Investigational New Drug (IND)-enabling and Early-Stage Development of Medications to Treat Alcohol Use disorder and Alcohol-Associated Organ Damage (U43/U44 Clinical Trial Optional)

Background Currently, there are only three medications (four formulations) approved by the FDA for the treatment of alcohol use disorder (AUD). The need for additional medications to treat those affected by AUD is urgently needed.In addition,alcohol misuseaffects virtually all tissues and is linked with dysfunction and failure of many organs and systems including the liver, heart, pancreas, lung, bone, and skeletal muscle, as well as digestive, vascular, endocrine, and immune systems.There are currently no FDA-approved therapies for alcohol-associated organ damage (AAOD) so effectivetherapies to prevent and treat AAOD are urgently needed. Purpose The purpose of this Funding Opportunity Announcement (FOA) is to provide support to SBC for the optimization, development, and translation of pharmaceutical research discoveries into new treatments for disorders that fall under the mission of NIAAA.The goal is to advance small molecules, natural products or biologics for AUD and AAOD through the drug development pipeline towards FDA approval and ultimately, commercialization. Due to the urgency of this public health need, projects supporting a lead compound with a robust body of background data in the basic science and early discovery phases to be poised for transition to the preclinical and clinical phases of medications development will be prioritized. Background data may include rigorous preclinical testing, sufficient bioactivity, stability, manufacturability, bioavailability, and in vivo efficacy and/or target engagement. Applications focusing solely on basic science research such as: novel target identification/validation, generation of new animal models, development/testing of new human laboratory models, assay development, new biomarkers, or mechanistic studies of the neurobiology of AUD are not considered responsive. By the end of the funding period, projects are expected to achieve milestones that significantly move the compound towards the next phase of drug development (e.g., pre-IND meeting, Investigational New Drug (IND) application). Women-owned and socially or economically disadvantaged small business are encouraged to apply. Research Objectives This FOA seeks applications that propose to advance the following classes of therapeutics beyond pre-clinical development by preparing to seek regulatory approval for future trials: small molecules, natural products, and biologics, which broadly include peptides, proteins, oligonucleotides, gene therapies, and cell therapies. Applicants are strongly encouraged to contact NIAAA Scientific/Research staff regarding the agent under development, to determine the fit for the FOA prior to submission Examples of responsive drug development activities and corresponding SBIR Phase assignment includes but is not limited to, Pre-clinical development – SBIR Phase I (Proof of Concept Phase) Chemistry, Manufacturing, and Control (CMC) activities (e.g., master and working banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing or cGMP manufacturing) for IND-enabling pharmacology/toxicology tests Pharmacokinetic evaluations in species relevant for toxicology or human dose-prediction Preliminary safety such as safety pharmacology and/or dose-range finding toxicology Optimizing and/or validation of appropriate assays for pharmacokinetics, bioactivity (potency), target engagement markers or other assays to monitor safety to be used in human trials Drug interaction studies between medication and alcohol Further evaluation of compound safety/efficacy in established animal models, IND-enabling studies Pre-clinical development – SBIR Phase II (Research and Development) The Phase II can support more extensive IND-enabling development activities. IND-enabling toxicology, with toxicokinetics, if applicable Tumorigenicity evaluations particularly for gene therapies and cell therapies, if applicable Immunogenicity evaluations, if applicable Biodistribution studies, if applicable Large animal study to assess biocompatibility of means of clinical delivery of the candidate, if applicable Validation of appropriate assays such as for target engagement markers to enable human use IND and other regulatory submissions Clinical development – SBIR Phase I Evaluation of pharmacokinetics, preliminary safety, tolerability, alcohol interaction, dose-ranging, and/or initial efficacy in human subjects. Clinical development - SBIR Phase II For more advanced projects, a small early phase clinical trial can also be supported when feasible during the Phase II. Applications seeking to supportonlyearly-stage clinical trials with preliminary POC efficacy and safety data supported outside the SBIR/STTR program, may apply for a Direct to Phase II under this FOA. Small, early-phase clinical trials that are appropriate include: Proof-of-Concept Pilot studies Safety and Efficacy testing in a larger sample of human subjects Milestones Because therapy development is an inherently high-risk process, it is anticipated that there may be significant attrition as projects move through the therapy development process. Milestones are goals that are quantifiable for measuring success that can be used for go/no-go decision-making for the project, and should have quantitative criteria associated with them (see Section IV.2 for details). NIAAA intends to only move forward agents that are both efficacious and safe. Although the primary goals are to assess safety and toxicology, lack of evidence of a trend towards efficacy in the dose range where the candidate is safe can also be a consideration for discontinuation. U44 Phase I/II transition Applicants can submit separate Phase I (U43) or Phase II (U44) applications. However, if Phase I and Phase II are submitted together in one application (U44 Fast-Track), then an administrative review will be conducted by NIAAA Program staff to decide whether a project will be considered for transition from the Phase I to the Phase II. Phase II eligible projects must have a candidate that has been manufactured with satisfactory purity and stability, verified to have activity in vivo and/or in vitro as necessary, have bioavailability with a proper formulation, and have a good preliminary safety profile. Prior to commencement of the clinical trial (defined as first subject signature on an informed consent form), the applicant must provide the following to NIAAA for review and/or approval. Investigational Review Board (IRB) approval; IRB approved Study protocol and Informed Consent; FDA IND or IND waiver; New or revised/updated data and safety monitoring plan; Data and Safety Monitoring Board configuration and charter; Agreement with NIAAA staff on updated timeline, milestones and budget for clinical trial NIAAA approval of protocol and safety monitoring plan Quality and Compliance Requirements 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). Investigational products should be produced under current Good Manufacturing Practices (cGMP). Bioassays such as pharmacokinetics, pharmacodynamics or immunogenicity should, when possible, be performed under GLP guidelines. All clinical trials must be performed following Good Clinical Practices (GCP) and be in accord with NIAAA Policy. Intellectual Property (IP) Since the ultimate goal of the SBIR/STTR 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.2). Awardees are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the therapy development process. PDs/PIs are expected to work closely with their institutional technology transfer officials 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. For rare or ultra-rare diseases where commercialization may be challenging, applicants are encouraged to discuss alternative strategies with NIAAA Scientific/Research staff to get further guidance. Applications including the following types of studies will be considered non-responsive and will not be reviewed: Animal model development, basic research and studies of disease mechanisms, assay development Early research such as identifying and validating targets and generation of preliminary agents that are not suitable for human testing Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers. (NIAAA recognizes that target engagement markers developed under the Phase I may evolve into predictive markers for treatment trials, but it is not the intent of this FOA to develop predictive biomarkers.) Activities already performed utilizing other private or public funds to advance the agent HIV/AIDS related research studies