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. These activities are largely the domain of large pharmaceutical and biotechnology companies and contract research organizations, and all of the necessary expertise and resources are not commonly available to small companies.
To facilitate drug discovery and development by the neuroscience community, the NIH Blueprint for Neuroscience Research (http://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 and the opportunity to collaborate with NIH-funded consultants and contract research organizations (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 http://neuroscienceblueprint.nih.gov/bpdrugs/bpn.htm.
This Funding Opportunity Announcement (FOA) invites applications for new BPN projects. Applicants may propose to conduct all drug discovery and development activities themselves or collaborate with BPN contractors on activities of their choice. For example, a Program Director/Principal Investigator (PD/PI) with medicinal chemistry expertise and resources may request funding to conduct structure-activity relationship (SAR) studies in his or her own lab but collaborate with BPN contractors on drug manufacturing and IND-enabling toxicology studies. By contrast, a PD/PI with limited experience in drug discovery and development may opt to collaborate with all available BPN contractors.
For each project funded under this FOA, the NIH will assemble a customized Lead Development Team (LDT). The LDT typically will be co-chaired by the PD/PI and a BPN consultant and will include members of the PD/PI's team, additional BPN consultants, and NIH staff. The LDT will establish an overall strategy for the project, including milestones, plan studies to be conducted by BPN contractors, and coordinate activities across different research sites.
Potential applicants are strongly encouraged to read Frequently Asked Questions (FAQs) on the BPN website (http://neuroscienceblueprint.nih.gov/bpdrugs/faqs.htm) and contact NIH Scientific/Research staff prior to preparing an application to discuss how they may best utilize BPN resources. For this funding opportunity announcement, 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.
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. Applicants should contact NIH Scientific/Research staff regarding small peptides and other complex chemical structures, as well as combination therapies, to determine suitability for optimization and development within the BPN.
Projects should 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 of the participating Institutes and Centers and alternative programs to consider.
Projects can enter the BPN either at the Discovery stage, to optimize well-validated hit compounds through medicinal chemistry, or at the Development stage, to advance development candidates through Investigational New Drug (IND)-enabling toxicology studies and Phase I clinical testing. Applications that propose entry at the Discovery stage can include Development work as well.
Past experience with BPN suggests that many otherwise excellent awarded projects often require additional proof of concept data or the generation of tools in the first year 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 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, which will be funded by the U44 Phase II award. 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. A schematic of this project structure is available on the BPN website at http://neuroscienceblueprint.nih.gov/resources/projectSchematic.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/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.
Projects that require medicinal chemistry to improve the potency and 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. 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 selection of a development candidate with sufficient bioactivity and drug-like properties to proceed to IND-directed pre-clinical safety assessment with reasonable projected human doses.
It is anticipated that most projects that enter BPN will begin at the Discovery stage.
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)
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 < 1µM in biochemical assays and <10µM in cell-based assays relevant to the drug target), confirmed by repeat dose-response testing, with more than one batch of compound
- Selectivity for the intended target over closely related targets, if desired (and when the target is known)
- Availability of primary and secondary in vitro bioactivity assays that can be used or optimized for driving SAR studies
- Availability of preclinical animal model(s) that can be used to assess in vivo efficacy or target engagement (measurement of target binding or proximal downstream effects).
- Availability of selectivity and counter-screening assays to address potential activity at related targets and other undesirable activities or artifacts
- No obvious legal (e.g., intellectual property) constraints to pursuing the proposed chemical scaffold(s) and using the proposed assays and models for research purposes and/or commercial development
Feasibility Studies for Discovery Stage (U44 Phase I)
All Discovery projects will begin with a U44 Phase I award of up to one year to prepare for SAR studies, which will be supported under the U44 Phase II award. The following are general expectations for a BPN project to initiate SAR studies:
- Completion of an in vitro ADME and physicochemical profile for the starting compound that includes measures of aqueous solubility, microsome stability, CYP inhibition, and permeability (e.g., MDCK or Caco-2)
Demonstration that the primary assay meets the following validation criteria to reliably rank compounds with similar activities:
- A statistical demonstration of reliability, e.g., a Z’ score ≥0.5 and a coefficient of variation (CV) ≤20%
- Concentration response testing over at least 10 concentrations generates reproducible EC50 values within a 3-fold range for at least 4 compounds
- Blinded test-retest reliability with r2 of at least 0.75 on at least 8 compounds exhibiting EC50 values across a 100-fold range of potencies
- Throughput of at least 10 compounds per week, run with sufficient replicates to produce robust and reproducible 10-point dose-response curves
- Demonstration that the proposed secondary bioactivity assays and counter-screening and selectivity assays have sufficient reliability and throughput for their proposed use in the project
- Demonstration of a clear correlation between activity in the primary assay and activity in confirmatory assays and models, sufficient to justify advancement criteria in a testing funnel
Examples of activities that can be supported during the Discovery preparatory phase include:
- Establishment of a project milestone plan, including milestones that must be met to initiate SAR studies and desired compound profiles at completion of lead optimization
- Establishment of a compound testing funnel, including studies to correlate activity across different bioactivity assays to justify advancement criteria
- In vivo pharmacology studies to demonstrate target engagement
- Studies to develop or validate target engagement markers that will be used in critical-path experiments
- Optimization and validation of bioactivity, selectivity, and counter-screening assays
- Critical-path pharmacology studies to clarify the compound mechanism of action (e.g., agonist vs. positive allosteric modulator)
- ADMET profiling of starting compound(s) to identify liabilities to address through medicinal chemistry
The PD(s)/PI(s) will be responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools. Applicants may propose to use BPN contractors for chemical synthesis and ADMET profiling or request funds to conduct this work themselves.
Discovery Activities after Feasibility Phase (U44 Phase II)
The BPN typically supports up to two years of medicinal chemistry. By the end of the first year, the PD/PI is expected to demonstrate in vivo activity for a representative compound from the lead series, delivered by any route of administration. By the end of the second year of chemistry, the PD/PI should identify a development candidate that meets the entry criteria for Development (below).
The Discovery U44 Phase II award typically supports the following activities:
- Procurement of commercially available analogs ("SAR by catalog")
- Design and synthesis of analogs for SAR studies
- Compound scale up for in vivo testing
- Testing of analogs in bioactivity assays and animal models
- Testing of analogs in selectivity and counter-screening assays
- Testing of analogs in ADMET assays (e.g., microsome stability, CYP induction and inhibition, solubility, permeability in MDCK or Caco-2 cells, plasma protein binding, brain/plasma ratio, pharmacokinetics [PK] in multiple species)
The PD/PI will be responsible for conducting primary in vitro biological assessment of compounds on a one-to-two week schedule to inform the design of subsequent iterations of compound synthesis. In addition to a regular testing schedule in the primary assay, the PD/PI will provide confirmation of the activity of select compounds in secondary and counter-screening assays and animal models relevant to the drug target and therapeutic indication.
BPN contractors can produce compound analogs for SAR testing, scale up compounds as needed for in vivo testing, and provide standard screening services to assess in vitro and in vivo ADMET characteristics of the compounds. Typically, BPN will assign four medicinal chemist FTEs to a project, generating approximately 4-8 compounds per week, plus additional staff to support computational chemistry modeling and ADMET studies as appropriate.
Compounds that meet the BPN's criteria for a development candidate can continue on into Development.
The Development stage includes IND-directed preclinical safety studies, GMP synthesis of clinical trial material, formulation development, and phase I clinical testing. Projects that have completed medicinal chemistry optimization and identified a development candidate may initiate Development activities within BPN. The BPN does not support SAR studies during Development.
Entry Criteria for Development Stage
Projects must meet the following requirements prior to entering Development:
- A strong package of data linking the putative drug target/affected pathway to the proposed disease indication and supporting the hypothesis that altering the target activity as proposed will produce desirable outcomes for the disease.
Proposed compounds must have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use (i.e., the disease indication, patient population, delivery mode, treatment duration, and treatment regimen) and outcomes.
- Applicants should show that their proposed compounds are efficacious when delivered by the clinically intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.
- Proposed compounds should give defensible results in tests for Ames mutagenicity, hERG activity, microsome stability, CYP inhibition, plasma protein binding, and aqueous solubility.
- In cases where the molecular target of compound action is known, the applicant should demonstrate the degree of selectivity for the intended target over closely related targets.
- Counter-screening to determine selectivity across a broad panel of unrelated pharmacological targets (e.g., G protein-coupled receptors, kinases, etc.) is also required.
- Demonstration that the ability of the PD/PI's institution to develop and commercialize the proposed compound(s) is unlikely to be blocked or impeded by legal (e.g., intellectual property) constraints.
Feasibility Studies for Development (U44 Phase I)
All projects entering at the Development stage will begin with a U44 Phase I award of up to one year, to prepare for IND-enabling studies, which will be supported under the U44 Phase II award. (Projects that began in Discovery will conduct these activities during their U44 Phase II award.) The following are general expectations for a project to initiate IND-enabling studies within BPN:
- Dose-range finding toxicology studies show an acceptable safety margin (e.g., 5x if toxicity can be monitored, reversible, and has premonitory signs; 10x if toxicity is more severe but controllable/reversible; 30x if toxicity is unlikely to be easily monitored, controllable, reversible, or have premonitory signs)
- Viable synthetic route for manufacturing (acceptable cost, number of steps and purification techniques needed)
- Viable API (active pharmaceutical ingredient; salt and polymorph selection complete, acceptable stability to support initial clinical trial)
Examples of activities that can be supported during the Development preparatory phase include:
- Establishment of a preclinical development plan, including milestones for advancement into IND-enabling studies and the desired profile for a development candidate
- Design and planning for the first-in-human clinical trial (if applicable)
- Validation of ADMET data
- Replication/confirmation of key in vivo pharmacology data
- Scale-up synthesis
- Salt and polymorph screening
- Compound stability studies
- Pre-formulation studies
- Multiple-dose rodent PK testing, with pharmacodynamic (PD) correlations if applicable
- Dose-range finding toxicology
- Metabolite identification
The PD(s)/PI(s) is responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools. BPN contractors can perform all other work.
Development Activities after Feasibility Phase (U44 Phase II)
The Development U44 Phase II award may include the following:
- GMP manufacturing of material for phase I clinical testing
- IND-enabling toxicology studies
- IND document preparation
- Phase I clinical trial (a single and/or multiple ascending dose study to characterize safety, PK, and PD)
The PD(s)/PI(s) will be responsible for the submission of the IND application and scheduling meetings with the FDA. NIH staff and consultants on the LDT must be included in all meetings with the FDA.
The development of the protocol and management of the phase I clinical trial will be performed by a Clinical Development Team (CDT), which will evolve from the LDT and include the PD/PI, clinical consultants identified by the PD/PI and NIH, and NIH staff. The protocol, selected supporting trial documents, and regulatory documents will be submitted to NIH for administrative review prior to commencement of the clinical trial (defined as signing of first informed consent).
BPN contractors can conduct the preclinical safety studies, GMP synthesis, formulation and other activities required to prepare for human testing. BPN contractors will provide data and reports in a format suitable for inclusion in an IND application and will assist in the development of the application. The phase I clinical trial can also be conducted through BPN contractors.
Projects Not Appropriate for this Announcement include:
- Screening to identify hit compounds
- Basic research and studies of disease mechanism
- Animal model development
- Development of risk, detection, diagnostic, prognostic, predictive, and prevention biomarkers
- Development of diagnostics and diagnostic devices
- Development of biologics and biotechnology products
- Studies directed beyond phase I clinical testing
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Without a specific “receptor”, alcohol has numerous molecular targets in the brain, and alcohol-seeking behavior and alcoholism are influenced by multiple neurotransmitter systems, neuromodulators, hormones, and signal transduction pathways. Many potential target sites for which new pharmaceuticals may be developed have, therefore, been identified. These include neurotransmitter systems related to opioids, serotonin, dopamine, glutamate, γ-aminobutyric acid (GABA), endocannabinoids, the hypothalamic-pituitary-adrenal (HPA) axis, adenosine, neuropeptide systems (for example, neuropeptide Y, corticotropin releasing factor), signal transduction pathways (such as, protein kinase A and protein kinase C); and gene transcription factors (delta fos B and cAMP response element-binding protein [CREB]). NIAAA is interested in research aimed to develop pharmaceuticals targeting new molecular sites to provide effective therapy to a broader spectrum of alcoholic individuals. Research has discovered specific genetic variants that may contribute to the risk for alcoholism and/or render alcohol dependent individuals responsive to specific therapeutic agent. NIAAA is interested in supporting research to develop pharmaceuticals targeting individuals with identified genotypic and phenotypic characteristics to improve efficacy and safety.
National Institute of Dental and Craniofacial Research (NIDCR)
NIDCR is interested in neurotherapeutics development for chronic painful disorders of the orofacial region including temporomandibular joint disorder, burning mouth syndrome, and other conditions. Recent advances in genomics and phenotyping of subjects with chronic pain conditions have expanded the scope of potential targets to treat these conditions. New receptor systems, ion channels, and pro- and anti-inflammatory molecules have been implicated in chronic pain. NIDCR is interested in supporting research that will lead to highly efficacious and specific pharmacological treatments of subjects with chronic orofacial pain disorders.
Investigators are encouraged to contact NIDCR Scientific/Research/Research staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.
National Institute of Mental Health (NIMH)
The NIMH is interested in applications proposing development of therapies aimed at novel molecular and clinical targets for the treatment of mental disorders, especially treatment-resistant depression, bipolar disorder, schizophrenia, PTSD, and autism spectrum disorder (see From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses). Studies aimed at the development of new ligands for targets where a high-quality probe or therapeutic already exists are generally of lower priority.
Investigators are strongly encouraged to discuss their research plans with NIMH Scientific/Research staff prior to submission to determine alignment of the planned studies with NIMH priorities and to assess whether this or other NIMH funding opportunities are most appropriate. Please see the NIH/NIMH Therapeutics Discovery web page for links to NIMH drug discovery FOAs: Drug Discovery for Nervous System Disorders PAR-13-048, National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-13-086 (U19) and PAR-13-087 (UM1).
NIMH is particularly interested in the development and testing of novel interventions that target operationally defined, biologically linked functional domains whose disruption is hypothesized to drive functional deficits in mental disorders. For example, NIMH Research Domain Criteria (RDoC, http://www.nimh.nih.gov/research-priorities/rdoc/nimh-research-domain-criteria-rdoc.shtml) constructs may inform mechanism-based hypotheses and the selection of interventions, outcome measures and clinical subjects. Intervention targets related to RDoC constructs are of interest for this FOA, but other, biologically relevant targets may be suitable as well, especially if they maximize the probability that subjects share the same mechanism of disorder.
Rigor of Data: Translating discoveries into evidence-based treatments is predicated on the existence of strong, well powered, adequately controlled, and replicated preclinical data. In addition, the value of such research is greatly enhanced when detailed information is made available about study design, execution, analysis and interpretation. Examples of critical elements for a well-designed study are summarized on the NIMH website (http://www.nimh.nih.gov/research-priorities/policies/enhancing-the-reliability-of-nimh-supported-research-through-rigorous-study-design-and-reporting.shtml). Please also see http://grants.nih.gov/grants/guide/notice-files/NOT-MH-14-004.html .
National Institute of Neurological Disorders and Stroke (NINDS)
A list of diseases that is relevant to the research mission of the NINDS can be found at http://www.ninds.nih.gov/disorders/disorder_index.htm; applicants are encouraged to contact NINDS Scientific/Research staff to discuss disease areas of interest.
This FOA serves as the primary support mechanism at NINDS for the discovery and development of small molecule drugs. Researchers focused on the development of biologics and biotechnology products should consider the CREATE-Bio program (http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-FAQ.htm). Applicants seeking support only to conduct early stage clinical trials should consider applying for an NINDS Exploratory Clinical Trials R01, through PAR-13-281, which provides additional flexibility in budget and time, as well as the option of including a phase II trial.
There is growing recognition that the quality and reproducibility of both preclinical and clinical research depend on the rigor with which researchers conduct studies, control for potential bias, and report essential methodological details. Examples of critical elements of a well-designed study are summarized on the NINDS website http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf. NINDS urges applicants to this program to consider these elements when describing supporting data and proposed studies.
National Center for Complementary and Alternative Medicine (NCCAM)
NACCAM is interested in supporting research aimed at naturally occurring compounds (e.g., cannabinoids, venoms, conotoxins) that may be used or developed to modulate CNS-based symptoms with priority given to pain and pain related symptoms. Investigators are strongly encouraged to discuss their research plans with NCCAM Scientific/Research staff prior to submitting their application.
Because drug discovery and development are inherently high risk, it is expected that there will be significant attrition as projects progress. Go/No-Go milestones (typically every six months) will be established by the LDT at the start of each project and updated as needed.
An administrative review will be conducted by NIH Program staff, with technical input from an Independent Experts Committee (composed of senior non-federal scientists who are not directly involved in BPN projects) who will provide advice about milestones achievements and technical strengths and weaknesses. Advancement from the U44 Phase I to the Phase II award and the progression after each subsequent milestone will be based on:
- Successful achievement of milestones
- The overall feasibility of project advancement, considering data that may not have been captured in milestones
- Competitive landscape for the disease indication and drug target
- Program priorities
- Availability of funds
Approval for commencement of a clinical trial (defined as signing of informed consent by first prospective subject) will include the following:
- Successful achievement of the defined preclinical development milestones;
- Submission of an IND with documentation for one of the following: 1) acceptance of clinical protocol by FDA; 2) elapse of the 30 day post filing waiting period without comment from the FDA; 3) 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;
- Agreement on updated timeline and milestones for the clinical trial.
PLEASE NOTE: If a funded project does not make sufficient progress toward the agreed upon milestones at any stage, funding for the project and access to BPN contract resources may be discontinued (see section VI.2).
Since the goal of this program is to generate therapeutics which will be eligible for FDA approval, adherence to compliance and quality criteria is required.
- It is expected that all IND enabling nonclinical studies will be performed in a manner consistent with Good Laboratory Practices (GLP).
- All clinical trials must be performed following Good Clinical Practices (GCP) and in accord with NIH Policy for Data and Safety Monitoring (http://grants.nih.gov/grants/guide/notice-files/not98-084.html; http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Investigational products should be produced under current Good Manufacturing Practice (cGMP) practices.
Since the ultimate goal of this program is to bring new drugs to the market, the creation and protection of intellectual property (IP) that will make drug candidates attractive to potential licensing commercialization partners are significant considerations in designing research strategies and prioritizing projects for funding. This program is structured so that the small business concern can gain assignment of IP rights (and thereby control the patent prosecution and licensing negotiations) for drug candidates developed through the BPN. It is expected that the small business concern will take responsibility for patent filings and licensing toward eventual commercialization. The PI is expected to work closely with technology transfer officials at his or her 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. Award recipients will be encouraged to identify and foster relationships with potential licensing and commercialization partners early in the drug development process, consistent with the goals of the BPN.