CREATE Bio Optimization Track for Biologics (SBIR-U44)

A. Overview

This Funding Opportunity Announcement (FOA) is part of a suite of complementary programs to encourage the translation of research discoveries into new treatments for disorders that fall under the NINDS mission.

The NINDS Cooperative Research to Enable and Advance Translational Enterprises for Biologics (CREATE Bio) program is dedicated to biotechnology product- and biologics-based therapies, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, cell therapies and novel emerging modalities.  The program includes two tracks:  the Optimization Track supports optimization in order to obtain a candidate appropriate for entering the Development Track, and the Development Track supports IND-enabling studies for the candidate.

For entry into the Optimization Track, projects must have strong scientific rationale and demonstrate relevant, convincing in vivo data of one or more agent(s) that are sufficiently profiled so that the parameters to be optimized can be quantitatively specified (see entry criteria for details) in the application.  At the end of the funding period, a candidate should be identified that has sufficient bioactivity, stability, manufacturability, bioavailability, in vivo efficacy and/or target engagement (measurement of target binding or proximal downstream effects) with defined minimal and optimal doses, and other favorable properties consistent with the desired clinical application (see Scope below for details).

Projects are funded through the SBIR U44 cooperative agreement award mechanism, which involves NINDS Scientific/Research staff's participation in developing the project plan, monitoring research progress, and establishing appropriate milestones.  NINDS staff will also provide assistance to academic investigators in guiding them with the therapeutic development process and the criteria needed to advance therapeutic leads to the clinic. 

For more information about earlier stage translational funding opportunities and programs, visit the NINDS Division of Translational Research website and, for more information specifically about the CREATE Bio Program, visit the website.  Applicants are strongly advised to read through the CREATE Program FAQs.

B. Scope

Projects should focus on a single disorder that falls within the NINDS mission.

The CREATE Bio FOAs focus on biotechnology products and biologics, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, cell therapies and novel emerging modalities.  Applicants should contact NINDS Scientific/Research staff regarding small peptide derivatives, natural products, molecules with complex structures, or combination products, to determine the fit for this FOA.  

Entry Criteria:

Applicants are encouraged to talk to NINDS Scientific/Research staff about the stage of their activity and receive advice as to which program is the best fit.  Applicants cannot simultaneously submit both an Optimization and Development Track application on the same agent and disease.

To be eligible for funding through this Optimization Track FOA, projects must meet the following criteria:

(1) One or more biological agents sufficiently profiled so that the parameters to be optimized can be quantitatively specified.

Note: NINDS recognizes that, depending on the type of agent and how it was identified and characterized, projects will enter at different stages, where certain required properties may have been optimized (repurposing a marketed therapy for a new indication is an extreme example). In the case of repurposing, the applications must show feasibility to proceed to an Investigation New Drug (IND) or IND exemption application, assuming the results from the Optimization Track funding period are positive.  For example, the applicants should have collaborations that enable access to existing toxicology or human trial data required by the Food and Drug Administration (FDA), and have the decision rights or partnership(s) to further the development of the agent for the proposed new indication.

2) In vivo efficacy and target engagement using existing agent(s) in relevant animal model(s) to support scientific premise that the proposed mechanism of action (MOA) and modulation of the target are likely to result in a therapeutic outcome. The agent(s) should show in vivo efficacy using clinically relevant outcome measures (e.g., anatomical, and functional when possible) and in vivo target engagement (measurement of target binding or proximal downstream effects) at the clinically intended site of action, using sufficient experimental and statistical rigor.

3) Data demonstrating that the key in vitro and in vivo assays proposed are suitable for the proposed purpose and are available in either the applicant's or collaborator's laboratories.  Appropriate controls should be employed and efforts should be taken to demonstrate dynamic detection range and acceptable variability so the feasibility of conducting the proposed studies can be adequately assessed.

4) An established and engaged multi-disciplinary project team to execute the proposed pre-clinical development plan that will deliver an optimized therapeutic candidate at the end of the funding period.

At the end of this Optimization Track, successful projects should have minimally achieved the following:

(1) Optimization is finished and the final characterization of the candidate, such as structure/identity, selectivity, stability, manufacturability, and other modality- specific characteristics is complete.

(2) For a candidate with sufficient purity, its minimal effective dose, optimal effective dose, and time and duration of treatment have been determined in relevant in vivo assays using clinically relevant functional and/or anatomical outcome measures, and/or in vivo target engagement assays.  [This normally should have been done using the clinically intended route of administration and special formulations if proposed (such as slow release, liposomes, nanoparticles, etc.), unless justified to use other routes of administration in which case the dose-response must have been reliably bridged by pharmacokinetics measurements]. The in vivo study results should also include assessment of pharmacokinetics, bioavailability at the relevant site of action, and pharmacokinetics-pharmacodynamics relationship. In particular for CNS disorders, there needs to be rigorous evidence that the agent is blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the CNS) and available at an effective dose, or evidence that the agent can act in the periphery.  Key studies should be sufficiently replicated, powered and controlled with experimental and statistical rigor to lend a high degree of confidence in the results, with sufficient information available about study design, execution, analysis, and interpretation. 

(3) Feasibility of reproducible production of the candidate.

Only the most promising agents that have undergone rigorous preclinical testing and are considered state-of-the-art for the disease of interest will be considered for advancement to IND-enabling studies in the Development Track.   This Optimization Track thus affords applicants the opportunity to build collaborations, conduct comparative studies among related agents and standard of care agents, and, ultimately, advance their most promising candidate therapeutics. 

Activities Appropriate for this FOA include, but are not limited to:

• Optimization of the agents, like improvement of potency, specificity, bioavailability, and suitability for human testing, etc.  Specific examples include but are not limited to: optimize selectivity/specificity, selection of the best promoter or viral serotype for a gene therapy product, ideal length and/or sequence of an miRNA derivative to hone its specificity, optimization of a protein for an acceptable stability in vitro or half-life in vivo, humanization of a mouse monoclonal antibody, minimizing a predicted or previously encountered toxicity, optimization of acceptable level of production, optimization to have better suitability for the route of administration
• Characterization of identity and properties (e.g., cell phenotype, aggregation, epitope mapping, glycosylation or other post-translational modification, number of unpaired cysteines, oxidation, deamination, isomerization, proteolytic sites, sequences, viscosity, stability)
• Assessment of in vitro activities (e.g., affinity, specificity, activity in cells, cellular uptake)
• Assessment of in vivo pharmacology such as determination of dose range, dosing regimen, route of administration, and ideal time and duration of treatment. This includes but is not limited to assessment of efficacy and/or target engagement, pharmacokinetics, pharmacodynamic measurements (including pharmacodynamic biomarkers), relationships among pharmacokinetics, target engagement and/or pharmacodynamic measurements, correlations between in vitro and in vivo activities, bioavailability at the site of action such as blood-brain-barrier penetration
• Studies to support independent replication, appropriate powering, or an assessment of efficacy in additional animal models if necessary to gain higher level of confidence for translatability of the discovery to the clinic, along with the model in which the leads were shown to have efficacy. However, these activities are restricted to the purpose of supporting the proposed development of a therapy and should be a limited portion of the application
• Evaluation of metabolism
• Optimization of production (e.g., expression levels, purification yield, purity, yield of vector or cells)
• Process development for scale-up manufacturing
• Stage-appropriate bioanalytical assay development and optimization in compliance with regulatory requirements
• Optimization of delivery systems and special formulations (such as slow release, liposomes, nanoparticles, etc.)
• Development of regulatory strategy and stage-appropriate interactions with regulatory agency
• Validation of target engagement assays, including experiments using human specimens, are within the scope of this FOA. However, these activities are restricted to the purpose of supporting the proposed development of a therapy.

To minimize potential funding gaps between the NINDS CREATE Bio Optimization and Development Tracks, applicants of this Optimization Track FOA may propose limited initial work for the Development Track, such as starting to identify species for toxicology study or preliminary safety evaluations, preliminary biodistribution study.  These transitioning activities are generally restricted to the last year of Optimization Track applications. Awardees are encouraged to apply to the Development Track FOA as soon as they are eligible while finalizing studies in the Optimization Track.

Examples of Activities Inappropriate for this FOA include:

• Developing animal models
• Basic research of disease mechanisms
• Early activities such as target identification and validation
• Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers.  (NINDS recognizes that target engagement markers developed may evolve into predictive markers for making clinical decisions for treatment trials, but it is not the intent of this FOA to support development of predictive biomarkers.)
• Manufacture of therapeutics for clinical trials
• Clinical research and clinical trials involving human subjects, except those in scope using human samples to validate target engagement assays
• Stand-alone studies to identify, validate, or qualify a target engagement marker and other bioanalytical assays
• Activities that are supported through the NINDS CREATE Bio Development Track FOA with the exception of the transitioning activities designed to enable easy transition from the Optimization to the Development Track as described above.

C. Milestones

Milestones are quantifiable goals that are used to monitor project progress and facilitate dialogue and go/no-go decision making between program staff and the project team to effectively manage the project. NINDS recognizes time sensitivity in developing therapeutics for patients who urgently need new or better treatment.

Prior to funding an application, NINDS Program staff will contact the applicant to discuss the proposed milestones and any changes suggested by the NINDS review panel or NINDS Program staff.  A final set of approved milestones will be specified in the Notice of Award.

Progress towards achievement of the final set of milestones will be evaluated by NINDS Program staff.  NINDS Program staff may seek advice from independent consults with relevant expertise as necessary.  If justified, future year milestones may be revised based on data and information obtained during the previous year. Funding for the project may be discontinued if milestones are not met.  In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.

NINDS emphasizes the importance of the rigor and reproducibility of experimental results.  In some cases, conducting additional critical experiments will be important for NINDS to have confidence in making a funding decision.  Therefore, NINDS Program staff, in consultation with the PD/PI, may add experiments that need to be conducted prior to or during the award as additional milestone(s). In most cases, these studies will be supported by additional funds from NINDS.

If the research contains parallel activities from an independently funded, ongoing study prior to or during the funding period, it should be noted with appropriate milestones.

Applicants are encouraged to read examples of milestones (CREATE Bio Example Milestones), and see a summary chart of a milestone timeline (CREATE Bio Milestone Summary and Timeline).

For details see the Application and Submission section below.

D. Intellectual Property (IP)

Since the ultimate goal of the CREATE Bio program is to bring new therapies to the market/patients, the program strongly encourages the awardees and/or their collaborators to obtain and retain any IP developed around the therapy during the project period (see instructions on attachment of letters to address IP issues in Section IV).   In compliance with the Bayh-Dole Act, this program is structured so that the awardee institution can elect to retain title to inventions; not withstanding the rights reserved by the U.S. Government if title is elected by awardee institution, NINDS/NIH does not intend to hold any additional IP rights for therapies developed in this program.  NIH policy requires invention reporting in iEdison.  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, prosecution, and maintenance as well as 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 over the course of the project.  Award recipients are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the therapy development process. For rare or ultra-rare diseases where commercialization may be challenging, applicants are encouraged to discuss alternative strategies with NINDS Scientific/Research staff to get further guidance.

E. Pre-application Consultation

As an U44 cooperative agreement, implementation will involve the participation of NINDS Program staff in the planning and execution of the therapy-directed projects.  Applicants and their multidisciplinary team are strongly encouraged to consult with NINDS Scientific/Research staff when planning an application. Early contact provides an opportunity for NINDS Scientific/Research staff to provide further guidance on program scope, goals, developing appropriate milestones, and budget. Applicants should contact NINDS Scientific/Research staff at least 12 weeks before a receipt date.   

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