L-NUCLEOSIDES AS ANTI-HBV AGENTS

B型肝炎病毒（HBV）感染困扰着全世界多达3亿人。 仅在美国，每年就有20万例新的HBV感染病例。 许多慢性感染HBV的个体发展为相关的病理，如慢性肝功能不全、肝硬化和肝细胞癌。 目前可用的HBV治疗相当不令人满意。 例如，α-干扰素只有有限的疗效，拉米夫定在一年内在超过14%的治疗个体中选择耐药病毒。 大多数抗HBV核苷类似物由于掺入线粒体DNA而具有毒性。此外，当作为单一药物使用时，HBV快速发展对抗病毒核苷的耐药性。目前迫切需要更好的抗HBV核苷用于联合治疗。最近，在诺维里奥制药公司，天然胸苷的L-对映体（即，L-胸苷）被发现在体外和慢性感染的土拨鼠中具有抗HBV活性。 这是一种独特的核苷，是天然核苷的镜像，对线粒体功能没有影响。然而，由于缺乏大规模制备这种核苷的有效方法，进一步的发展受到阻碍。Novirio Pharmaceutical是Pharmasset，Inc.的战略合作伙伴，他们依靠我们来开发工艺化学。因此，我们计划在第一阶段开发大规模合成所有四种天然存在的2 '-脱氧核苷的每一种L-核苷对应物的简便方法。 将与Novirio合作研究合成的L-核苷，用于进一步的抗HBV评价和早期毒理学研究。在第二阶段，我们将选择最有前途的核苷，并与Novirio合作，使用土拨鼠模型生产足够数量的核苷，以进行体内药理学和高级毒理学评价，从而获得IND。第三阶段将与Novirio合作，重点关注IND申请和临床研究。药物开发的这一部分将在II期申请中更详细地讨论。拟议的商业应用：美国每年新增200，000例乙型肝炎病毒感染病例。这些病例中约有1-2%发展为暴发性肝炎，死亡率为60- 70%。6%到10%的感染者会发展成慢性活动性肝炎。美国约有6,000人死于HBV肝硬化和HBV相关肝癌。这个数字正在增长，这表明需要更有效的治疗方法。全世界数百万慢性感染患者需要治疗。

Hepatitis B virus (HBV) infection afflicts as many as 300 million people worldwide. In the United States alone, 200,000 new cases of HBV infection occur annually. Many individuals who are chronically infected with HBV develop associated pathologies such as chronic hepatic insufficiency, cirrhosis, and hepatocellular carcinoma. Currently available HBV treatment are quite unsatisfactory. For example, alpha-Interferon has only limited efficacy, and Lamivudine selects for resistant virus in more than 14% of treated individuals within one year. Most anti-HBV nucleoside analogues are toxic due to incorporation into mitochondrial DNA. Moreover, HBV quickly develops resistance to antiviral nucleosides when used as single agents. There is an urgent need for better anti-HBV nucleosides for use in combination therapy. Recently, at Novirio Pharmaceuticals, Inc., the L-enantiomers of natural thymidine (i.e., L-thymidine) were found to be active against HBV in vitro and in chronically infected woodchucks. This is a unique nucleoside which is a mirror image of the natural nucleoside and has no effect on mitochondrial function. Further development, however, has been hampered due to the lack of an efficient procedure for large-scale preparation of this nucleoside. Novirio Pharmaceutical is a strategic partner of Pharmasset, Inc., and they depend on us for development of process chemistry. Therefore, we plan to develop facile methods of large-scale synthesis of each of L-nucleosides counterparts of all four naturally-occurring 2'- deoxynucleosides in Phase I. The synthesized L-nucleosides will be studied, in collaboration with Novirio, for further anti- HBV evaluation and early toxicological studies. In Phase II, we will select the most promising nucleoside and manufacture a sufficient quantity to carry out in vivo pharmacological and advanced toxicological evaluations using the woodchuck model in collaboration with Novirio leading to IND. Phase III will be focused on an IND application and clinical studies in collaboration with Novirio. This part of drug development will be discussed in more details in the Phase II application. PROPOSED COMMERCIAL APPLICATIONS: In the US 200,000 new cases of HBV infection occur annually. About 1-2% of these cases develop fulminant hepatitis with a mortality rate of 60-70%. Six to ten percent of infected patients progress to chronic active hepatitis. About 6,000 people in the US die from HBV cirrhosis and HBV-related liver cancer. This number is growing, which indicates that more effective treatments are needed. Worldwide millions of chronically infected patients need be treated.