FAST-TRACK PHASE I and II Without treatment, chronic hepatitis B virus (HBV) infection can lead to cirrhosis of the liver, hepatocellularcarcinoma or liver failure. Current therapies effectively control the disease, but are rarely curative. The goal ofthis proposal is to develop a therapeutic providing a "functional cure" for chronic HBV infection, i.e., a therapyproducing sustained, undetectable HBV surface antigen (HBsAg) and rcDNA (a measure of virions) in serum. Afunctional cure will potentially benefit about 257 million people worldwide, including approximately 1.4 millionindividuals with chronic HBV infection in the USA. The applicant, Evrys Bio, has recently described a host-targeted vulnerability of viruses - the sirtuin family of deacylases, or SIRTs. SIRT modulators have broad-spectrum antiviral activity against multiple, diverse viruses including HBV. Of direct relevance to this proposal,Evrys has identified a SIRT2-inhibitor series with potent anti-HBV activity in cultured primary humanhepatocytes, blocking the accumulation of extracellular HBV rcDNA, HBsAg and HBeAg as well as intracellularcccDNA - antiviral effects that suggest SIRT2 inhibitors have potential to contribute to a functional cure. PhaseI of this proposal will demonstrate the feasibility of Evrys SIRT2-inhibitors to treat HBV: Specific Aim 1 willvalidate the reduction of cccDNA in infected hepatocytes. This aim will extend the results with HBV genotype Dto include HBV genotype A, generalizing the conclusion that HBV is inhibited by SIRT2 inhibitors; it will confirmthe qPCR-based conclusion that cccDNA levels are reduced by SIRT2 inhibitors by measuring cccDNA inSouthern blot analysis; and it will delineate the relative contributions of the in vitro block to accumulation versusdestabilization to the reduction of cccDNA levels by SIRT2 inhibition. Specific Aim 2 will determine a dosingstrategy for an exemplar of Evrys SIRT2-inhibitors in FRG KO huHep mice, identifying a well-tolerated dose thatcan achieve the desired anti-HBV EC95. Specific Aim 3 will demonstrate feasibility using the exemplar to treatHBV-infected FRG KO huHep mice. Phase II will develop a prototype: Specific Aim 4 will identify a developmentcandidate plus at least one backup for IND enabling studies from an existing series of nearly 600 Evrys SIRT2-inhibitors. Specific Aim 5 will probe the mechanisms by which the development candidate blocks HBVreplication in human hepatocytes to facilitate clinical translation.
Public Health Relevance Statement: Chronic hepatitis B virus (HBV) infection can lead to cirrhosis of the liver, hepatocellular carcinoma or liver
failure; current treatments control the disease but are rarely curative. The applicant has developed preliminary
data suggesting that sirtuin-2 (SIRT2) inhibitors can potentially contribute to a cure for chronic HBV. The goal
of this proposal is to advance these results to proof of principle in a mouse model of chronic HBV infection,
followed by identification of a development candidate that can be advanced to IND status and clinical studies
for treatment of chronic HBV infections.
Project Terms: inhibitor/antagonist ; inhibitor ; Surface Antigens ; Cell Surface Antigens ; Immunologic Surface Markers ; Immunological Surface Markers ; Antiviral Agents ; Antiviral Drugs ; Antivirals ; anti-viral agents ; anti-viral drugs ; anti-virals ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Southern Blotting ; DNA blotting ; southern hybridization ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Clinical Research ; Clinical Study ; Crystallization ; Cytomegalovirus ; CMV ; HCMV ; Salivary Gland Viruses ; cytomegalovirus group ; DNA ; Deoxyribonucleic Acid ; DNA Viruses ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Enzymes ; Enzyme Gene ; Family ; Genotype ; Goals ; Hepatitis B e Antigens ; HBeAg ; Hepatitis Be Antigens ; e Antigens ; Primary carcinoma of the liver cells ; Hepatocarcinoma ; Hepatocellular Carcinoma ; Hepatocellular cancer ; Hepatoma ; Liver Cells Carcinoma ; liver carcinoma ; Human ; Modern Man ; In Vitro ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Liver ; hepatic body system ; hepatic organ system ; Liver Cirrhosis ; Hepatic Cirrhosis ; Inbred BALB C Mice ; BALB C Mouse ; BALB/c ; Mus ; Mice ; Mice Mammals ; Murine ; Patients ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Proteins ; RNA Viruses ; Testing ; Translations ; Virion ; Virus Particle ; Virus Diseases ; Viral Diseases ; viral infection ; virus infection ; virus-induced disease ; Virus Replication ; viral multiplication ; viral replication ; virus multiplication ; Virus ; Measures ; Liver Failure ; Hepatic Failure ; base ; improved ; Phase ; Series ; Hepatocyte ; Hepatic Cells ; Hepatic Parenchymal Cell ; Liver Cells ; Serum ; Blood Serum ; Individual ; Therapeutic ; programs ; Clinic ; extracellular ; chronic HBV infection ; chronic hepatitis B virus infection ; Chronic Hepatitis B ; Lytotoxicity ; cytotoxicity ; success ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Structure ; Modeling ; response ; computational chemistry ; disease control ; disorder control ; Silent Mating Type Information Regulator 2-like Proteins ; Sir2-like Proteins ; Sirtuins ; Effectiveness ; Dose ; Data ; Dose-Limiting ; in vivo ; Development ; developmental ; design ; designing ; anti-hepatitis B ; HBV Genotype ; hepatitis B virus genotype ; Hepatitis B Therapy ; HBV therapy ; HBV treatment ; Hepatitis B Therapeutic ; Hepatitis B Treatment ; mouse model ; murine model ; prototype ; in vitro testing ; candidate selection ; phase 2 study ; phase II study ; Regimen ; screening ; pharmacodynamic biomarker ; pharmacodynamic marker ; small molecule therapeutics ; clinical translation ; Hepatitis B Virus ; HBV ; Homologous Serum Hepatitis Virus ;
