Hepatitis C virus (HCV) infection remains a significant health problem in our country. The World Health Organization estimated that 71 million people worldwide had chronic HCV infection in 2015. And 399,000 people died from cirrhosis or primary hepatocellular carcinoma caused by HCV infection. In 2006, the positive rate of HCV antibody in the population aged 1-59 was 0.43%. Therefore, it was estimated that there were about 5.6 million HCV infected people in the general population, and about 10 million cases of HCV infected people in high-risk groups and high incidence areas.
Universal genotype direct antiviral agent (DAA) is the preferred antiviral therapy for hepatitis C. Sofosbuvir/velpatasvir are direct antiviral agents for hepatitis C. The results of Asian clinical trials mainly in Chinese population showed that the sustained virologic response (SVR) rates of sofosbuvir/velpatasvir at 12 weeks in genotype 1a, 1b, 2, 3a, 3b and 6 were 100%, 100%, 100%, 95%, 76% and 99%, respectively. Limited data showed that the SVR rate of sofosbuvir/velpatasvir at 12 weeks was 96% in Chinese genotype 3b patients without cirrhosis and 50% in patients with cirrhosis.
After standard antiviral therapy for hepatitis C, there are still some patients who cannot obtain SVR, and these patients are defined as DAA-experienced patients. The guidelines recommend that Sofosbuvir/Velpatasvir combined with ribavirin be used as salvage therapy for patients with DAA-experienced failure. Vosevi is a new generation of antiviral therapy for hepatitis C, which contains three components, (Sofosbuvir, Velpatasvir and Voxilaprevir. It was a salvage treatment plan for DAAs-experienced patients which was recommended by the Chinese hepatitis C prevention and treatment guidelines in 2019. However, there are insufficient data on the proportion of SVR acquired in Vosevi treated DAAs-experienced patients in Asian populations and the effectivity of antiviral therapy between Vosevi and Sofosbuvir/Velpatasvir combined with ribavirin.
In the present study, the investigators enroll DAAs-experienced hepatitis C patients. The participants are randomly divided into two groups. Then the participants are treated with Vosevi or Sofosbuvir/Velpatasvir combined with ribavirin respectively. All enrolled participants are followed-up for 3 years. Objectives of the present study are as follows:
A. To clarify the sustained virologic response rate after Vosevi therapy for DAAs-experienced patients.
B. To clarify the safety and efficacy between the Vosevi therapy and the Sofosbuvir/Velpatasvir combined with ribavirin therapy.
C. To clarify the changes of biochemistry indexes in DAAs-experienced patients after Vosevi therapy.
D. To clarify the virological relapse rate at 12 weeks after Vosevi therapy. E. To clarify the rate of cirrhosis and liver cancer during the follow-up.

开始日期2023-02-28

申办/合作机构

The Third Affiliated Hospital of Guangzhou Medical University

NCT05467826 / Not yet recruiting临床4期IIT

Efficacy and Safety of Sofosbuvir/Velpatasvir Plus Ribavirin for 12 Weeks or Sofosbuvir/Velpatasvir/Voxilaprevir for 12 Weeks in DAA Treatment Naïve HCV Subjects With GT3b, Compensated Cirrhosis in China

Direct-acting antiviral agents (DAAs) targeting HCV have revolutionized the treatment of HCV. The efficacy of DAA-based therapy can depend on patient-related factors such as treatment experience, cirrhosis, but also on viral genotype. The high prevalence of genotype 3, which is considered difficult to cure, remains a challenge because many oral DAAs are less effective for this genotype, particularly subtype 3b than for others. Current guidance generally recommends sofosbuvir (SOF)/velpatasvir (VEL) ± ribavirin (RBV), glecaprevir/pibrentasvir and SOF/VEL/voxilaprevir (VOX) as first-line therapy for genotype 3, and an interferon-based regimen - SOF plus pegylated interferon and ribavirin is still recommended as an alternative treatment option. These recommendations are based on clinical data generated in regions where genotype 3a predominates. Our recent study indicated that sofosbuvir plus ribavirin for 24 weeks in subjects with HCV genotype 3 infection resulted in high rates of SVR. However, the SVR12 rate among subjects with genotype 3b was lower than that observed in subjects with genotype 3a infection, particularly among treatment-experienced subjects with cirrhosis.
Our study aimed to investigate the efficacy and safety of SOF/VEL plus RBV for 12 weeks or SOF/VEL/VOX for 12 weeks in DAAs treatment naïve HCV subjects with GT3b, compensated cirrhosis in China.

开始日期2022-09-01

申办/合作机构

北京大学人民医院

100 项与 NS3/NS4A x NS5B polymerase x NS5A 相关的临床结果

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100 项与 NS3/NS4A x NS5B polymerase x NS5A 相关的转化医学

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项与 NS3/NS4A x NS5B polymerase x NS5A 相关的文献（医药）

2021-07-01·Clinics and Research in Hepatology and Gastroenterology4区 · 医学

Treatment of hepatitis C virus infection

4区 · 医学

Review

作者: Pol, Stanislas ; Hollande, Clémence ; Parlati, Lucia

Hepatitis C virus infection affects 71 million people worldwide. It is at the origin of a multi-organ disease associating hepatic manifestations, cryoglobulinemic vasculitis and general manifestations linked to chronic inflammation (diabetes, cardio-, reno- or cerebrovascular manifestations, extra-hepatic cancers including non-Hodgkin's lymphoma). The significant morbidity and mortality linked to the hepatitis C virus therefore justify its screening and access to treatments which have increased considerably over the past two decades. Understanding the replicative cycle of the hepatitis C virus has enabled the development of direct HCV-specific antivirals targeting viral proteins (NS3/4A protease, NS5B polymerase and the multifunctional NS5A replication complex). The combination of two to three specific inhibitors often co-formulated in a capsule, without pegylated interferon and most often without ribavirin, allows high antiviral efficacy (more than 97% cure) for a treatment duration of 8-12 weeks with satisfactory tolerance. HCV infection is the only chronic viral infection that can be cured and the hepatic or extrahepatic manifestations are mainly reversible. This underlines the importance of strengthening screening and access to care policies in order to achieve the elimination of viral infection C in the short term, in 2030, as expected from the program of the World Health Organization. If this elimination is possible in some countries (Iceland, France, Germany …), it seems compromised in others where prevention (USA), screening and/or access to care are still insufficient (Sub-Saharan Africa, Russia…).

2020-02-01·European Journal of Medicinal Chemistry

Molecular design, synthesis, and biological evaluation of bisamide derivatives as cyclophilin A inhibitors for HCV treatment

Article

作者: Li, Xiaoli ; Yang, Suhui ; Han, Jinhe ; Cho, Won-Jea ; Khadka, Daulat B ; Jin, Yifeng ; Lee, Hye Won ; Kim, Meehyein

Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment. However, some DAAs are associated with increased drug resistance and undesired side effects. Previous reports have shown that bisamides could be a novel class of cyclophilin A (CypA) inhibitors for treating HCV as a member of combinational therapies. To fully elucidate structure-activity relationships of bisamide derivatives and find a better hit compound with diverse binding modes, 16 biamides were designed with the help of docking program. They were then synthesized using one-pot four-component Ugi reaction. 7e with selectivity index of more than 18.9 (50% effective concentration of 5.3 μM, but no cytotoxicity at 100 μM) and unique binding mode that could be dived into gatekeeper pocket was selected as a new hit compound. Surface plasmon resonance experiments revealed that 7e is able to bind to CypA with a K_D of 3.66 μM. Taken together, these results suggest that 7e as a CypA inhibitor could be used as an alternative anti-HCV agent in combinational therapy in the future.

2019-04-01·Trends in Microbiology1区 · 生物学

Hepatitis C Virus

1区 · 生物学

Article

作者: Pietschmann, Thomas ; Brown, Richard J P

Hepatitis C virus (HCV) is an enveloped, RNA virus transmitted through blood-to-blood contact. It infects humans only and primarily targets liver cells. HCV evades innate and adaptive immunity and establishes chronic infections in 70% of cases. If untreated, 20% of patients develop liver cirrhosis, and a fraction of these progress to hepatocellular carcinoma. Annually, 400000 patients die globally due to HCV infection. Direct-acting antivirals (DAAs) are licensed and target three viral proteins: the NS3-4A protease needed for processing the viral polyprotein, the NS5A phosphoprotein that regulates RNA replication and virus assembly, and the viral RNA-dependent RNA polymerase (NS5B) that catalyzes genome replication. Combination therapies cure more than 95% of treated patients. Approximately 71 million people are chronically infected and 1.7 million new infections occur annually. Treatment-induced cure does not protect from viral reinfection. A prophylactic vaccine is under development.

项与 NS3/NS4A x NS5B polymerase x NS5A 相关的新闻（医药）

2021-05-26

·E药经理人

默沙东250亿重磅药国内注销批文，艾伯维曾经明星丙肝药撤市，药监局公布283个药品注销批文

仿制药正在倒逼原研药撤市。 5月24日，国家药监局发布了一批药品注册证书撤销的公告，涉及283个药品，值得注意的是，其中包含了多家跨国药企的重磅产品，艾伯维的明星鸡尾酒疗法奥比帕利、默沙东超四十亿美金市场的降糖药西格列汀片（25mg和50mg）以及杨森的普芦卡必利片等。通常意义上，注销药品证书相当于一个产品退出市场。关于奥比帕利是否意味着退出中国市场，E药经理人第一时间得到了艾伯维的官方回应：新一代产品已在中国上市，奥比帕利的申请注销是全球同步。默沙东的西格列汀目前已有多款仿制药上市，超过10家仿制药正在审批；杨森的普芦卡必利是第三批集采品种，杨森未中标并且随后在多省已撤销挂网。 01 艾伯维曾经的明星药退出中国市场在药监局的公告中，本次艾伯维依申请注销药品批文的为两款产品——奥比帕利片（每片含奥比他韦12.5mg,帕立瑞韦75mg和利托那韦50mg）和达塞布韦钠片（250mg）。奥比帕利片联合达塞布韦钠片治疗方案于2017年9月20日首次在中国获批，2018年1月上市，作为一种全口服、无干扰素的治疗方案，用于治疗无肝硬化或伴代偿期肝硬化的基因1型慢性丙肝，但遗憾的是，在2019年的医保谈判中失利。 2019年5月，艾伯维在中国又上市了新一代丙肝产品——格卡瑞韦哌仑他韦片，用于治疗基因1、2、3、4、5或6型慢性丙型肝炎病毒感染的无肝硬化或代偿期肝硬化成人患者。格卡瑞韦哌仑他韦片是中国全新的泛基因型丙肝治疗方案，对于初治、无肝硬化的所有主要基因型(基因1-6型)丙肝患者，病毒学治愈率高达99%以上，疗程可短至8周。该产品的高疗效与低副作用一度被认为是挑战吉三代的有力产品。但根据医保局规定，2019年的医保谈判药品需要在2018年12月31日前获批的产品才有资格参与评选，格卡瑞韦哌仑他韦片不在这次医保谈判范围。这甚至直接导致了格卡瑞韦哌仑他韦片也无缘2020年医保谈判。在2019年的医保谈判中，由于彼时进入谈判的4家企业的6款产品本质上并非原研与仿制的关系，且均为丙肝药物、疗效相似，医保局即采取同组竞争的方式“仅允许2个全疗程费用最低的药品进入目录，且承诺2年内不再纳入新的同类药品”，最终，默沙东的艾尔巴韦格拉瑞韦片（NS3/4A抑制剂）、吉利德的来迪派韦索磷布韦片（NS5A/NS5B抑制剂）和索磷布韦维帕他韦片（NS5A/NS5B抑制剂）降价超过85%成功进入医保目录，且2年内不会有同类竞品进入。也就是说2019年5月上市的格卡瑞韦哌仑他韦片或许要等到2021年的谈判中才有机会进入医保。从公司战略层面讲，适应证相同、疗效更高、副作用更低的新一代产品进入市场，上一代产品撤市也稀疏平常，“价格过低，丙肝患者市场逐渐萎缩，赛道竞争过于激烈”，一位业内专家指出。事实上，国内丙肝药市场竞争的激烈程度更为惊人。一方面是上市节奏十分紧密，公开资料显示，从2017年BMS的阿舒瑞韦上市，到2020年歌礼的达维拉韦上市，短短四年，国内共上市了15款丙肝新药，而目前已有4款产品进入医保目录；另一方面，丙肝市场实际上萎缩从未停止，丙肝是可被治愈的疾病始终是客观事实。IQVIA统计，随着治愈率提高，全球的丙肝药物市场逐年下滑，各家的销售业绩也在2016年开始下滑，2018年全球丙肝药市场规模约为166亿美元，较2015年巅峰时期缩水超过40%。进入医保对于药品的市场准入来说是重中之重，资本市场对此反应也十分明显。2019年医保谈判结果消息传出当天，歌礼制药股价暴跌25%。在2020年的医保谈判中，本土企业凯因科技的可洛派韦胶囊被纳入2020版医保目录，适用范围为经HCV基因分型检测确诊为基因1b型以外的慢性丙型肝炎患者。在剂型方面，凯因科技的产品可洛派韦的规格剂型为胶囊，艾尔巴韦格拉瑞韦片、来迪派韦索磷布韦片和索磷布韦维帕他韦片是全口服、泛基因型、单一片剂。上述专家也指出，药品的剂型对产品的市场竞争也会产生一定影响。国内丙肝新药市场已经是中外创新药同台竞争，而1年后，企业们将面临的市场则是2019年谈判承诺过期、丙肝治愈率更高，如此看来价格之战或将更加激烈。 02 仿制药倒逼原研撤市本次药监局的公告中还涉及了两款大品种——默沙东的西格列汀片（25mg和50mg）和杨森的普芦卡必利片。药审中心官网显示，默沙东的西格列汀片（100mg）未注销批文。而这两款产品在国内目前的状态十分相似，西格列汀片已有4款仿制药获批上市，普芦卡必利片是第三批集采品种，原研药未中标，三批集采后，杨森产品在多省撤销挂网。据悉，默沙东西格列汀片于2009年9月首次在中国获批，用于治疗2型糖尿病。西格列汀是全球第一个上市的口服二肽基肽酶-4抑制剂（DPP-4抑制剂），DPP-4抑制剂是一类2型糖尿病的治疗药物，由于其对体质量无影响、低血糖发生率低、可口服等显著特点，在国内外临床指南中逐步得到充分认可，治疗地位不断提升，市场份额逐年提升，全球占有率已接近糖尿病药物市场的四分之一。默沙东的原研药于2006年获FDA批准上市，2009年获NMPA批准进入中国市场。西格列汀片是目前世界上销售额最大的DPP-4产品，年销售额曾达40亿美元，接近其他列汀产品总和。但随着2020年2月，正大天晴首仿药进入市场，石药、东阳光的仿制药也相继获批，默沙东原研药市场大不如前，此前也有业内传言，默沙东调整了西格列汀的中国销售团队。公开资料显示，目前市场上按照作用机制的不同，降糖药可以分为双胍类、胰岛素增敏剂（噻唑烷二酮类）、胰岛素促泌剂（磺脲类、格列奈类）、α-葡萄糖苷酶抑制剂（阿卡波糖、伏格列波糖）、DPP-4抑制剂、SGLT-2抑制剂、GLP-1受体激动剂和胰岛素八类主要药物。其中，DPP-4抑制剂、SGLT-2抑制剂、GLP-1受体激动剂被称为新型抗糖剂。 DPP-4抑制剂主要通过抑制DPP-4而减少GLP-1在体内的失活，使内源性GLP-1的水平升高，代表产品为列汀类产品；SGLT2抑制剂通过抑制肾脏肾小管重吸收，促进尿葡萄糖排泄，从而降低血糖，代表产品为列净类产品；GLP-1受体激动剂是大分子药，通过激动GLP-1受体而发挥降低血糖的作用，代表产品为那肽、鲁肽类产品。有分析报告显示，2019年，新降糖机制药物DPP-4抑制剂占比25.5%，保持平稳；SGLT-2抑制剂增长趋于平稳，目前来看无法冲击DPP-4的市场地位；GLP-1受体激动剂占比16.2%，保持快速增长，是整个糖尿病市场扩容的重要推动力。而值得注意的是，随着国内第一款上市的GLP-1，诺和诺德的利拉鲁肽进入医保目录，GLP-1激动剂市场迅速放量，2018年销售额达5.3亿元，同比增长76.7%，2019年利拉鲁肽销量进一步攀升，销售额跃升至9.4亿元，同比增长77.4%。诺和诺德财报显示，利拉鲁肽占据92.8%国内GLP-1市场。而2020年的医保谈判中，长效抑制剂度拉糖肽、洛塞那肽以及两款国产GLP-1和赛诺菲的利司那肽也都进入医保目录。多款疗效各异、给药方式各异的GLP-1产品同台竞争，再加上有仿制药上市的多款DPP-4抑制剂和SGLT-2抑制剂，国内糖尿病市场竞争日趋白热化。诸如西格列汀片的市场情况，仿制药上市，“新型”抑制剂不再“新”；大分子药悉数也降幅超50%进入医保，将资源给予更具竞争优势的产品，调整、优化销售团队也不失为更可持续发展的企业战略。

仿制药带量采购免疫疗法财报创新药