rigor in the evaluation of candidate therapeutics entering Phase II, including, when possible, preliminary assessments of drug-like characteristics. It is expected that Phase II applications are focused on the generation and/or testing of potential therapeutic agents along a pathway headed towards regulatory filing.

Particular areas of interest appropriate for Phase II applications include, but are not limited to:

  • Medicinal chemistry efforts leveraging existing structure activity relationships of a chemical scaffold to optimize a lead pre-clinical candidate, including characterization of efficacy as well as  absorption, distribution, metabolism, excretion, and toxicity properties;
  • Protein engineering to produce a lead clinical candidate molecule that modulate the activity of key regulators of tissue and organ regeneration;
  • Pharmacological testing of novel pre-clinical lead candidates in state of the art efficacy models as well as the evaluation of novel models to better predict the efficacy of compounds (e.g. next-generation animal models, interconnected human organoid systems);
  • The finalization of a novel nanoparticle formulation, such as one incorporating multiple agents, and demonstration of its potential to significantly enhance the therapeutic efficacy of the molecule(s) being studied.

Phase II applications may, and Phase IIB applications must, include pre-clinical studies which specifically generate data to support regulatory filing, and applicants are encourage to have had discussions with regulatory agencies prior to submission.

Particular areas of interest appropriate for Phase II or IIB applications include, but are not limited to:

  • Scale-up GMP manufacturing of a small molecule pre-clinical lead and GLP IND-enabling pharmacological and toxicological testing;
  • IDE-enabling toxicological studies of a nanoparticle based formulation of an existing medication to enhance tissue-specific uptake and target accessibility.

Applicants should refer to Section IV.2 for additional application instructions.

Utilization of Related Resources

Applications may propose interaction with experts involved in NIDDK-funded existing research consortia, such as the Beta Cell Biology Consortium (, the Nuclear Receptor Signaling Atlas (, the Diabetic Complications Consortium (, the Mouse Metabolic Phenotyping Centers (, the Intestinal Stem Cell Consortium (, or the GenitoUrinary Development Molecular Anatomy Project ( If applicable, applicants should include letters of collaboration from experts detailing the nature of the collaboration.

Applicants are encouraged to take advantage of the resources provided by the National Center for Advancing Translational Sciences' Clinical Translational Science Awards (CTSAs) program, ( to leverage resources for therapeutic discovery in areas described in this FOA. CTSA resources include, for example, core facilities, super computer centers, biostatistics, bioinformatics, community engagement network, tissue repositories, and animal models. For more information about resources available at individual CTSAs, please contact the Program Officials listed at

Applicants that have not yet identified pre-therapeutic lead candidates as starting points should consider the Molecular Libraries Program ( and the following FOAs: Development of Assays for High-Throughput screening for use in Probe and Pre-therapeutic Discovery (R01); Solicitation of Assays for High Throughput Screening (HTS) to Discover Chemical Probes (R01) (; Early-Stage Pharmacological Validation of Novel Targets and Accompanying Pre-Therapeutic Leads for Diseases of Interest to the NIDDK (R01) (

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