Development of a host-targeted antiviral as a chronic hepatitis B therapeutic with potential to achieve a functional cure

开发一种针对宿主的抗病毒药物作为慢性乙型肝炎治疗剂，有可能实现功能性治愈

• 批准号: 10324480
• 负责人: Stacy Remiszewski
• 金额: $ 30万
• 依托单位: EVRYS BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324480
• 关键词: Animal Model; Antiviral Agents; Biological Assay; Biological Availability; Chronic Hepatitis B; Clinic; Clinical Research; Crystallization; Cytomegalovirus; DNA; DNA Viruses; Data; Development; Dose; Dose-Limiting; Effectiveness; Enzymes; Family; Genotype; Goals; HBV Genotype; Hepatitis B Therapy; Hepatitis B Virus; Hepatitis B e Antigens; Hepatocyte; Human; In Vitro; Inbred BALB C Mice; Individual; Lead; Liver; Liver Cirrhosis; Liver Failure; Measures; Modeling; Mus; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Primary carcinoma of the liver cells; Proteins; RNA Viruses; Regimen; Series; Serum; Sirtuins; Southern Blotting; Structure; Surface Antigens; Testing; Therapeutic; Translations; Virion; Virus; Virus Diseases; Virus Replication; anti-hepatitis B; base; candidate selection; clinical translation; computational chemistry; cytotoxicity; design; disorder control; extracellular; improved; in vitro testing; in vivo; inhibitor/antagonist; mouse model; pharmacodynamic biomarker; phase 2 study; programs; prototype; response; screening; small molecule therapeutics; success

FAST-TRACK PHASE I and II ABSTRACT Without treatment, chronic hepatitis B virus (HBV) infection can lead to cirrhosis of the liver, hepatocellular carcinoma or liver failure. Current therapies effectively control the disease, but are rarely curative. The goal of this proposal is to develop a therapeutic providing a “functional cure” for chronic HBV infection, i.e., a therapy producing sustained, undetectable HBV surface antigen (HBsAg) and rcDNA (a measure of virions) in serum. A functional cure will potentially benefit about 257 million people worldwide, including approximately 1.4 million individuals 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 human hepatocytes, blocking the accumulation of extracellular HBV rcDNA, HBsAg and HBeAg as well as intracellular cccDNA – antiviral effects that suggest SIRT2 inhibitors have potential to contribute to a functional cure. Phase I of this proposal will demonstrate the feasibility of Evrys SIRT2-inhibitors to treat HBV: Specific Aim 1 will validate the reduction of cccDNA in infected hepatocytes. This aim will extend the results with HBV genotype D to include HBV genotype A, generalizing the conclusion that HBV is inhibited by SIRT2 inhibitors; it will confirm the qPCR-based conclusion that cccDNA levels are reduced by SIRT2 inhibitors by measuring cccDNA in Southern blot analysis; and it will delineate the relative contributions of the in vitro block to accumulation versus destabilization to the reduction of cccDNA levels by SIRT2 inhibition. Specific Aim 2 will determine a dosing strategy for an exemplar of Evrys SIRT2-inhibitors in FRG KO huHep mice, identifying a well-tolerated dose that can achieve the desired anti-HBV EC95. Specific Aim 3 will demonstrate feasibility using the exemplar to treat HBV-infected FRG KO huHep mice. Phase II will develop a prototype: Specific Aim 4 will identify a development candidate 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 HBV replication in human hepatocytes to facilitate clinical translation.

快速轨道第一阶段和II摘要 没有治疗，慢性丙型肝炎病毒（HBV）感染会导致肝硬化，肝细胞质 癌或肝衰竭。当前的疗法有效地控制了该疾病，但很少治愈。目标 该建议是开发一种治疗性，为慢性HBV感染提供“功能治愈”，即一种疗法 在血清中产生持续的，无法检测到的HBV表面抗原（HBSAG）和rcDNA（病毒的测量）。一个 功能固化可能会受益于全球约2.57亿人，其中约140万 在美国患有慢性HBV感染的人。申请人evrys bio最近描述了一个宿主 - 病毒的有针对性脆弱性 - 脱酰酶的Sirtuin家族或SIRTS。 SIRT调节器具有广泛的 针对包括HBV在内的多种潜水病毒的频谱抗病毒活性。与该提案的直接相关性， EVRYS已确定了一个具有潜在抗HBV活性的SIRT2抑制剂系列 肝细胞，阻塞细胞外HBV RCDNA，HBSAG和HBEAG的积累以及细胞内 CCCDNA - 表明SIRT2抑制剂的抗病毒作用有可能有助于功能治愈。阶段 该提案的I将证明EVRYS SIRT2抑制剂治疗HBV的可行性：特定目标1将 验证感染肝细胞中CCCDNA的减少。此目标将扩大HBV基因型D的结果 为了包括HBV基因型A，概括了SIRT2抑制剂抑制HBV的结论；它将确认 基于QPCR的结论是，通过测量CCCDNA，SIRT2抑制剂降低了CCCDNA水平 Southern印迹分析；它将描述体外阻滞对积累的相对贡献 通过SIRT2抑制作用降低CCCDNA水平。特定目标2将决定给药 FRG KO Huhep小鼠中EVRYS SIRT2抑制剂的示例策略 可以达到所需的抗HBV EC95。特定的目标3将证明使用示例治疗的可行性 HBV感染的FRG KO Huhep小鼠。第二阶段将开发一个原型：特定目标4将确定开发 候选人加上至少一项备份，以实现现有的近600 evrys sirt2-的研究 抑制剂。具体目标5将探测开发候选者阻止HBV的机制 在人肝细胞中复制以促进临床翻译。