Preclinical Development of SB 44 as an Orally Bioavailable Anti-HBV Agent

SB 44 作为口服生物可利用的抗 HBV 药物的临床前开发

• 批准号: 8262159
• 负责人: RADHAKRISHNAN P IYER
• 金额: $ 59.09万
• 依托单位: SPRING BANK TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-03 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262159
• 关键词: Academia; Acute; Affect; Antiviral Agents; Antiviral Therapy; Antiviral resistance; Bioavailable; Biological Assay; Cell Culture Techniques; Cells; Chronic; Chronic Hepatitis B; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Cyclic GMP; DNA biosynthesis; Data; Development; Dose; Drug Kinetics; Drug resistance; Escape Mutant; Fluorescence; Future; Genes; Goals; Grant; Hepatitis B Virus; Hepatitis C virus; High Pressure Liquid Chromatography; Hospitalization; Human; Hybrids; Illinois; Immune; In Vitro; Industry; Interferons; Laboratories; Liver; Macaca fascicularis; Manufacturer Name; Medical; Methods; Mitochondria; Modeling; Monkeys; National Institute of Allergy and Infectious Disease; No-Observed-Adverse-Effect Level; Nucleic Acids; Oral; Oral Administration; Organ; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma; Process; Prodrugs; Property; Proteins; Protocols documentation; Public Health; Rattus; Research; Rivers; Role; Safety; Sampling; Signaling Protein; Solutions; Technology Transfer; Toxic effect; Toxicology; Transgenic Mice; Transgenic Organisms; Tretinoin; Universities; Utah; Vaccination; Vaccines; Validation; Viral; Virus; Virus Diseases; Virus Replication; Woodchuck; anti-hepatitis B; anti-hepatitis C; antimicrobial; cost; economic cost; in vivo; indexing; liquid chromatography mass spectrometry; liver infection; method development; mouse model; novel; nucleoside analog; nucleotide analog; pgRNA; pre-clinical; preclinical study; prevent; public health relevance; resistant strain; small molecule; viral DNA

DESCRIPTION (provided by applicant): Acute and chronic liver infections caused by Hepatitis B virus (HBV) constitute a major worldwide public health problem. There are over 350 million chronic carriers of the virus worldwide, including 1.7 million chronic carriers in the US, who are affected by chronic hepatitis B (CHB). In addition to human suffering, the economic costs are large - more than $1 billion/year is spent for HBV-related hospitalizations in the US. Although HBV infection can be prevented by vaccination, emergence of escape mutants has been noted, there is concern that vaccines will become ineffective. Thus, there is a clear need for effective antiviral therapy. The future treatment of CHB is expected to be combination therapy with two or more direct-acting antiviral drugs with different mechanisms of action. We have discovered SB 40, as a first-in-class, small molecule nucleic acid hybrid (SMNH) with novel mechanism(s) of action. Extensive studies conducted over the past several years, (supported in part by a UO1 Grant from NIAID), have led to an oral prodrug designated as SB 44. SB 44 has direct antiviral and potential immunomodulatory properties. SB 44, (i) has multiple mechanisms of action including activation of RIG-I, a host target, hence less potential to elicit antiviral resistance, (ii) is not a chain terminator of HBV DNA synthesis; hence less potential for mitochondrial toxicity, (ii) is synergistic with other anti-HBV and anti-HCV drugs, (iv) is active against resistant strains of HBV, and (v) is a potential replacement for Interferon. Preclinical proof of concept has been demonstrated. SB 44, (i) inhibits HBV replication in cell culture studies with good selectivity index, (ii) is active against HBV and Hepatitis C virus (HCV), (iii) shows efficacy against HBV in the transgenic mouse model of HBV, (iv) suppresses HBV DNA synthesis in cells and in vivo, and unlike nucleoside and nucleotide analogs, is not a chain terminator of DNA synthesis, and (iv) stimulates expression of EEEH protein in HBV transgenic mice; hence SB 44 has potential for broad-spectrum antimicrobial activity. SB 44 has good pharmaceutical properties. SB 44 is: (i) orally available with significant disposition in the liver, the target organ for HBV and HCV, (ii) non-toxic in initial preclinical studies and has less potential for toxicity upon longer term use, and (iii) a small molecule that is readily manufactured. Given its excellent preclinical profile, SB 44 merits further development as a novel anti-HBV agent. This 5-year project will be carried out in partnership with a team of outstanding collaborators in academia and industry. Studies conducted thus far have resulted in substantial know-how, hence the project goals and defined milestones are achievable. The studies proposed in the project will help advance SB 44 to IND and human clinical trials. PUBLIC HEALTH RELEVANCE: Acute and chronic liver infections caused by HBV constitute a major worldwide public health problem with a significant unmet medical need. There are serious issues with the existing approved anti-HBV agents, including antiviral resistance and toxicity upon long-term use. The goal of this project is the advancement of SB 44 as a novel first-in-class orally bioavailable antiviral agent towards human clinical trials.

描述（由申请人提供）：由乙型肝炎病毒（HBV）引起的急性和慢性肝脏感染是全球主要的公共卫生问题。全球有超过3.5亿慢性乙肝病毒携带者，其中美国有170万慢性乙肝病毒携带者。除了人类的痛苦之外，经济成本也很大——在美国，每年用于hbv相关住院治疗的费用超过10亿美元。虽然HBV感染可以通过接种疫苗来预防，但已经注意到逃逸突变体的出现，人们担心疫苗会失效。因此，显然需要有效的抗病毒治疗。未来慢性乙型肝炎的治疗有望采用两种或两种以上不同作用机制的直接抗病毒药物联合治疗。我们发现了一种新型的小分子核酸杂合体（SMNH） sb40。在过去几年中进行的广泛研究（部分由NIAID的u01资助）已经产生了一种被指定为SB 44的口服前药。sb44具有直接抗病毒和潜在的免疫调节特性。SB 44, (i)具有多种作用机制，包括激活宿主靶点RIG-I，因此引发抗病毒抗性的可能性较小，（ii）不是HBV DNA合成的链终止者；因此线粒体毒性的可能性较小，（ii）与其他抗HBV和抗hcv药物协同作用，（iv）对HBV耐药菌株有效，(v)是干扰素的潜在替代品。概念的临床前证明已被证明。sb44, (i)在细胞培养研究中具有良好的选择性指数抑制HBV复制，（ii）对HBV和丙型肝炎病毒（HCV）有活性，（iii）在HBV转基因小鼠模型中显示对HBV有效，（iv）抑制细胞和体内HBV DNA合成，与核苷和核苷酸类似物不同，它不是DNA合成的链终止物，（iv）刺激HBV转基因小鼠EEEH蛋白的表达；因此SB 44具有广谱抗菌活性的潜力。sb44具有良好的药用性能。SB 44是：(i)可口服，在肝脏（HBV和HCV的靶器官）中有显著分布，（ii）在初步临床前研究中无毒，长期使用毒性可能性较小，（iii）易于制造的小分子。鉴于其优异的临床前表现，SB 44作为一种新型抗hbv药物值得进一步开发。这个为期5年的项目将与学术界和工业界的杰出合作者合作进行。迄今为止进行的研究已经产生了大量的专有技术，因此项目目标和确定的里程碑是可以实现的。该项目提出的研究将有助于推进sb44进入IND和人体临床试验。