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，慢性乙肝病毒(乙肝病毒)感染可导致肝硬变，肝细胞 癌症或肝功能衰竭。目前的治疗方法有效地控制了这种疾病，但很少能治愈。的目标是 这项建议是开发一种治疗方法，为慢性乙肝病毒感染提供一种“功能治疗”，即一种治疗方法 在血清中产生持续的、检测不到的乙肝病毒表面抗原(HBs Ag)和rcDNA(病毒粒子的量度)。一个 功能性治愈可能使全球约2.57亿人受益，其中包括约140万人 美国慢性乙肝病毒感染者。申请人Evrys Bio最近描述了一名宿主- 病毒的靶向脆弱性--Sirtuin脱酰酶家族，或SIRT。SiRT调制器具有广泛的- 光谱抗病毒活性对多种不同的病毒，包括乙肝病毒。与这项提议直接相关的， Evrys已经在培养的原代人类中发现了一种具有强大抗乙肝病毒活性的SIRT2抑制剂系列 肝细胞，阻断细胞外和细胞内的HBVrcDNA、HBs Ag和HBeAg的积聚 CCcDNA-抗病毒作用，表明SIRT2抑制剂有可能有助于功能性治疗。阶段 这项提案的第一部分将论证Evrys SIRT2-抑制剂治疗乙肝病毒的可行性：具体目标1将 验证在感染的肝细胞中cccDNA的减少。这一目标将扩展HBVD型的研究结果 包括乙肝病毒A型，推广了乙肝病毒被SIRT2抑制剂抑制的结论；它将证实 基于定量聚合酶链式反应的结论：SIRT2抑制剂通过检测细胞内的cccDNA水平降低了cccDNA水平 Southern印迹分析；它将描绘体外阻断对蓄积的相对贡献 SIRT2抑制对cccDNA水平降低的不稳定作用。特定目标2将确定剂量 在FRG KO huHep小鼠中使用Evrys SIRT2-抑制剂样本的策略，确定了一个耐受性良好的剂量 可以达到理想的抗HBVEC95。具体目标3将展示使用样本治疗的可行性 感染乙肝病毒的FRG KO huHep小鼠。第二阶段将开发一个原型：具体目标4将确定一个开发 候选者加上来自现有的近600个Evrys SIRT2系列的至少一个IND支持研究的备份- 抑制剂。具体目标5将探索开发候选病毒阻止乙肝病毒的机制 在人类肝细胞中复制以促进临床翻译。