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Development of Novel Compounds to Treat Alcohol Use Disorder

Background
Efforts to develop medications for the treatment of alcohol use disorder have expanded rapidly in recent years. Developing novel compounds for alcohol treatment is high priority for NIAAA Medications Development Program. Three agents directed at the addictive behavior in the use of alcohol ?disulfiram, naltrexone, and acamprosate?are now approved for use in the United States and many other countries. Still, these medications do not work for everyone. Because of this, further research is needed to develop additional medications to treat Alcohol Use Disorder and organ damage caused by alcohol consumption.
During the past decade, many new targets in the brain and liver have evolved that alter alcohol-seeking and drinking behavior. Brain effects and behavior may be influenced by agents directed at CRF, adrenergic, opioid kappa, vasopressin V1b, NK1, orexin, NPY, NOP, glutamate mGluR2/3, mGluR5, GABAa _-1 and _-5 receptors. Several intracellular targets in additional (peripheral) organs have also been identified that alter outcomes of chronic alcohol use, including ALDH-2; PKC; PPARg; epigenetic modulators, (HDAC inhibitors, methylases, demethylases, and microRNAs); rapamycin complex 1; and GDNF. Tissue damage induced by the influence of alcohol or acetaldehyde on any of the above have serious negative consequences including development of steatohepatitis, cirrhosis or hepatocellular carcinoma.  Agents affecting these, and any other validated targets, may be synthetically derived or developed from plant materials.
Summary
This solicitation seeks to support the preliminary work required for the development of novel compounds to interact with recently identified targets to alter alcohol-seeking, drinking behavior and/or organ tissue damage caused by excessive alcohol consumption. 
Project Goals
The goal of this solicitation is to provide support for the development of novel therapeutic agents to treat alcohol use disorder and tissue damage caused by excessive alcohol consumption. 
Phase 1 Activities
If compounds have not yet been identified, activities include conducting high-throughput screening of libraries for novel compounds for further development. For identified candidate compounds, conducting preclinical animal studies to demonstrate proof of concept and safety; drug formulation and pharmacokinetic testing; drug optimizations and GMP manufacturing; IND-directed animal toxicology.
Phase 1 Expected Deliverables
?       Conduct animal toxicology and pharmacology studies as appropriate for the agent(s) selected.
?       Develop a detailed plan for future regulatory activities.
 
Phase II Activities and Expected Deliverables
?       Complete IND-enabling experiments and assessments according to the plan developed in Phase I (e.g., demonstration of desired function and favorable biochemical and biophysical properties, PK/PD studies, safety assessment, preclinical efficacy, GMP manufacturing, and commercial assessment). The plan should be re-evaluated and refined as appropriate.
?       Develop and execute an appropriate regulatory strategy. If warranted, provide sufficient data to file an IND or an exploratory IND for the candidate therapeutic agents (i.e., oncologic indications for CSCs).
?       Demonstrate the ability to produce a sufficient amount of clinical grade material suitable for an early clinical trial.
National Institute of Allergy and Infectious Diseases (NIAID)
 
The National Institute of Allergy and Infectious Diseases (NIAID) conducts and supports basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases. For more than 60 years, NIAID research has led to new therapies, vaccines, diagnostic tests, and other technologies that have improved the health of millions of people in the United States and around the world. To learn more about the NIAID, please visit our web page at https://www.niaid.nih.gov/about/whoWeAre/Pages/moreWhoWeAre.aspx. 

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