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.

快速通道第一阶段和第二阶段摘要 如果不进行治疗，慢性乙型肝炎病毒 (HBV) 感染可导致肝硬化、肝细胞性肝病 癌症或肝功能衰竭。目前的疗法可以有效控制该疾病，但很少能治愈。目标是 该提案旨在开发一种治疗方法，为慢性乙型肝炎病毒感染提供“功能性治愈”，即一种疗法 在血清中产生持续的、不可检测的 HBV 表面抗原 (HBsAg) 和 rcDNA（病毒粒子的测量方法）。一个 功能性治愈可能使全球约 2.57 亿人受益，其中约 140 万人 美国慢性乙型肝炎病毒感染者。申请人 Evrys Bio 最近描述了一种宿主—— 病毒的目标脆弱性——去酰基酶的去乙酰化酶家族（SIRT）。 SIRT 调制器具有广泛的 针对多种不同病毒（包括乙型肝炎病毒）的谱抗病毒活性。与本提案直接相关的是， Evrys 鉴定出一系列 SIRT2 抑制剂，在培养的原代人类中具有有效的抗 HBV 活性 肝细胞，阻断细胞外和细胞内 HBV rcDNA、HBsAg 和 HBeAg 的积累 cccDNA – 抗病毒作用表明 SIRT2 抑制剂有可能有助于功能性治愈。阶段 该提案的 I 将证明 Evrys SIRT2 抑制剂治疗 HBV 的可行性：具体目标 1 将 验证受感染肝细胞中 cccDNA 的减少。这一目标将扩展 HBV 基因型 D 的结果 纳入 HBV 基因型 A，概括出 HBV 被 SIRT2 抑制剂抑制的结论；它将确认 基于 qPCR 的结论是，通过测量 cccDNA，SIRT2 抑制剂可降低 cccDNA 水平 Southern印迹分析；它将描述体外阻断对积累的相对贡献与 通过抑制 SIRT2 来降低 cccDNA 水平的不稳定。具体目标 2 将确定剂量 在 FRG KO huHep 小鼠中使用 Evrys SIRT2 抑制剂的策略，确定了耐受良好的剂量 可以达到预期的抗HBV EC95。具体目标 3 将证明使用范例来治疗的可行性 感染 HBV 的 FRG KO huHep 小鼠。第二阶段将开发原型：具体目标 4 将确定开发 候选者加上至少一个 IND 备份，可以从现有的近 600 个 Evrys SIRT2 系列中进行研究- 抑制剂。具体目标 5 将探讨开发候选药物阻断 HBV 的机制 在人肝细胞中复制以促进临床转化。