Phase I Amount
$1,000,000
Despite the availability of a safe and effective vaccine, there remains over 257 million people chronically infected with hepatitis B virus (HBV) world-wide. Individuals with chronic HBV infections are at risk for complications due to liver disease and liver cancer. Chronic HBV is currently managed with nucleos(t)ide reverse transcriptase inhibitors (NrtI) which partly suppress HBV DNA replication, normalize alanine aminotransferase levels (ALT) and slow disease progression. Front-line therapies, however, are not curative and patients with chronic HBV exhibit poor off-treatment responses requiring life-long therapy. New antivirals and immunomodulatory approaches are, therefore, needed to further suppress viral replication and provide the conditions that are required for immune control known as a "functional cure". One of the most promising classes of compounds under investigation are the core protein allosteric modulators (CpAM) that block HBV replication at multiple stages of the viral life-cycle. Here, we report on a best-in-class CpAM that exhibits potent pan-genotypic antiviral activity. In this project, we propose to advance our lead CpAM into definitive INDenabling studies to ready the compound for Phase 1 clinical trials in healthy volunteers and chronic HBV patients. Combination regimens that include a CpAM, antivirals possessing distinct mechanisms of action and/or novel immunomodulatory agents will be evaluated in a mouse model of HBV infection in preparation for Phase 2 development in chronic HBV patienst.
Public Health Relevance Statement: RELEVANCE TO PUBLIC HEALTH Infection with hepatitis B virus (HBV) is typically self-limiting in otherwise healthy adults leading to an acute form of hepatitis. Vertical transmission or perinatal exposure during early childhood, however, results in a chronic life-long infection in the vast majority of infected individuals. Despite the presence of a safe and effective vaccine to prevent HBV infection, there are over 257 million individuals world-wide that are chronically infected. Persons living with HBV are at significant risk for complications due to liver cirrhosis and liver cancer. Although a sterilizing cure may not be possible for chronic HBV, due to the long-lived cccDNA species and relatively low turnover rate of infected hepatocytes, a shift towards complete immune control of viral replication termed a "functional cure" may be obtainable. A functional cure is an ideal endpoint for therapy and is defined as a chronically infected person that has achieved HBV DNA undetectable and has lost HBsAg expression (with or without seroconversion to anti-HBs antibodies). HBsAg loss occurs spontaneously in about 1% of patients/yr and is associated with a reduced risk of progression to cirrhosis and hepatocellular carcinoma (HCC). Several combination strategies are currently under investigation to accelerate the loss or silencing of cccDNA, as indicated by loss of HBsAg expression, including direct-acting antivirals, gene silencing of HBsAg expression and immunomodulatory therapies. Combinations of these agents are likely required to achieve a significant increase in functional cure rates for chronic HBV infection.
Project Terms: Adult; 21+ years old; Adult Human; adulthood; Alanine Transaminase; ALT1; Alanine Aminotransferase; Alanine-2-Oxoglutarate Aminotransferase; Glutamic-Alanine Transaminase; Glutamic-Pyruvate Transaminase; Glutamic-Pyruvic Transaminase; Interferon-alpha; (IFN) a; (IFN)-a; (IFN)a; Alferon; IFN Alpha; IFN a; IFN-a; IFNa; IFNa; Interferon Alfa-n3; Interferon-a; Leukocyte Interferon; Lymphoblast Interferon; Lymphoblastoid Interferon; inhibitor/antagonist; inhibitor; Antibodies; Antiviral Agents; Antiviral Drugs; Antivirals; anti-viral agents; anti-viral drugs; anti-virals; Back; Dorsum; Capsid; Cell Culture Techniques; cell culture; Cell Nucleus; Nucleus; viral DNA; virus DNA; Drug Design; Investigational Drugs; Investigational New Drugs; Exhibits; Genotype; Goals; Hepatitis; Hepatitis B; Hepatitis B Infection; Viral Hepatitis B; infection with HBV; infection with hepatitis B virus; serum hepatitis; Hepatitis B Surface Antigens; Au antigen; Australia Antigen; HBsAg; HBsAg (hepatitis B surface antigen); hepatitis associated antigen; Primary carcinoma of the liver cells; Hepatocarcinoma; Hepatocellular Carcinoma; Hepatocellular cancer; Hepatoma; Liver Cells Carcinoma; liver carcinoma; Human; Modern Man; In Vitro; Infection; Life Cycle; life course; Life Cycle Stages; hepatic body system; hepatic organ system; Liver; Hepatic Cirrhosis; Liver Cirrhosis; Hepatic Disorder; hepatic disease; hepatopathy; liver disorder; Liver diseases; Crab-Eating Macaque; Crab-Eating Monkey; Cynomolgus Monkey; Cynomolgus macaque; M fascicularis; M. fascicularis; Macaca fascicularis; Persons; Patients; Pharmacology; Common Rat Strains; Rat; Rats Mammals; Rattus; Risk; Rodentia; Rodents Mammals; Rodent; Safety; Testing; Toxicology; Vaccines; Viral Diseases; viral infection; virus infection; virus-induced disease; Virus Diseases; viral multiplication; viral replication; virus multiplication; Virus Replication; Virus; Core Protein; Investigational New Drug Application; base; Nucleocapsid; Acute; Chronic; Phase; Histologically; Histologic; Series; Hepatic Cells; Hepatic Parenchymal Cell; Liver Cells; Hepatocyte; Individual; Vertical Transmission; mother to child transmission; Vertical Disease Transmission; Disease Progression; analog; anti-viral therapy; viral infectious disease treatment; Antiviral Therapy; Toxicokinetics; Reverse Transcriptase Inhibitors; Hepatic Cancer; liver cancer; malignant liver tumor; Malignant neoplasm of liver; Life; programs; Viread; Tenofovir; Investigation; Immunes; Immune; Oral; Viral; chronic HBV infection; chronic hepatitis B virus infection; Chronic Hepatitis B; interest; experience; success; DNA Replication; DNA Synthesis; DNA biosynthesis; Gene Inactivation; transcriptional silencing; Gene Silencing; early childhood; Toxicities; Toxic effect; Structure; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; immunoregulation; novel; Reporting; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Property; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; Phase I Clinical Trials; Bioavailable; entecavir; preventing; prevent; Dose; Data; Clinical Evaluation; Clinical Testing; clinical test; research clinical testing; Perinatal Exposure; SBIR; Small Business Innovation Research; Small Business Innovation Research Grant; Characteristics; developmental; Development; cirrhotic; Cirrhosis; safety study; preclinical; pre-clinical; pre-clinical study; preclinical study; HBV Genotype; hepatitis B virus genotype; scale up; Resistance profile; Resistant profile; healthy volunteer; treatment response; response to treatment; therapeutic response; screening; Genetic study; seroconversion; Pharmacology Study; Pharmacological Study; preclinical development; pre-clinical development; Hepatitis B Virus; HBV; Homologous Serum Hepatitis Virus; phase 1 testing; phase 1 evaluation; phase I evaluation; phase I testing; first-in-human; first in man
