Catalyze: Product Definition for Small Molecules, Biologics and Combination Products - Target Identification and Validation, and Preliminary Product/Lead Series Identification (R61/R33 – Clinical Trials Not Allowed)

RFA-HL-26-017

RFA-HL-26-016 , R33 Exploratory/Developmental Grants Phase II
RFA-HL-26-018 , R33 Exploratory/Developmental Grants Phase II
RFA-HL-26-019 , R61/ R33 Phase 1 Exploratory/Developmental Grant/ Exploratory/Developmental Grants Phase II
RFA-HL-26-020 , R33 Exploratory/Developmental Grants Phase II

Purpose

Catalyze Product Definition: Small Molecules, Biologics and Combination Products

The NHLBI Catalyze innovation program is designed to provide a suite of comprehensive support and services to facilitate the transition of basic science discoveries into new treatments for diseases and disorders that fall under the NHLBI mission. The Catalyze Program initiatives support product development (supporting product definition studies and pre-clinical research and development) and enabling technologies and transformative platforms. Catalyze is coordinated by the Catalyze Coordinating Center, which provides program administration and evaluation, milestone-driven project management, communications and outreach, as well as development guidance for projects in the Catalyze portfolio. The Catalyze program aims to create cultural and systemic changes to more rapidly move breakthrough innovations to products that will have health, economic, and societal impact. Information on the Catalyze programs can be found on the Catalyze website.

This specific Catalyze Product Definition NOFO will provide the early stage translational support needed for the activities required to develop potential therapeutic candidates and combination products to treat HLBS diseases and disorders. This NOFO is intended to provide support for early stage projects through use of a bi-phasic approach. The R61 phase allows investigators to identify, validate and screen compounds of interest, and develop the individual components of a combination drug product and the R33 phase supports identification of a lead series for pre-clinical testing and development. A companion NOFO (RFA-HL-26-018) is available for more advanced projects that have already completed the activities supported by the R61 phase of this initiative, but need continued support to identify a lead series or further test a combination product. A therapeutic candidate with two or more distinct, individual components should use RFA-HL-26-017 and its companion RFA-HL26-018. Individual components may be include a drug, a biologic, a combination product including a cell or genetic therapy component, or an eligible biologic regulated by the FDA's Center for Biologics Evaluation and Research (CBER), or  Center for Drug Evaluation and Research (CDER). Through Catalyze, the small molecule and biologics initiatives have companion initiatives that support development of devices and diagnostics (RFA-HL-26-019 and RFA-HL-26-020) and an initiative that supports the development of enabling technologies and transformative platforms (RFA-HL-26-016). See website for additional information.

It is anticipated that projects supported by this NOFO will provide a robust data set that can be used to pursue further NIH or other private funding for preclinical optimization and development of therapeutic candidates.

Objectives

1. Novelty: This NOFO seeks applications that propose to apply new knowledge around novel targets, mechanisms and pathways. Projects should aim to develop therapeutics that are significant improvements over existing therapeutics for HLBS diseases and disorders. It is expected that the proposed projects will aim to identify and validate disease targets, compound library screening and hit development, develop assays to test binding affinity, that are significant improvements over existing screening methods and should provide evidence of the unmet gaps and needs to support proposed activities.
2. Biological rationale and preliminary data: This NOFO will fund projects that have a strong biological rationale for the intended approach, which have preliminary data that reflect well-designed experiments (either from the literature, data from other sources, or, when available, from investigator-generated data).
3. Relevance for therapy development: Projects that propose to develop novel therapeutic agents that can be advanced towards development of NHLBI mission-relevant therapies and cures and fulfill the clinical gaps and needs are of high programmatic interest.

Phased Award Activities

The purpose of the R61 phase is to identify, validate and screen therapeutic compounds of interest, and for combination products: to develop the constituent parts such as screen a therapeutic component and prototype a delivery component 

Examples of activities for R61 phase include, but are not limited to:

• Synthesis of the novel therapeutic agent(s) to support proposed activities.
• Synthesis of novel molecular imaging agents for imaging, therapy monitoring, and risk stratification.
• Development and validation of assay(s) (including phenotypic assays) to support a succinct testing funnel, including for example, assays to measure specificity, potency, stability to protease and/or other metabolic enzymes, and cellular uptake.
• Development of in vitro assays or ex vivo potency/efficacy studies designed to indicate the specific ability of an agent to achieve a desired biological effect.
• Structure activity relationship studies.
• Development of assays to evaluate cellular uptake, engagement, infection, aggregation, downstream functional measures in vitro or ex vivo, purity and specificity. Assays to measure DNA, RNA, and protein levels of either endogenous genes or delivered products, downstream in vitro or ex vivo functional read-outs, viral titer, viral particle load stability and specificity.
• Development of assays to evaluate purity and identity of the therapeutic by surface markers or specific proteins, morphological measures, differentiation, functional measures in vitro or ex vivo, stability and immunogenicity.
• Assay development and optimization for low-throughput or high-throughput screening.
• A combination of assays may be developed to demonstrate relevant biological activity when a single assay may not provide adequate measurement of overall potency due to a complex mechanism of action or multiple activities of a preliminary therapeutic agent.
• Initial survey of patent literature followed by inventions disclosures and patent filing.

The purpose of the R33 phase is to identify promising lead compounds for pre-clinical testing and development, and for combination products: to test and optimize the combined constituent components into a preliminary prototype

Examples of activities for the R33 phase include, but are not limited to:

• Synthesis and characterization of select library of therapeutic agents or molecular imaging agents.
• Development and selection of cell lines/vectors to produce bioactive agents with acceptable potency and stability, cellular uptake/engagement, or secondary in vitro functional assays.
• Assessment of therapeutic candidate's properties using computational analysis and early physicochemical measurements, solubility, cell permeability and efflux.
• Assessment of initial pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion (ADME) in animal models.
• Assessment of potential off target activities.
• Physico-chemical and biological characterization of therapeutic agent(s). This could include for example, confirmation of purity, stability, absorption, distribution, metabolism, and excretion pharmacokinetics and pharmacodynamic studies.
• For gene and cell therapy, these include characterization of gene copy numbers or tropism in tissues or cell engraftment.
• Validation and replication studies to confirm observed results.

Application budgets must not exceed direct costs of $400,000 per year during the R61 phase and also must not exceed direct costs of $400,000 per year during the R33 phase. The total budget (Federal award and non-Federal matching contributions) should reflect the actual needs of the overall proposed project. Annual project budgets should reflect the actual costs anticipated in each year.

30 days before application due date

February 11, 2025; June 18, 2025; October 21, 2025

Mike Pieck, Ph.D.
Telephone: 301-827-7986
Email: nhlbi_catalyze@nih.gov