Alcoholic Liver Disease (ALD) is caused by excessive long term consumption of alcohol via increased oxidative stress, reduction of oxygen to liver tissue (hypoxia), altered fat metabolism, increased pro-inflammatory signaling molecules (or cytokines), and increased inflammation. ALD begins with increased fat deposit in the liver. With continued excessive alcohol consumption, disease severity increases as the inflammatory component accelerates, leading to the disease states referred to as alcoholic steatohepatitis (ASH) or alcoholic hepatitis (AH). Persistent alcohol consumption then leads to extensive liver cell death and fibrosis (scarring). Extensive fibrosis results in cirrhosis and ultimately liver failure necessitating liver transplantation. It is estimated that more than 2 million people in the U.S. have ALD and in 2006, chronic liver disease with cirrhosis was the 12th leading cause of death in the U.S. with ~46% of deaths directly related to alcohol (National Vital Statistics Reports, 2007). The overall cost of health care expenditures associated with alcohol consumption was estimated at $26 billion in 1998 in the U.S. (NIAAA website). Cardax Pharmaceuticals, Inc. (Cardax) is developing a novel, proprietary, orally bioavailable small molecule, Heptax, which exhibits robust anti-inflammatory, anti-oxidant activity in relevant animal models of ALD. The compound accumulates in cellular membranes including those of liver mitochondria where much of the pro-inflammatory oxidative stress occurs. Animal studies with oral Heptax as well as human exposure through diet or dietary supplements of the active metabolite have demonstrated an unusually benign safety profile. The goal of this Fast Track Phase I/II SBIR grant is to advance the preclinical development and understanding of Heptax for the treatment of Alcoholic Liver Disease (ALD). Specifically, the grant proposes: 1) 7 day and 4 week toxicity studies of Heptax; 2) expanding the understanding of Heptax in various animal models of liver disease; and 3) pilot plant production (including process development) of the kilogram quantities of Heptax necessary for these studies. The 4 week toxicity study reports would be suitable for inclusion as part of an Investigational New Drug (IND) application to the FDA to begin human clinical trials. Company personnel are highly qualified to supervise and coordinate this activity. Cardax also has significant in-house bioanalytical capability and will transfer its proprietary bioanalytical methods to the independent contract laboratories that will perform the bioanalysis required by the FDA. Cardax will provide oversight and validation. The additional animal efficacy work will be undertaken in collaboration with experienced investigators with Cardax personnel supplying oversight, co-design, and review capabilities.
Public Health Relevance: Alcoholic Liver Disease affects more than 2,000,000 people in the U.S., resulting in significant illness and death with minority groups disproportionately affected. Current treatments are expensive, can have significant side effects, and are only marginally effective. A safer, more efficacious, and economical therapy for this disease would represent a major medical breakthrough for this under-served population.
Public Health Relevance Statement: Project Narrative Alcoholic Liver Disease affects more than 2,000,000 people in the U.S., resulting in significant illness and death with minority groups disproportionately affected. Current treatments are expensive, can have significant side effects, and are only marginally effective. A safer, more efficacious, and economical therapy for this disease would represent a major medical breakthrough for this under-served population.
NIH Spending Category: Alcoholism; Chronic Liver Disease and Cirrhosis; Digestive Diseases; Hepatitis; Liver Disease; Nutrition; Substance Abuse
Project Terms: Absolute ethanol; Adverse effects; Affect; Alcohol Drinking; Alcohol consumption; Alcohol, Ethyl; Alcoholic; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animal Model; Animal Models and Related Studies; Animals; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; Antioxidants; Benign; Bioavailable; Blood Plasma; Body Tissues; Boozer; Cause of Death; Cell Death; Cellular Membrane; Cessation of life; Chemical Class, Alcohol; Chronic; Cicatrix; Cirrhosis; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Contracting Opportunities; Contracts; Cyclic GMP; Death; Dependent drinker; Deposit; Deposition; Detection; Development; Diet; Diet Supplement; Dietary Supplements; Disease; Disorder; Dose; Drug Formulations; Drugs, Investigational; ETOH; EtOH drinking; Ethanol; Ethanol-induced hepatitis; Ethnic and Racial Minorities; Evaluation; Exhibits; Fats; Fatty acid glycerol esters; Fibrosis; Formulation; Formulations, Drug; Goals; Government; Grafting, Liver; Grain Alcohol; Grant; Guanosine Cyclic 3',5'-Monophosphate; Guanosine Cyclic Monophosphate; Guanosine, cyclic 3',5'-(hydrogen phosphate); Hand; Health Expenditures; Heavy Drinking; Hepatic Cells; Hepatic Disorder; Hepatic Failure; Hepatic Parenchymal Cell; Hepatic mitochondria; Hepatitis, Alcoholic; Hepatocyte; Housing; Human; Human Resources; Human, General; Hypoxia; Hypoxic; INFLM; Inflammation; Inflammatory; Infusion; Infusion procedures; Injury; Investigational Drugs; Investigational New Drug Application; Investigational New Drugs; Investigators; Kilogram; Laboratories; Left; Liver; Liver Cells; Liver Failure; Liver Mitochondria; Liver Transplant; Liver diseases; Mammals, Rodents; Man (Taxonomy); Man, Modern; Manpower; Measurement; Medical; Metabolism, Lipids/Lipoproteins/Membrane Constituents; Methods; Methylcarbinol; Minority Groups; Mitochondria, Liver; Modeling; NIAAA; National Institute on Alcohol Abuse and Alcoholism; Nutritional Supplement; O element; O2 element; Oral; Oxidative Stress; Oxygen; Oxygen Deficiency; Pathology; Persons; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Plants; Plants, General; Plasma; Process; Production; Qualifying; Reporting; Research; Research Personnel; Researchers; Reticuloendothelial System, Serum, Plasma; Rodent; Rodentia; Rodentias; Role; Route; SBIR; SBIRS (R43/44); Safety; Scars; Serum, Plasma; Severity of illness; Signaling Molecule; Small Business Innovation Research; Small Business Innovation Research Grant; Steatohepatitis; Tissues; Toxic effect; Toxicities; Transplantation of liver; Transplantation, Hepatic; Treatment Side Effects; Underserved Population; Validation; Vital Statistics; Work; alcohol induced hepatic injury; alcohol induced liver disorder; alcohol induced liver injury; alcohol ingestion; alcohol intake; alcohol product use; alcohol use; alcohol-induced hepatic dysfunction; alcohol-induced liver disease; alcohol-induced liver dysfunction; alcohol-mediated liver dysfunction; alcohol-mediated liver injury; alcoholic beverage consumption; alcoholic drink intake; analytical method; animal efficacy; anti-oxidant; attenuation; body system, hepatic; cGMP; cGMP production; clinical investigation; cost; cytokine; design; designing; disease severity; disease/disorder; drink heavily; ethanol consumption; ethanol drinking; ethanol induced hepatic injury; ethanol induced liver disorder; ethanol induced liver injury; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; ethanol-induced hepatic dysfunction; ethanol-induced liver disease; ethanol-induced liver dysfunction; ethanol-mediated liver dysfunction; ethanol-mediated liver injury; etoh use; excess alcohol consumption; excess alcohol ingestion; excess ethanol ingestion; excessive alcohol consumption; excessive alcohol ingestion; excessive alcohol intake; excessive drinking; excessive ethanol ingestion; experience; exposed human population; extreme drinking; fat metabolism; guanosine 3'5' monophosphate; health care expenditure; heavy alcohol use; hepatopathy; human exposure; lipid metabolism; liver disorder; liver transplantation; method development; model organism; mouse model; necrocytosis; novel; organ system, hepatic; personnel; pre-clinical; preclinical; problem drinker; process optimization; public health relevance; side effect; small molecule; social role; therapy adverse effect; treatment adverse effect; under served population; underserved people; web site
