Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development for Disorders of the Nervous System (U44 Clinical Trial Optional)

Active
Yes
Status
Open
Release Date
November 1st, 2023
Open Date
January 9th, 2024
Due Date(s)
February 9th, 2024July 15th, 2024January 15th, 2025July 15th, 2025January 15th, 2026July 15th, 2026
Close Date
August 19th, 2026
Topic No.
PAR-24-063

Topic

Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development for Disorders of the Nervous System (U44 Clinical Trial Optional)

Agency

Department of Health and Human ServicesNational Institutes of Health

Program

Type: SBIRPhase: Phase IIYear: 2024

Summary

The Department of Health and Human Services, specifically the National Institutes of Health, is seeking proposals for the Blueprint Neurotherapeutics Network (BPN) program. This program focuses on small molecule drug discovery and development for disorders of the nervous system. The goal is to facilitate drug discovery and development by offering funding to neuroscience researchers for activities that can be conducted in their own laboratories. Researchers have the opportunity to collaborate with NIH-funded consultants and contract research organizations (CROs) specializing in various aspects of drug development. The Principal Investigator (PI) will be responsible for conducting disease- or target-specific assays and models, with the option to collaborate with BPN contractors on various activities. Each funded project will have a customized Lead Development Team (LDT) consisting of the PI, BPN consultants, and NIH staff. The LDT will establish an overall strategy for the project and coordinate activities across different research sites. The program is open for applications, with multiple application due dates throughout the year. More information can be found on the grants.gov website.

Description

Recent advances in neuroscience offer unprecedented opportunities to discover new treatments for nervous system disorders. However, before a new chemical entity can be tested in a clinical setting, it must undergo a process of chemical optimization to improve potency, selectivity, and drug-like properties, followed by pre-clinical safety testing to meet the standards set by the Food and Drug Administration (FDA) for clinical testing. All of the necessary expertise and resources are not commonly available to small companies as these activities are largely the domain of large pharmaceutical and biotechnology companies and contract research organizations (CROs).

To facilitate drug discovery and development by the neuroscience community, the NIH Blueprint for Neuroscience Research (https://neuroscienceblueprint.nih.gov/) established the Blueprint Neurotherapeutics Network (BPN), which offers neuroscience researchers funding for drug discovery and development activities that can be conducted in their own laboratories. Researchers have the opportunity to collaborate with NIH-funded consultants and CROs that specialize in medicinal chemistry, pharmacokinetics, toxicology, formulations development, chemical synthesis under Good Manufacturing Practices (GMP), and Phase I clinical testing. A current list of BPN contractors and consultants is available at https://neuroscienceblueprint.nih.gov/bpdrugs/bpn_resources.htm. This Notice of Funding Opportunity (NOFO) invites applications for new BPN projects.

The Principal Investigator (PI) will be responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools. A PI with- for example medicinal chemistry expertise and resources may additionally request funding to conduct structure-activity relationship (SAR) studies in their own lab but collaborate with BPN contractors on in vitro ADMET, in vivo PK, drug manufacturing and IND-enabling toxicology studies. By contrast, a PI with limited experience in drug discovery and development may opt to collaborate with all available BPN contractors. Applicants may propose to conduct all drug discovery and development activities themselves or collaborate with BPN contractors on activities of their choice.

For each project funded under this NOFO, the NIH will assemble a customized Lead Development Team (LDT). The LDT will be co-chaired by the PI and a BPN consultant and will include members of the PI's team, additional BPN consultants, and NIH staff. The LDT will establish an overall strategy for the project, including milestones proposals, outline estudies to be conducted by BPN contractors, and coordinate activities across different research sites.

Potential applicants are strongly encouraged to read the Frequently Asked Questions (FAQs) on the BPN website (http://neuroscienceblueprint.nih.gov/bpdrugs/faqs.htm) and contact NIH Scientific/Research staff and participating NIH Institutes/Centers (IC) prior to preparing an application to discuss how they may best utilize BPN resources and whether their application fits the mission of a particular NIH IC.

For this NOFO, Phase I clinical testing, studies or trials refer to the common phases of a clinical trial. U44 Phase I and II refer to the project phases of the SBIR program.

B. Scope The BPN is dedicated to the discovery and development of small molecule compounds, of a size and structure that can be readily synthesized and chemically modified (if optimization is required). This program is not designed to support development of biologics or biotechnology products, including oligonucleotides and proteins, or devices - see BPN-Biologics NOFO PAR-21-233 (https://grants.nih.gov/grants/guide/pa-files/PAR-21-233.html) and Blueprint MedTech NOFO PAR-21-282 (https://grants.nih.gov/grants/guide/pa-files/PAR-21-282.html). Applicants should contact NIH Scientific/Research staff regarding small peptides (typically less than 6 amino acids) and other complex chemical structures, as well as combination therapies, to determine suitability for optimization and development within the BPN.

To be eligible for this NOFO, a project must focus on a nervous system condition that falls within the mission of one of the participating Institutes or Centers. Please see Section C below for more information on the interests and restrictions of the participating Institutes and Centers and alternative programs to consider.

Projects can enter either at the Discovery (Exploratory, Hit to Lead or Lead Optimization Stage (BPN milestone orientation)) or the Development stage (preclinical candidate chosen no medicinal chemistry optimization required, or the IND enabling Stage). In the Discovery phase the goal is to characterize and optimize promising hit compounds using medicinal chemistry to establish structure activity relationships (SAR) and structure property relationships (SPR) including in vitro and in vivo properties such as metabolism, selectivity, toxicity, etc. As projects enter or advance to the Development stage the goal is to advance a single development candidate through Investigational New Drug (IND)-enabling toxicology studies and phase I clinical testing. Projects can enter the program at the Development stage and progress in a shorter period to IND enabling toxicology studies and phase I clinical testing.

Typical Project Research Objectives by Stage (see also the BPN milestone orientation that shows typical project structure and resources available through BPN contractors to supplement your resources):

Exploratory Stage Goals:

Demonstrating primary and counterscreen assays are robust, reproducible and can support proposed SAR studies Screening funnel is finalized with plans for all in vitro and in vivo assays in place for timely execution to move project to the clinical phase within the grant period Target Product Profile refined and approved Identification of at least one chemical series for future optimization where preliminary SAR and SPR is generated and demonstrates sufficient results to formulate a data driven strategy for multi-parameter optimization, improving physicochemical and ADMET properties in addition to potency Hit to Lead Stage Goals:

SAR should meet perspective criteria for advancement with sufficient results; data should be compelling to formulate data-driven strategy to combine compound attributes into a single stereo- and enantiomerically-pure compound meeting clinical candidate selection in the Lead Optimization stage Pharmacokinetics (PK) should support proposed pharmacodynamic (PD) studies achieving reasonable exposures and duration to achieve efficacy at a dose supportive of advancement to Lead Optimization stage Lead Optimization Stage Goals:

Identify a preclinical candidate to advance to the development phase of the program that demonstrates a reasonable therapeutic index (comparing dose range finding data to PK/PD experiments) Complete dose range finding study Patent position established Production of lead compound in sufficient quantity to enable large animal dose range studies Predevelopment Stage Goals:

Complete Candidate characterization including dose range finding (DRF) toxicology studies not yet completed in prior stage (large animal DRF typically), compound characterization salt screen/polymorph, tractable and economical synthesis to enable Phase I, in vitro ADMET characterization to support IND (for example FDA's Guidance In Vitro Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions ) Complete any efficacy studies under rigorous requirements to support clinical dose selections Engage clinician support for TPP and clinical plans IND Enabling Stage Goals:

Hold any pre-IND meetings as required Produce materials to enable GLP toxicology studies Complete all required studies for IND and produce reports suitable for IND filings. This includes GLP repeat dose toxicology studies in two species, safety pharmacology, genotoxicity evaluation, hERG as well as other studies that may be required for a particular target or route of administration Manufacture GMP drug and demonstrate suitable drug product formulation for use in Phase I trial Experience with BPN suggests that many otherwise excellent awarded projects often require additional proof of concept data or the generation of tools in order to meet the program's requirements for initiating medicinal chemistry or IND-enabling studies. For this reason, all BPN SBIR projects will begin with the U44 Phase I to conduct feasibility studies required to launch full scale medicinal chemistry (if entering at the Discovery stage) or IND-enabling studies (if entering at the Development stage). During the U44 Phase I award, the NIH will form the LDT, which will identify and oversee the studies necessary to meet the BPN requirements for initiating medicinal chemistry or IND-enabling studies. The LDT will also design plans and go/no-go milestones for all subsequent Discovery and/or Development work. Progression from U44 Phase I to Phase II will be based on administrative review (see Section D., Milestones). A project that completes all U44 Phase I and Phase II Discovery activities and advances into Development will conduct all Development work (including Development feasibility studies) under the U44 Phase II award. After successful completion of the U44 Phase I, a project may proceed either to the U44 Phase II in either hit-to-lead/lead optimization (SAR) (the discovery stage) or to IND-enabling studies (the development stage). A schematic of this project structure is available on the BPN website at: https://neuroscienceblueprint.nih.gov/bpdrugs/bpn_resources.htm

The following sections describe the Discovery and Development stages in more detail, including the program entry criteria, the program requirements for initiating medicinal chemistry and IND-enabling studies, and examples of activities that can be conducted during the U44 Phase I award. Potential applicants are strongly encouraged to contact NIH Scientific/Research staff prior to preparing an application to clarify which entry stage is most appropriate for their project and what to include in their plans for the U44 Phase I award.

Discovery

Projects that require medicinal chemistry to improve the potency and/or drug-like properties of promising bioactive compounds will enter the BPN at the Discovery stage. The process of understanding the structure-activity relationship (SAR) for desired drug properties typically requires dozens of rounds of compound synthesis and testing. Initially, medicinal chemistry will focus heavily on optimizing activity and potency of compounds in primary and secondary in vitro assays. Therefore, it is required to demonstrate robust SAR driving assays and tractable synthetic routes during the UG3 phase including blinded test-retest reliability and sufficient throughput with the primary and secondary screening assays (other standard reliability metrics are listed in the first year BPN milestones). Subsequently, SAR will increase emphasis on ADMET (absorption, distribution, metabolism, excretion, toxicity) properties of the compounds, with continued monitoring and optimization of bioactivity. The ultimate goal of the SAR effort is the selection of a single development candidate with sufficient bioactivity, therapeutic index, and drug-like properties to proceed to IND-directed pre-clinical safety assessment with reasonable projected human doses.

Entry Criteria for Discovery Stage

Projects must meet the following requirements prior to entering Discovery:

Rigorous data supporting the hypothesis that modulating the putative drug target/affected pathway will produce a desirable outcome for the intended disease indication (it is not necessary to know the precise drug target or mechanism of action). These data may be supporting literature; evidence of the translational relevance from human studies is also encouraged. It is not required nor is it expected that a project entering at the exploratory stage of discovery (BPN milestones) will have in vivo data with the proposed hit compounds. The preparatory phase (U44 Phase I) should be used to characterize the hits in order to develop appropriate tool compounds for in vivo testing in the Hit to Lead stage where in vivo efficacy may be a milestone if in vivo testing is proposed. A bioactive compound, in hand, that will serve as a starting point for optimization with: Proof of identity and purity (typically >95%, as determined by, e.g., NMR, melting point, or LC/MS, with no single impurity > 0.5%) In vitro biological activity (typically < 1 M in biochemical assays and

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