High-Throughput Screening (HTS) Platform for Discovery of Medications to Treat Alcohol Use Disorder (R41/R42 Clinical Trials Not Allowed)

Active
No
Status
Closed
Release Date
December 21st, 2023
Open Date
March 5th, 2024
Due Date(s)
April 9th, 2024
Close Date
April 10th, 2024
Topic No.
RFA-AA-24-002

Topic

High-Throughput Screening (HTS) Platform for Discovery of Medications to Treat Alcohol Use Disorder (R41/R42 Clinical Trials Not Allowed)

Agency

Department of Health and Human ServicesNational Institutes of Health

Program

Type: STTRPhase: BOTHYear: 2024

Summary

The Department of Health and Human Services, through the National Institutes of Health, is seeking proposals for the development of a High-Throughput Screening (HTS) Platform for the discovery of medications to treat Alcohol Use Disorder (AUD). The current drug development process for Central Nervous System (CNS) medications is lengthy and costly, with a high failure rate. The goal is to develop a more efficient screening model that can test multiple candidate compounds and drug combinations using new compound discovery approaches such as Connectivity Maps and artificial intelligence (AI). The HTS platform should incorporate cell- and tissue-based models, including brain cells and organoids derived from induced pluripotent stem cells, as well as small vertebrate and invertebrate model organisms like zebrafish, fruit flies, and roundworms. The platform should be sensitive to alcohol and produce measurable changes within the model. The development of AI and the use of molecular networks within the brain could lead to the identification of new candidate compounds. The Phase I activities include the development or optimization of a screening platform, incorporation of AI, testing of compounds with known clinical profiles, and specifying evaluation metrics. Phase II activities involve benchmarking the system against existing data, testing additional compounds, and validating promising compounds in animal models. The successful development of a validated HTS platform would have significant commercialization potential, benefiting pharmaceutical companies and researchers in discovering new compounds for AUD and potentially other medical and psychiatric disorders.

Description

Drug development is challenging, particularly for Central Nervous System (CNS) medications. It takes approximately 18 years to move a potential CNS medication from its initial discovery phase to the marketplace, often costing several billion dollars. The failure rate is high (only 8% of new CNS compounds entering Phase I studies will reach the market) and contributes to the high costs and slow rate of development. One way to improve the efficiency of the drug development process is to develop better screening models. Currently, a variety of animal models (i.e., rodent vertebrate and other higher order vertebrate) exist that reflect the different stages of the addiction cycle: binge-intoxication, withdrawal-negative affect, and preoccupation-anticipation. However, studies using these models can be somewhat lengthy and expensive and are generally only able to test one compound at a time. Given this current state, it is desirable to develop a HTS platform, including the use of new model cells, tissues, and organisms, to test multiple candidate compounds and drug combinations identified using new compound discovery approaches (e.g., Connectivity Maps and artificial intelligence [AI]).

Recent HTS approaches use cell- and tissue-based model systems for screening compounds. This may include brain cells and organoids derived from induced pluripotent stem cells. Advances in three-dimension (3D) technology help to visualize the complex biology of the cell and isolated tissues/organoids. In addition, recent evidence suggests that small vertebrate and invertebrate model organisms have the potential to be used as models for HTS. These include zebrafish, Drosophila (fruit flies) and the nematode C. elegans (roundworms). These models preserve the complexity and architecture of intact cells, organs, and organisms and have proven useful in studying alcohol’s mechanisms underlying withdrawal.

The most promising compounds to run through these models can be identified using powerful methodological approaches such as the Connectivity Map approach; a methodology that compares the gene expression profile of compounds with that of a particular disorder. In addition, the development of AI in exploring different molecular networks within the brain could lead to many new candidate compounds. Narrowing those choices using HTS could save time and resources and lead to a more efficient drug development process.

Purpose/Research Objectives

The purpose of this NOFO is to develop in vivo and/or in vitro HTS platforms to identify potential compounds to treat for AUD. Potential screening platform models consist of small vertebrate and invertebrate organisms such as nematode C. elegans, zebrafish, and Drosophila (fruit flies) and cell- and tissue-based models. Models consisting of rodents and other higher order vertebrates are not considered responsive to this NOFO; however human derived cell- and tissue-based models are acceptable. The HTS models must be sensitive to alcohol and produce measurable changes within the model. Compounds are then evaluated for their ability to prevent these changes caused by alcohol. One important hurdle is to validate the model, showing that its assay(s) is predictive of clinical success in humans. Validation can be accomplished by showing the relationship between the compound efficacy in human trials and the predictiveness of the platform model.

Examples of Phase I Activities:

Development of a new or optimization of an existing screening platform (i.e., cell, tissue, or organism) that has the following qualities:

Has assays that are sensitive to alcohol and produce reliable and reproducible changes within the model When applicable, incorporates AI into the prediction of alcohol-mediated changes within the model Tests at least one compound with a known clinical profile for the treatment of AUD in the platform. Compounds of choice should include at least one of the following: naltrexone, acamprosate, topiramate, gabapentin, and varenicline. Specifies the metrics that will be used to evaluate assay success Examples of Phase II Activities:

Benchmarked performance of the developed system against existing data obtained from well-established in vivo animal model(s) and clinical model(s) Tests of multiple, additional compounds with known clinical profile in prototype system Compounds of choice include naltrexone, acamprosate, topiramate, gabapentin, and varenicline. Test at least one compound that has proven efficacious in animal studies but not in clinical trials Tests of additional promising compounds identified as promising for the treatment of AUD using novel approaches (e.g., Connectivity Mapping; and NIH Library of Integrated Network-Based Cellular Signatures (LINCS)) for treatment of AUD Validate the additional promising compound in a well-established animal model to evaluate the performance of the screening platform. Commercialization Potential

A validated HTS platform would allow drug developers and researchers to quickly identify and develop compounds to treat AUD. This platform would be of considerable value to pharmaceutical companies and research scientists in discovering new compounds. This platform could also have the potential to be used in screening compounds for other medical and psychiatric disorders. This will be particularly valuable as AI is advanced, undoubtedly producing perhaps thousands of compounds to be tested for the treatment of AUD as well as other medical disorders.

Similar Opportunities

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)
Department of Health and Human Services
The Department of Health and Human Services, specifically the National Institutes of Health, is seeking proposals for the development of medications to treat Alcohol Use Disorder (AUD) and Alcohol-Associated Organ Damage (AAOD). Currently, there are only three FDA-approved medications for AUD, and there are no approved therapies for AAOD. The goal of this funding opportunity is to advance small molecules, natural products, or biologics for AUD and AAOD through the drug development pipeline towards FDA approval and commercialization. Projects should focus on lead compounds with strong background data in basic science and early discovery phases, and should aim to achieve milestones that move the compound towards the next phase of drug development. The funding period is open until December 5, 2024, and women-owned and socially or economically disadvantaged small businesses are encouraged to apply. The research objectives include advancing small molecules, natural products, and biologics through pre-clinical development, IND-enabling toxicology, and clinical development phases. The program emphasizes the importance of adherence to compliance and quality criteria, including Good Laboratory Practices (GLP) and Good Clinical Practices (GCP). Intellectual property development and retention is strongly encouraged, and applications that focus on animal model development, basic research, or activities already funded by other sources will not be considered. For more information and to apply, visit the solicitation agency URL: [link](https://grants.nih.gov/grants/guide/pa-files/PAR-22-102.html).
Harnessing Artificial Intelligence and Polypharmacology to Discover Pharmacotherapeutics for Substance Use Disorders (R43/R44 Clinical Trials Not Allowed)
Department of Health and Human Services
The Department of Health and Human Services, specifically the National Institutes of Health, is seeking proposals for the topic of "Harnessing Artificial Intelligence and Polypharmacology to Discover Pharmacotherapeutics for Substance Use Disorders (R43/R44 Clinical Trials Not Allowed)". This solicitation aims to leverage AI/ML tools to identify pharmacotherapeutic development candidates with lower toxicity and higher efficacy for the prevention or treatment of substance use disorders (SUDs). The traditional drug discovery paradigm of single-target-based approaches has limitations in addressing the complex mechanisms and polysubstance use associated with SUDs. Polypharmacology, the study of how drug molecules interact with multiple targets, is emerging as a new paradigm for drug development in multifactorial diseases like SUDs. The use of AI/ML technologies trained in polypharmacology can enhance the identification of SUD pharmacotherapeutics by evaluating and predicting the effects of binding to multiple biological targets, reducing toxicity, and informing in vitro and in vivo assays. The research objectives include identifying and validating disease targets, screening potential compounds, developing assays, synthesizing novel compounds, and conducting toxicity and efficacy studies. The Small Business Innovation Research (SBIR) program offers Phase I and Phase II funding opportunities to establish technical merit, feasibility, and commercial potential. Successful SBIR projects are expected to attract strategic partners or investors for ultimate commercialization. Phase I, Fast Track, and Direct to Phase II applications are accepted in response to this solicitation. The application due date is July 25, 2024. For more information, visit the [solicitation agency website](https://grants.nih.gov/grants/guide/rfa-files/RFA-DA-25-054.html).
Investigational New Drug (IND)-enabling and Early-Stage Development of Medications to Treat Alcohol Use disorder and Alcohol-Associated Organ Damage (UT1/UT2 Clinical Trial Optional)
Department of Health and Human Services
The Department of Health and Human Services, specifically the National Institutes of Health, is seeking proposals for the investigational new drug (IND)-enabling and early-stage development of medications to treat alcohol use disorder (AUD) and alcohol-associated organ damage (AAOD). Currently, there are only three FDA-approved medications for AUD, and there are no approved therapies for AAOD. The goal of this funding opportunity is to advance small molecules, natural products, or biologics for AUD and AAOD through the drug development pipeline towards FDA approval and commercialization. Projects should have a robust body of background data in the basic science and early discovery phases and should aim to achieve milestones that move the compound towards the next phase of drug development. The research objectives include pre-clinical development, IND-enabling toxicology, clinical development, and small early-phase clinical trials. The funding period is open until December 5, 2024, and women-owned and socially or economically disadvantaged small businesses are encouraged to apply. For more information, visit the solicitation agency URL: [link](https://grants.nih.gov/grants/guide/pa-files/PAR-22-103.html).
Developing Regulated Therapeutic and Diagnostic Solutions for Patients Affected by Opioid and/or Stimulants use Disorders (OUD/StUD) (R41/R42 Clinical Trial Optional)
Department of Health and Human Services
The Department of Health and Human Services, specifically the National Institutes of Health, is seeking proposals for the development of regulated therapeutic and diagnostic solutions for patients affected by opioid and/or stimulants use disorders (OUD/StUD). The current drug crisis surrounding OUD/StUD is a significant issue, with over 100,000 overdose deaths reported in a one-year period. The goal of this solicitation is to offer new medical products that can monitor, diagnose, and treat patients suffering from these disorders. The solicitation is open to small business companies that have developed or are developing FDA-regulated products for different indications and are interested in demonstrating their potential application in the OUD/StUD space. The research and development activities may fall into two areas: pharmacotherapeutics (small molecules and biologics) and medical therapeutic and diagnostic devices, including software as a medical device. The proposed projects should aim to address the needs of patients suffering from OUD/StUD and may include activities such as target identification, lead optimization, preclinical studies, formulation development, and clinical trials. The funding for these projects will be provided through the Small Business Innovation Research (SBIR) program, with Phase I and Phase II funding available. The application due dates are August 15, 2023, February 14, 2024, August 13, 2024, and February 14, 2025. For more information and to apply, interested parties can visit the grants.gov website or the solicitation agency URL provided.