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Lead Optimization and Preclinical Development of Therapeutic Candidates for Diseases of Interest to the NIDDK (R43/R44)



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 Projects in areas that are primarily within the missions of other Institutes or Centers (ICs) of the NIH are not appropriate for this FOA and will not be supported.

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 preclinical development. For the purposes of this FOA, these stages are defined as:

I. Identification of prototype therapeutic leads: This may occur through a variety of approaches and stages such as identifying targets, screening compound libraries, or constructing prototype non-viral biologics with preliminary evidence that they may significantly impact a disease process.

II. Early-stage preclinical validation:  A process of preclinical hypothesis testing to generate data that, over time, increases confidence that manipulation of disease processes via a specific therapeutic strategy 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.

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

IV. Clinical therapeutic validation: 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.

This FOA is intended to stimulate research and development activities focused on III. Lead optimization and preclinical development to a point where there is sufficient scientific evidence to justify filing of regulatory approval. It is not intended to support identification of prototype therapeutic leads or early-stage preclinical validation or clinical therapeutic validation.

Research Goals and Objectives

This funding opportunity announcement is intended to support lead optimization and preclinical 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 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 preclinical 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 SBIR Phase I is to conduct key studies in support of SBIR Phase II applications, which are expected support projects that proceed through IND- or IDE-enabling studies.

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

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

SBIR Phase I projects must result in one or more identified preclinical 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 SBIR Phase II award. Preliminary data should demonstrate rigor in the evaluation of candidate therapeutics entering SBIR Phase II, including, when appropriate, preliminary assessments of therapeutic-like characteristics. It is expected that SBIR 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 SBIR 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 preclinical 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 modulates the activity of key regulators of tissue and organ regeneration;
  • Pharmacological testing of novel preclinical 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, microfluidic-based 3D human organoid systems);
  • Ex vivo engineering of cellular or tissue constructs, probiotic or commensal microbes, or consortia of these microbes, and assessing the efficacy and safety of their transplant in preclinical disease models;
  • 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.

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

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

  • Scale-up GMP manufacturing of a small molecule preclinical 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 NIDDK-funded existing research consortia, such as the Human Islet Research Network (, the Rebuilding a Kidney 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 also 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 see the list of CTSA Hubs (

Applicants that have not yet identified therapeutic lead candidates as starting points should consider the Molecular Libraries Program ( and the following FOAs: Assay Development and Screening to Discover Therapeutic or Imaging Agents for Diseases of Interest to the NIDDK (R01) (; Early-Stage Preclinical Validation of Therapeutic Leads for Diseases of Interest to the NIDDK (R01) (     


See Section VIII. Other Information for award authorities and regulations.

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