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Section I. Notice of Funding Opportunity Description Blueprint Neurotherapeutics Network for Biologics (BPN Biologics) The NIH Blueprint for Neuroscience Research is a collaborative framework through which 13 NIH Institutes, Centers, and Offices jointly support neuroscience research, with the aim of accelerating transformative discoveries for the nervous system in health, aging, and disease. For further information, see: https://neuroscienceblueprint.nih.gov. Recent advances in biologics-based therapeutics offer unprecedented opportunities to develop new treatments for nervous/neuromuscular system disorders across multiple emerging modalities, including gene and cell therapies, oligonucleotides, and novel antibody technologies. However, biotherapeutics development has inherent complexities with regard to characterization, manufacturing, delivery, and administration and requires specialized expertise and resources. The Blueprint Neurotherapeutics Network for Biologics (BPN Biologics) program seeks to bridge this gap by providing awarded projects with: Grant funding for investigator-led discovery and development activities In-kind access to BPN Biologics contract resource organizations (CROs) that specialize in industry-standard manufacturing, nonclinical, and early phase clinical services Assistance from BPN Biologics-contracted consultants with industry expertise across drug development areas and therapeutic modalities Project management support and milestone and strategy planning resources The overarching goal of the program is to accelerate the development of diverse biotherapeutic modalities for the treatment of nervous and neuromuscular system disorders by advancing therapies through early clinical development. For more information, please visit our website at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics. A. Overview The purpose of this Notice of Funding Opportunity (NOFO) is to support the development of biologics-based therapies for disorders affecting the nervous and neuromuscular systems. Activities supported by this NOFO include lead optimization through first-in-human phase 1 clinical trials. Applicants may propose to use grant funding to conduct all experimental activities or collaborate with BPN Biologics CROs on activities of their choice. The PD/PI will be responsible for conducting all studies involving disease- or target-specific assays, animal models, and other research tools. This NOFO uses a phased, milestone driven U44 Fast-Track cooperative agreement that involves close collaboration and regular interactions with NIH program staff (see Section VI.2). All projects must have two phases and start with a U44 Phase I award. The U44 Phase I may not exceed two years. Progression from U44 Phase I to Phase II will be based on administrative review and availability of funds (see Section I.H, Milestones). Note: For this NOFO, Phase 1 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. As part of the cooperative agreement, a multi-disciplinary and highly collaborative “Lead Development Team” (LDT) composed of the PD/PI’s research team, NIH staff, and NIH-contracted consultants will be assembled for each project. Consultants will be selected by NIH program staff based on the specific expertise needed. The LDT will meet once every two weeks at a fixed time throughout the funding period. Relevant project staff from BPN Biologics CROs will join when appropriate. The LDT will participate in: Developing the overall project strategy Refining milestone plans and advising on appropriate go/no-go decision criteria Designing study plans to be conducted by BPN Biologics CROs and coordinating activities across research sites Regularly presenting new project-related data and troubleshooting issues as they arise B. Scope Projects must focus on a single nervous or neuromuscular system condition that falls within the mission of participating NIH Blueprint Institutes and Centers (see Section I.C below). Biologics-based therapeutic agents that are within scope of this program include, but are not limited to, antibodies, peptides, proteins, oligonucleotides, gene therapies, cell therapies, and other emerging therapeutic modalities (e.g., microbial or microbiome-based). Note: This NOFO does not support small molecules drugs (see Companion BPN Funding Opportunities PAR-24-043 and PAR-24-063). Applicants should contact NIH Scientific/Research staff regarding small peptides (less than 6 amino acids), natural products, and/or combination therapies to determine the fit for this NOFO. C. Institutes and Centers (IC) Interests and Guidance For specific IC requirements and interest statements refer, to the BPN Biologics website at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/contacts. D. Entry Criteria All projects will begin with a U44 Phase I award regardless of therapeutic starting point. Applicants may enter the program at either the “Discovery Stage” after one or more lead biologic agent has been identified or at the “Development Stage” once a single clinical candidate has been selected. At minimum, all projects entering the program must have a strong body of evidence linking the putative drug target/affected pathway to the proposed disease pathophysiology and compelling data suggesting the proposed mechanism or mode of action is likely to produce desirable outcomes for the intended patient population. Discovery-stage entry criteria Projects entering at this stage must have: One or more lead agent(s) that have been sufficiently profiled for lead optimization and require no more than two years of further optimization to select a single clinical candidate Preliminary target engagement data (i.e., target binding or proximal downstream effects) with lead agent(s) in a relevant animal model Preliminary in vivo efficacy data (e.g., histological, functional, and/or behavioral outcomes) with lead agent(s) in a disease relevant animal model Readily available in vitro or ex vivo assays (e.g., binding, bioactivity, selectivity) with sufficient reliability and throughput to drive lead optimization in the PD/PI’s or collaborator’s lab Available animal model(s) that have been sufficiently validated and characterized and are ready for dosing with the proposed lead(s) in the PI/PD or collaborator’s lab No obvious legal (e.g., intellectual property) constraints to pursuing the proposed biologic agent(s), using the proposed assays and models for research purposes, and/or commercial development. If patents have not been filed at this stage, it is expected that a strategy is in place for future IP filings. Development-stage entry criteria Projects must have selected a single clinical candidate prior to entering the program that: Requires no further optimization Has suitable pharmacokinetics (for gene and cell therapies, this may include biodistribution/tropism) and pharmacokinetic-pharmacodynamic (PK-PD) relationship with the planned route of administration Demonstrated in vivo target engagement and efficacy with defined minimal and optimal doses with the intended route of administration in the relevant animal model(s) Is protected by granted or pending patents and is unlikely blocked or impeded by legal (e.g., intellectual property) constraints E. Activities Supported Through This Program U44 Phase I activities The U44 Phase I award supports lead optimization, candidate selection, and any remaining activities required to initiate Investigational New Drug (IND)-enabling studies. The U44 Phase I award must not exceed two years. Projects entering at the Development stage are expected to complete U44 Phase I activities within one year since they are further advanced. The following are examples of in-scope U44 Phase I activities for projects entering at the Discovery stage: Optimization of lead agent(s) to improve bioactivity, selectivity, and ADME (absorption, distribution, metabolism, excretion) and reduce toxicity Research-grade synthesis of new analogs for in vitro and in vivo testing as part of lead optimization Characterization of identity and properties (e.g., cell phenotype, post-translational modifications, aggregation, epitope mapping, stability) In vivo pharmacology (e.g., dose-range, dosing regimen, treatment duration) In vivo efficacy studies assessing target engagement and functional outcomes in relevant animal model(s) Preliminary safety and tolerability Initial development of bioanalytical assays to measure drug levels in nonclinical and clinical PK studies Initial development of pharmacodynamic biomarkers to measure target engagement or downstream drug effects in nonclinical and clinical studies The following are examples of in-scope U44 Phase I activities for projects entering at the Development stage: Replication of in vivo efficacy studies in the same or different animal model (if needed) Remaining qualification of bioanalytical assays and pharmacodynamic biomarker assays Pre-formulation studies (e.g., buffer compatibility, freeze-thaw, excipient screening) Initial process development for drug production Initial development of analytical methods (i.e., potency, purity, identity, and safety testing) to monitor quality and consistency of drug substance and drug product manufacturing Pre-IND package preparation and pre-IND meeting U44 Phase II activities: The U44 Phase II award supports completion of safety and pharmacology in compliance with Good Laboratory Practices (GLP), production of material under current Good Manufacturing Practices (cGMP) in support of IND filing, and a first-in-human (FIH) clinical trial. Progression from the U44 Phase I to Phase II award will be based on administrative review of milestones progress (see section I.H, Milestones). After successful completion of the U44 Phase I award, a project may proceed to the U44 Phase II award. The following are examples of in-scope U44 Phase II activities: Non-GLP toxicology studies (e.g., dose range finding toxicology) IND-enabling safety pharmacology and toxicology in compliance with GLP Biodistribution and immunogenicity in vivo studies Tumorigenicity evaluations, particularly for gene and cell therapies Master and working cell bank development Manufacture of the candidate therapeutic for IND Formulation and stability studies IND preparation and submission FIH phase 1 clinical trial The goal by the end of the U44 Phase II award is to reach the clinical trial stage (at minimum, IND filing). Applicants are encouraged to include a FIH clinical trial if feasible within the funding period. Clinical trial activities FIH clinical trials supported in the U44 Phase II may use: Healthy subjects or subjects from the intended patient population Single dose or single ascending dose protocols, which may be placebo-controlled or open-label studies Safety, tolerability, pharmacokinetics, pharmacodynamics, and target engagement endpoints Applicants are strongly encouraged to contact Scientific/Research staff to ensure their proposed clinical trial plan can be supported by the program. F. Responsible parties for proposed activities PD/PI’s team Applicants may propose to use grant funding to perform all or some of the U44 Phase I and II research activities at the PD/PI’s institution and/or through collaborators/CROs selected and managed by the PD/PI through a sub-award. It is expected that grant funding will be used for the following: All activities using target- or disease-related assays (e.g., target binding, phenotypic assays, organoids) and animal models (e.g., transgenic, knockout, pharmacologically induced) Assembly and submission of regulatory meeting packages and the IND application. The PD/PI’s institution will be responsible for scheduling regulatory meetings with the FDA. Assistance from NIH-contracted consultants will be available to support preparation of regulatory materials. BPN Biologics CROs The use of BPN Biologics CROs is optional, and the costs are covered by NIH. Applicants may propose the number and types of activities that will be conducted through BPN Biologics contractors. These activities may include: Nonclinical studies, including bioanalytical and pharmacodynamic biomarker assay development and qualification, pharmacokinetics, biodistribution, and safety pharmacology and toxicology under non-GLP and GLP conditions Chemistry, Manufacturing, and Controls (CMC) activities including small-scale synthesis, process development, analytical methods development, cell bank development, formulations development, scale-up, and cGMP manufacturing FIH clinical trial study planning, coordination, conduct, data handling, and reporting. As the clinical trial needs/requirements of biologics therapeutics vary, applicants are strongly encouraged to contact NIH Scientific/Research staff (listed in Section VII) to discuss the types of human subject trials currently supported by BPN Biologics clinical contractors. Any IP developed through these activities will be assigned to the applicant’s institution. Consultants All awarded projects receive support from NIH-contracted consultants at no cost to the PD/PI. Consultants are selected after award based on the project needs. Consultant areas of expertise include assay development, pharmacokinetics, toxicology, CMC, regulatory, and medical writing Applicants may also use grant funding for consultants selected and managed by the PD/PI who have been integral parts of the project team. A current list of BPN Biologics contractors and consultants is available at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/resources G. Applications Not Responsive to this NOFO Non-responsive or incomplete applications will not be reviewed. The following activities are considered non-responsive to this NOFO: Basic research and studies of disease mechanism Animal model development and/or validation Mechanistic studies for how the proposed therapeutic acts at its target Stand-alone preclinical efficacy studies in animal models Development of in vitro screening assays for activity or selectivity Development of small molecule therapeutics (covered by PAR-24-043 and PAR-24-063) Development of diagnostics and medical devices Development of risk, diagnostic, prognostic, predictive, and safety biomarkers Stand-alone clinical trials Studies directed beyond a first-in-human (FIH) phase 1 study (including open-label extensions, and IND-enabling nonclinical toxicology to support longer-term dosing beyond the FIH trial) Natural history clinical studies H. Milestones The awards funded under this NOFO are cooperative agreements. Clear, definitive milestones that quantitatively measure success and form the basis for go/no-go decision-making will be established in collaboration with NIH staff. Prior to funding, milestone plans will be developed by NIH staff with input from the PD/PI based on the project aims and feedback from the review process. In some cases, NIH-contracted consultants may be engaged during milestone development for additional guidance. The final agreed upon and approved milestone plan will be incorporated into the Notice of Award. Milestones may be updated as needed with input from the LDT. Note: If a funded project does not make satisfactory progress toward the agreed upon milestones at any stage during the funding period, access to BPN Biologics contract resources and future year grant funding will be discontinued (see Section VI.2). U44 Phase I to Phase II Transition An administrative review will be conducted by NIH program staff, with technical input from an External Oversight Committee (composed of senior non-federal scientists who are not directly involved in BPN Biologics projects). Recommendations on whether projects will advance from the U44 Phase I to Phase II award will be made based on: Successful achievement of U44 Phase I milestones The overall feasibility of project advancement, considering data that may not have been captured in milestones Competitive landscape for the disease indication and biotherapeutic target Program priorities Availability of funds Clinical Trial Initiation (if applicable) NIH requires the following for approval to commence a clinical trial (defined as signing of informed consent by the first prospective subject): Successful achievement of the defined nonclinical and manufacturing milestones Submission of an IND application with documentation of one of the following: Acceptance of clinical protocol by FDA Elapse of the 30-day post filing waiting period without comment from the FDA Completion of protocol changes or amendments requested by FDA Submission of the clinical protocol and supporting documents to NIH for administrative review and notification of NIH approval. This may be done in collaboration with an NIH-provided CRO. Agreement on updated timeline and milestones for the clinical trial Submission of all NIH Human Subjects documentation if not using the NIH-provided CRO I. Intellectual Property (IP) Since the ultimate goal of this program is to bring new biotherapeutics to the market, the program expects that recipient institutions will file and maintain any IP developed around the biotherapeutic during the project period. Institutions retain their rights to existing IP and are assigned rights to any new IP developed within the program. The PD/PI(s) are expected to work closely with technology transfer/business development officials at their institution to ensure that royalty 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. Recipients are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the biotherapeutic development process, consistent with the goals of the BPN Biologics. J. Quality and Compliance Requirements Since the goal of this program is to generate therapeutics that will be eligible for FDA approval, adherence to compliance and quality criteria is required. IND-enabling nonclinical studies must be performed in a manner consistent with GLP and current FDA guidance. Investigational products for use in clinical trials must be produced under cGMP practices. All clinical trials must be performed following Good Clinical Practices (GCP) and in accord with NIH Policy for Data and Safety Monitoring and FDA guidelines. K. Rigor and Transparency NIH strives for rigor and transparency in all research it funds. For this reason, this NOFO explicitly emphasizes the NIH application instructions related to rigor and transparency and provides additional guidance to the scientific community. For example, this NOFO supports applications in which the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, this NOFO will support applicants that address how the current study design addresses the deficiencies in rigor and transparency. This NOFO supports proposed experiments that are designed in a manner that minimizes the risk of bias and ensures validity of experimental results. This NOFO intends to support applications with proposed clinical trials that must be based on robust and rigorous supporting data (e.g., from nonclinical in vivo and/or in vitro studies) and that demonstrate that there is an adequate scientific foundation to justify the proposed trial. This NOFO supports trial designs that also use rigorous and transparent approaches. L. Pre-Application Consultation Applicants are strongly encouraged to consult with the relevant Scientific/Research staff from the relevant NIH Institutes/Centers (see Section VII) when planning an application. Early contact provides an opportunity for staff to provide further guidance on program scope, goals, and how applicants may best utilize BPN Biologics resources. Ideally, applicants should contact program staff at least 12 weeks before a receipt date. See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.