Notice Number: NOT-AA-14-008

Key Dates
Release Date: April 24, 2014

Issued by
National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Purpose

The purpose of this Notice is to clarify that the scope of the funding opportunity announcements (FOA) PA-13-160, as described in the announcement, remains unchanged, but the section on “Medications Development for the Treatment of Alcohol Use disorders and Alcohol-Induced Tissue Damage” is replaced as follows:

Part 2. Section I. Funding Opportunity Description

1. Medications Development for the Treatment of Alcohol Use Disorders and Alcohol-Induced Tissue Damage
Efforts to develop medications for alcohol use disorders have expanded rapidly in recent years. Three agents disulfiram, naltrexone, and acamprosate are now approved for use in the United States and many other countries. However, because of the heterogeneous nature of alcohol use disorders, many patients have limited or no response to these medications. Therefore, developing new medications and evaluating their use in combination with other medications and with behavioral therapies are important steps toward improving treatment outcomes for all individuals with alcohol use disorders. Applications that propose standard efficacy trials of widely-studied and well-characterized medications such as naltrexone, topiramate, acamprosate, varenicline, ondansetron, gabapentin, baclofen, and disufiram in alcohol dependent subjects will not be considered. The collection of genetic samples and the use of biomarkers, particularly the ethanol metabolites ethyl glucuronide and phosphatidylethanol to verify drinking, are encouraged.

Alcohol-seeking behavior and drinking are influenced by multiple neurotransmitters, neuromodulators, hormones, and intracellular networks. Thus, there are many potential targets for drug development. Research to date has focused on opioid, serotonin, dopamine, glutamate, and gamma-aminobutyric acid (GABA); cannabinoids, corticotrophin-releasing factor (CRF), nicotine, adenosine, and neuropeptide systems (e.g., neuropeptide Y); signal transduction pathways (e.g., protein kinase A and protein kinase C); gene transcription factors (e.g., delta fos B and cAMP response element-binding protein [CREB]), DNA methylatioin, histone deacetylase; non-protein coding RNAs; and neuroimmune modulators. Efforts to define different elements of addiction include positive reinforcement (reward), negative reinforcement (anhedonia,stress), craving, explicit cognition/decision making, habituation, and impaired inhibitory control. It is important to identify the neurocircuits underlying these elements and investigate their interactions and integration. The ultimate goal is to target specific sites in these neurocircuits and develop and test novel compounds that modulate them.

Advances also have been made in understanding the mechanisms of alcohol-induced tissue damage. Oxidative stress and inflammation play a major role in the pathogenesis of alcohol-associated injuries of various organs, including the liver, pancreas, heart, lungs, brain, and peripheral nervous system. Potential therapeutic agents include those that attenuate the actions of pro-inflammatory cytokines (e.g., the tumor necrosis factor (TNF)-a), and antioxidants (e.g., S-adenosyl-L-methionine (SAMe), glutathione, and vitamins A and E). Other potential new treatments of alcoholic liver disease include cannabinoid CB1 antagonists and CB2 agonists, metformin (an insulin-sensitizing agent), antifibrotic agents, prebiotics, probiotics, and zinc.

Finally, to improve safety, efficacy, and efficiency of medications, it is important to identify and characterize patients who respond positively to the medications and those who experience adverse events.

Specific areas of research include, but are not limited to, the following examples:

• Discover, develop, and test new, more effective agents to prevent or reduce drinking.
• Discover and develop medications to reduce smoking in alcohol-abusing individuals.
• Discover and develop novel medications to treat alcohol-induced organ damage by attenuating or reversing the tissue damage. Identifying new targets for drug development based on mechanisms underlying the alcohol-induced damage is encouraged.
• Advance personalized medicine by employing approaches of pharmacogenetics, sophisticated modeling of human characteristics, brain imaging and physiological and biochemical markers.
• Evaluate combinations of medications to increase efficacy with minimal side effects.
• Identify barriers to and facilitate integration of pharmacotherapy into alcoholism treatment (e.g., in specialty addition, primary care, and mental health care settings); develop strategies to offset obstacles and promote facilitators.
• Develop quantitative biochemical markers and alcohol-sensing devices to measure alcohol consumption for pharmacotherapy trials.
• Characterize the placebo effect and develop strategies to minimize its impact in clinical trials.
• Develop human laboratory models to screen for promising novel medications. Outcome measures should be predictive of successful Phase 2 and 3 clinical trials.

All other aspects of this FOA remain unchanged.

Inquiries

Please direct all inquiries to:

Daniel E. Falk, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-0788
Email: [email protected]