Advancing Validated Drug Targets for Substance Use Disorders (R43/R44 - Clinical Trial Not Allowed)

Background Substance use disorders (SUDs) affect people from all walks of life and all age groups. These illnesses are common, recurrent, and often serious, but they are treatable, and many people recover. SUDs occur when the recurrent use of drugs causes clinically significant impairment, including health problems, disability, and failure to meet major responsibilities at work, school, or home. The National Institute on Drug Abuse (NIDA) describes addiction as the most severe form of a SUD (https://www.drugabuse.gov/publications/media-guide/science-drug-use-addiction-basics). SUDs are now recognized as chronic brain diseases, with the potential for both recovery and relapse. The economic toll of SUDs is staggering and is estimated to be more than $740 billion annually. The life expectancy in the United States has declined over the past few years, due in large part to an annual increase in lives cut short by opioid overdose. According to the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER), opioid-involved overdose deaths rose from 21,088 in 2010 to 47,600 in 2017 and remained steady in 2018 with 46,802 deaths. This was followed by a significant increase in 2019 to 49,860 overdose deaths. Opioid overdoses in the US likely reached a record high in 2020 due to COVID-19 causing increased substance use, exacerbating stress and social isolation, and interfering with opioid treatment. Like other chronic brain diseases, SUDs are treatable and can be successfully managed. The treatment is cost-effective: for every $1 spent on treatments, up to $12 is saved in legal and healthcare costs. Moreover, recent cost-effectiveness studies demonstrated that the use of medications, combined with contingency management, overdose education, and naloxone distribution to treat opioid use disorder (OUD), leads to significant health benefits and cost savings compared with no treatment. Research has also shown that for most patients, the combination of medication and behavioral therapy ensures the best chance of success. There is a continuing need for broadly effective and disseminated medications for SUDs, especially for cocaine and other stimulant use disorder (STUD) and cannabis use disorder (CUD). Nicotine-based formulations, bupropion, and varenicline are approved for tobacco use disorder (TUD). Methadone and buprenorphine/naloxone are approved for the medical management of severe OUDs. The short-acting antagonist naloxone has been approved for decades, as a parenteral injection, for the acute reversal of µ-agonist overdose. In 2018, the FDA approved lofexidine; the first medication made expressly to treat signs of opioid withdrawal. There are no medications approved for the management of CUDs. There are also no medications approved for the management of cocaine or other STUDs. Current therapies for CUD and STUD focus on psychosocial approaches, including cognitive-behavioral therapies. Several studies for STUD have explored the use of sustained-release formulations of methylphenidate or amphetamine for this indication, using an 'agonist-based' approach, and the use of the opioid antagonist naltrexone. In addition, specific types of polydrug exposure (e.g., smoking/cocaine/alcohol or cocaine/heroin) are common in persons with SUDs. There are no medications approved for persons with polydrug exposure, although this group may be at special risk. Thus, there is a great need to incentivize the discovery and development of medications to treat all SUDs. This Funding Opportunity Announcement invites projects aiming to continue drug discovery efforts beyond the target validation stage. The canonical view of the drug discovery and development (DDD) process is divided into milestone-driven phases of target identification (TI), target validation (TV), assay development (AD), lead identification (LI), lead optimization (LO), preclinical development (PCD), and clinical trials. TI is the earliest stage of drug discovery and begins with identifying the function of a therapeutic target and its biological role in the disorder. The next stage, TV, requires a demonstration that a molecular target is directly linked to a disorder and that the modulation of the target has the desired effect in disorder-related model(s). With a validated target, the next stage is usually AD, with the goal of performing either a high content (HC) or high throughput screening (HTS) of a validated screening assay that represents the disease biology and physiology. The HTS will identify active new chemical entities (NCEs) that are defined as molecules that show significant biological activity. With identified NCEs, the next stage is LI, where the objective is to prioritize and rank the NCEs to identify a chemical lead. The desired characteristics of the chemical lead are defined as a synthetically feasible, stable, and drug-like molecule active in in vitro assays and in vivo models with selectivity for the target. Following successful LI, the next stage is LO, where an optimized chemical lead becomes a development candidate (DC) to allow for the DC to enter Investigational New Drug (IND) enabling Good Laboratory Practice (GLP) studies wherein Good Manufacturing Practices (GMP) supplies will be produced for clinical trials. In the PCD stage, the selected DC molecule is further evaluated to predict safety and target dose range regimens; acceptable profile data will be required as part of an IND application to initiate clinical trials. This funding opportunity announcement seeks applications from investigators who have successfully validated novel targets for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined SUDs and are ready to move beyond the TV stage. In determining the readiness of the applicants to move past the TV stage and the responsiveness to this solicitation, NIDA will use both: A) robustly demonstrated proof of target validation and B) a clearly defined Target Product Profile (TPP). The proof of target validation (A) should include the following lines of evidence (e.g., in a form of a Target Dossier): Target engagement (measurement of target binding or proximal downstream effects); Genetic variation in the target has been shown to be significantly associated with the indication; Genetic variation in a molecule functionally linked to the target has been shown to be significantly associated with the indication; Expression of the target has been demonstrated in the appropriate human tissues; Expression or dysregulation of the target correlates with disease incidence/genetic confirmation (e.g., Knock-out, siRNA, shRNA, SNP, known mutations, etc.); Modulation of the activity of the target in vitro has phenotypic/biochemical effects consistent with the proposed function of the target; Modulation of the activity of the target in vivo has phenotypic/biochemical effects consistent with the proposed function of the target and has been confirmed by either chemical antagonism or through genetic approaches (Knock-out, siRNA, shRNA, SNP, known mutations, etc.); Availability of a low-throughput target validation assay that represents the biology. The TPP (B) is a planning tool for the development of a drug candidate from discovery to clinical development programs. Routinely, the TPP is designed in a format to summarize a drug development program described in terms of concepts and characteristics which will be listed on the drug label. With the TPP, a drug developer specifies the labeling concepts that are the goals of the drug development program and documents the specific studies that are intended to support the labeling concepts, which could then be used to assist in a constructive dialogue with the FDA. TPPs are productively used in advanced translational programs at NIH, and the published examples of TPPs could be found here: https://neuroscienceblueprint.nih.gov/sites/default/files/documents/tpp-worksheet_508c.pdf. Frequently, pharmaceutical companies establish TPPs with marketing attributes integrated into the framework of the drug's labeling concepts. In this case, the tool not only guides clinical development decisions but also directs the foundation for marketing success. The TPP also contributes to the ultimate goal of driving greater efficiencies and shorter timelines to the approval of an optimally marketable and profitable product. Research Objectives Research projects can enter either at the assay development (AD), lead identification (LI), lead optimization (LO), or preclinical development (PCD) stage. Projects proposing the development of therapeutics for a DSM-5 defined SUD will be considered responsive to this RFA. Projects that focus on alcohol use disorder or pain as the primary indication will not be responsive to this RFA. Projects failing to present the evidence supporting target validation and a TPP (https://neuroscienceblueprint.nih.gov/sites/default/files/documents/tpp-worksheet_508c.pdf.) will also be considered nonresponsive to this RFA. The Principal Investigators (PIs) are strongly encouraged to assemble a team that includes expert personnel with relevant drug development/biomedical product development expertise. Project applications submitted in response to this RFA may include, but are not limited to, the following activities: For the AD stage, activities consisting of the development of a primary HTS assay, chemical library selection, secondary confirmation or counter screens, criteria defined for active NCE, and performance of HTS, along with the follow-up confirmation of multiple active compounds. For the LI stage, activities consisting of structure-activity relationship (SAR), druggability (e.g., preliminary toxicity, Human ether-a-go-go-related gene (hERG) potassium channels, Ames), synthetic feasibility, select mechanistic assays, in vitro assessment of drug resistance and efflux potential, evidence of in vivo efficacy of chemical class, and pharmacokinetics (PK) and toxicity of chemical class known based on preliminary toxicity or in silico studies. For the LO stage, activities consisting of drug candidates demonstrating acceptable in vivo PK and toxicity, feasible formulation, in vivo preclinical efficacy (e.g., sufficiently powered) studies, dose range finding (DRF) pilot toxicology, process chemistry assessment of scale-up feasibility, and regulatory and marketing assessments. For the PCD stage, activities consisting of drug candidates demonstrating acceptable PK (with a validated bioanalytical method), absorption, distribution, metabolism, excretion (ADME) studies; demonstrating in vivo efficacy/activity, acceptable safety margin (e.g., toxicity in rodents or dogs, when appropriate), feasibility of GMP manufacture, acceptable drug interaction profile, and well-developed clinical endpoints. Other research and development (R&D) activities needed to meet the requirements and expectations of the relevant regulatory agencies may also be proposed, as necessary and required for commercialization. The recently issued "FDA guidance on Opioid Use Disorder: Endpoints for Demonstrating Effectiveness of Drugs for Treatment Guidance for Industry" (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/opioid-use-disorder-endpoints-demonstrating-effectiveness-drugs-treatment-guidance-industry) is a useful resource in guiding R&D activities in SUD. For all applicants pursuing opioid use disorder (OUD) as an indication, NIDA encourages using the term "medications for opioid use disorder" (MOUD) instead of "medication-assisted treatment" (MAT) or "opioid substitution therapy" (OST)" when referring to medications prescribed for the treatment of OUD. The term MOUD appropriately frames these life-saving medications as effective, frontline treatments. In contrast, the term MAT implies that medication should have a supplemental or temporary role in treatment. The term OST reinforces the misconception that MOUD "substitutes" one drug for another instead of supporting recovery. The terminology shift to MOUD aligns with the way other psychiatric medications are understood (e.g., antidepressants, antipsychotics), as critical tools that are central to a patient's treatment plan. In all submitted materials, NIDA encourages the use of preferred language that accurately describes addiction and substance without perpetuating stigma and bias. Specifically, research shows using person-first language—such as "person with a substance use disorder"—instead of "substance abuser" can reduce negative associations and punitive attitudes among clinicians and researchers. Further, the term "substance abuse" no longer has clinical relevance, as the DSM-5 dropped that term in favor of naming specific substance use disorders and other substance-related diagnoses. In addition to using person-first language, the term "substance abuse" and its derivatives should be avoided in favor of "use," "misuse," or "use disorder(s)" where appropriate. Similarly, "abuse potential" may be replaced with "addiction liability." These small but powerful substitutions may in turn combat feelings of stigma in patients and study participants, which research shows reduces willingness to seek and accept treatment, among other negative health outcomes. For more information on preferred language in addiction care, visit NIDAMED: https://www.drugabuse.gov/nidamed-medical-health-professionals/health-professions-education/words-matter-terms-to-use-avoid-when-talking-about-addiction The SBIR/STTR program is a phased program. The main objective in SBIR/STTR Phase I is to establish the technical merit and feasibility of the proposed research and development efforts, whereas in SBIR/STTR Phase II it is to continue the R&D efforts to advance the technology toward ultimate commercialization. An overall objective of the SBIR and STTR programs is to increase private sector commercialization of innovations derived from federally supported research and development. At the conclusion of an SBIR/STTR Phase II, it is expected that the small business will fully commercialize their product or technology using non-SBIR/STTR funds (either federal or non-federal). Four types of applications are accepted in response to this FOA: Phase I. The objective of Phase I is to establish the technical merit, feasibility, and commercial potential of the proposed R/R&D efforts and to determine the quality of performance of the small business awardee organization prior to proceeding to Phase II. Phase II. The objective of Phase II is to continue the R&D efforts initiated in Phase I. Funding is based on the results achieved in Phase I (or equivalent) and the scientific and technical merit and commercial potential of the project proposed in Phase II. NIDA seeks to determine that both technical feasibility and commercial feasibility are established in Phase I before making the decision about Phase II support. Fast Track. An NIH SBIR Fast-Track incorporates a submission and review process in which both Phase I and Phase II applications are submitted and reviewed together as one application to reduce or eliminate the funding gap between phases. Fast-Track (Phase I/ Phase II) applications should include clear rationale of feasibility of the proposed approach and/ or technology application in SUD area; demonstrate a high probability of commercialization; propose clear, appropriate, meaningful and measurable goals (milestones) to be achieved prior to initiating Phase II; and indicate potential Phase III support/interest (non SBIR/STTR) from future commercialization partners. The objective of Phase II (as a part of Fast Track applications) is to continue the R&D efforts initiated in Phase I to advance technologies to potential commercialization. Projects proposed for Phase II are based on the results achieved in Phase I (or equivalent) and aim to demonstrate scientific and technical merit and commercial potential. NIDA seeks to determine that both technical feasibility and commercial feasibility are established in Phase I before making the decision about proceeding to Phase II. Direct to Phase II. For small businesses that have already demonstrated scientific and technical merit and feasibility but have not received a Phase I SBIR or STTR for that project, NIH can issue a Direct to Phase II award. The NIH Direct to Phase II will accept Phase II submissions regardless of the funding source for the proof of principle work on which the proposed Phase II research is based. Small businesses that are eligible to submit Phase II applications for projects that were supported with a Phase I SBIR or STTR award are expected to submit the regular Phase II application as a "Renewal" application based on the awarded Phase I SBIR or STTR project. Only one Phase II application may be awarded for a specific project supported by a Phase I award.