Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus
Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus
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DOI：
10.1038/nbt.2020
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发表时间：
2011-11-01
影响因子：
46.9
通讯作者：
Mueller, Peter
中科院分区：
文献类型：
--
作者：
Kwong, Ann D.;Kauffman, Robert S.;Mueller, Peter
丙型肝炎病毒 (HCV) 感染是一个重大的医疗问题，全世界有超过 1.7 亿人感染。大量的发病率和死亡率与肝脏表现（肝硬化和肝细胞癌）相关，在感染 HCV 20 多年的人群中，肝脏表现的发生率越来越高。不太为人所知的是与肝外表现（糖尿病、B 细胞增殖性疾病、抑郁症、认知障碍、关节炎和干燥综合征）相关的 HCV 疾病负担。对于感染基因1型HCV的患者，聚乙二醇修饰干扰素（聚乙二醇干扰素）a和利巴韦林（PR）治疗的成功率较低（40-50%），存在严重的治疗限制性副作用，且治疗持续时间较长（48周）。在过去 15 年中，重大科学进步促进了新型 HCV 疗法的开发，即直接作用抗病毒药物，也称为丙型肝炎特异性靶向抗病毒疗法 (STAT-C)。结合PR，HCV NS3-4A蛋白酶抑制剂特拉匹韦最近在美国、加拿大、欧盟和日本被批准用于治疗基因1型慢性HCV。与 PR 相比，特拉匹韦联合疗法显着提高了病毒治愈率，并有可能缩短不同患者群体的治疗持续时间。创新药物的开发商必须开辟一条新的道路，而几乎没有经过验证的路标来指导道路。事实上，特拉匹韦的开发曾因其在标准 IC50 测定中的表现而被搁置。需要来自新假设和新实验的数据来证明进一步投资的合理性并降低药物在临床上失败的风险。此外，特拉匹韦较差的药物性质是制造和配方团队必须克服的一个巨大障碍。最后，开发了新颖的临床试验设计，以并行而不是顺序地提高疗效并缩短治疗时间。从特拉匹韦开发中吸取的经验教训表明，创新药物的制造商不能仅仅依赖传统的药物发现指标，而必须开发创新的、科学指导的成功途径。
Infection with hepatitis C virus (HCV) is a major medical problem with over 170 million people infected worldwide. Substantial morbidity and mortality are associated with hepatic manifestations (cirrhosis and hepatocellular carcinoma), which develop with increasing frequency in people infected with HCV for more than 20 years. Less well known is the burden of HCV disease associated with extrahepatic manifestations (diabetes, B-cell proliferative disorders, depression, cognitive disorders, arthritis and Sjogren's syndrome). For patients infected with genotype 1 HCV, treatment with polyethylene glycol decorated interferon (peginterferon) a and ribavirin (PR) is associated with a low (40-50%) success rate, substantial treatment-limiting side effects and a long (48-week) duration of treatment. In the past 15 years, major scientific advances have enabled the development of new classes of HCV therapy, the direct-acting antiviral agents, also known as specifically targeted antiviral therapy for hepatitis C (STAT-C). In combination with PR, the HCV NS3-4A protease inhibitor telaprevir has recently been approved for treatment of genotype 1 chronic HCV in the United States, Canada, European Union and Japan. Compared with PR, telaprevir combination therapy offers significantly improved viral cure rates and the possibility of shortened treatment duration for diverse patient populations. Developers of innovative drugs have to blaze a new path with few validated sign posts to guide the way. Indeed, telaprevir's development was once put on hold because of its performance in a standard IC50 assay. Data from new hypotheses and novel experiments were required to justify further investment and reduce risk that the drug might fail in the clinic. In addition, the poor drug-like properties of telaprevir were a formidable hurdle, which the manufacturing and formulation teams had to overcome to make the drug. Finally, novel clinical trial designs were developed to improve efficacy and shorten treatment in parallel instead of sequentially. Lessons learned from the development of telaprevir suggest that makers of innovative medicines cannot rely solely on traditional drug discovery metrics, but must develop innovative, scientifically guided pathways for success.