FDA专家小组建议批准Simeprevir C型肝炎

StephenW

FDA Panel Recommends Approval of Simeprevir for Hepatitis C

Medscape Troy Brown, RN
October 24, 2013

An advisory committee to the US Food and Drug Administration (FDA) unanimously recommended simeprevir (Janssen) for the treatment of chronic hepatitis C virus (HCV) genotype 1 (GT1) infection, combined with peginterferon alfa and ribavirin in adults with compensated liver disease (including cirrhosis) who are treatment naïve or who have failed previous interferon therapy with or without ribavirin.

Simeprevir is an HCV protease inhibitor, and if approved it will be the third HCV protease inhibitor approved in the US. Boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals, Inc) were approved in 2011, according to background information provided by the FDA. The proposed dose is 150 mg once daily, in combination with peginterferon alfa and ribavirin.

"We clearly need better drugs, and the evidence is strong that this is a better drug than we have," voting member Curt H. Hagedorn, MD, Chief, Medicine Service, at Central Arkansas Veterans Healthcare Service, in Little Rock, Arkansas, noted.

The vote follows a discussion of data from 3 phase 3 randomized, double-blind, placebo controlled clinical trials (C208, C216, and HPC3007) in patients with chronic HCV GT1. Patients in the treatment groups (N = 781) were given simeprevir 150 mg daily for 12 weeks plus peginterferon and ribavirin (PR) for 12 weeks, followed by PR only for either 12 or 36 weeks based on the individual's virologic response to therapy. Patients in the control groups (N = 397) were given placebo for 12 weeks combined with PR for 48 weeks.

Those in trials C208 and C216 were treatment-naïve, and those in HPC3007 had received 24 weeks or more of a pegylated interferon-based treatment and had relapsed within 1 year after the last medication dose. Efficacy data from C208 and C216 were pooled because the studies were nearly identical in design.

Efficacy

The trials' primary endpoint was sustained virologic response 12 weeks after the anticipated end of treatment (SVR12), which was defined as an undetectable HCV RNA at treatment end and HCV RNA < 25 IU/mL 12 weeks after the anticipated end of treatment.

The pooled results from C208 and C216 showed an SVR12 rate of 80% in the treatment group and 50% in the control group. For the relapsed patients in HPC3007, the SVR12 rate was 79% in the treatment group and 36% in the control group.

Secondary endpoints for all 3 trials included SVR24 and SVR 72. Both endpoints correlated well with the primary endpoint of SVR12, but data were incomplete at the week 60 data cut-off.

SVR rates were lower in patients with a high baseline viral load, advanced disease on liver histology (bridging fibrosis and cirrhosis), older age, African American ethnicity, and absence of the IL28B CC genetic polymorphism.

The presence of the Q80K HCV GT1a polymorphism (commonly found in GT1a patients in the US) at baseline had a substantial impact on the efficacy of simeprevir. In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups. In HPC3007, the SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group.

In those without the Q80K polymorphism, the SVR12 rates were 84% in the treatment groups vs 43% in the control group for the 2 pooled trials, and 78% in the treatment group vs 24% in the control group for the relapser trial. The committee recommends screening all patients with GT1a infection for the Q80K viral polymorphisms before initiating simeprevir (combined with pegylated interferon and ribavirin) and considering alternative treatment options for those with this polymorphism.

SVR12 rates were significantly higher in the simeprevir arm compared with the placebo arm in all other subgroup analyses.

Mean simeprevir area under the concentration-time curve 24-h postdose (AUC24h) values were 2.4 and 5.2-fold higher, respectively, in HCV-uninfected subjects with moderate or severe hepatic dysfunction, compared to healthy controls. Mean simeprevir AUC24h values were also approximately 3.4-fold higher in HCV infected patients of East Asian ancestry, compared with the pooled Phase 3 population which was about 91% Caucasian. For this reason, the committee would like to see additional studies in patients of East Asian origin.

Safety

A total of 4 deaths occurred in the treatment groups, and they were judged to be unrelated to treatment.

In the pooled analysis, 2% of those in the simeprevir group had serious adverse events, versus 3% of those in the control group during the initial 12 weeks. A total of 3 patients (0.4%) in the simeprevir group had significant adverse events, which were determined to be related to simeprevir by the study investigator; 1 patient experienced major depression and 2 patients experienced photosensitivity reactions.

Other common adverse events were rash (218 [28%] treatment groups; 79 [20%] control groups), influenza like illness (203 [26%] treatment groups; 84 [21%] control groups), pruritis (168 [22%] treatment groups; 58 [15%] control groups), and nausea (173 [22%] treatment groups; 70 [18%] control groups).

"I think this is a great opportunity at treating more HCV infected patients," said voting member Amanda H. Corbett, PharmD, BCPS, FCCP, a clinical associate professor at the University of North Carolina at Chapel Hill's Eshelman School of Pharmacy.

"Efficacy was clearly demonstrated and the safety profile is clearly favorable," explained voting member Thomas P. Giordano, MD, MPH, an associate professor of medicine at Baylor College of Medicine, medical director of HIV services at Harris Health System, and a research scientist at HSR&D Center of Excellence, Michael E. DeBakey VA Medical Center, in Houston, Texas.

Several committee members remarked on the need for postmarketing studies in racial and ethnic minorities, patients coinfected with HIV, and other underrepresented populations. A number of members suggested that the FDA should be more proactive with the pharmaceutical industry at the beginning of the clinical trial process to ensure a more diverse study population that more accurately represents the clinical population being studied.

StephenW

FDA专家小组建议批准Simeprevir C型肝炎

出处： WebMD特洛伊 - 布朗， RN
2013年10月24日

美国食品和药物管理局（FDA）的一个咨询委员会一致推荐simeprevir （扬森）结合聚乙二醇干扰素α和利巴韦林治疗慢性丙型肝炎病毒（HCV）感染基因型1 （GT1 ） ，代偿性肝脏疾病在成人（包括肝硬化）是初次接受治疗的患者，或谁没有以前的干扰素治疗或无利巴韦林。

Simeprevir是丙型肝炎病毒蛋白酶抑制剂，如获批准，这将是第三次在美国获得批准的丙型肝炎病毒蛋白酶抑制剂。 boceprevir治疗（ VICTRELIS ，默克公司）和telaprevir的（ Incivek ， Vertex制药公司）在2011年批准，根据FDA提供的背景资料。建议的剂量是150毫克，每天一次，结合聚乙二醇干扰素α和利巴韦林。

“我们显然需要更好的药物，证据充分，这是一个比我们有更好的药物， ”投票权的成员柯特·哈格多恩，医学博士，主任，中央阿肯色退伍军人医疗保健服务，医药服务，在小石城，阿肯色州，指出。

投票结果如下数据3 3期随机，双盲，安慰剂对照临床试验（ C208 ， C216 ， HPC3007 ）患者与慢性HCV GT1的讨论。各治疗组的患者（n = 781）给予simeprevir的每日150毫克12周加聚乙二醇干扰素和利巴韦林（ PR ）为12周，随后仅由PR​​基于对个人的病毒学应答治疗12或​​36周。对照组患者（N = 397 ） ，分别给予安慰剂结合PR 48周12周。

试验C208和C216治疗天真，那些在HPC3007收到了24周或以上的聚乙二醇化干扰素为基础的治疗，末次给药剂量后1年内复发。 C208和C216的疗效数据汇集，因为研究设计几乎相同。

功效

该试验的主要终点是持续病毒学应答（ SVR12 ）的治疗，被定义为无法检测治疗结束时HCV RNA和HCV RNA <25 IU / mL的12周后，预计治疗结束12周后，预期年底。

C208和C216的汇总结果显示SVR12率为80 ％，治疗组和对照组的50 ％ 。对于复发病人在HPC3007 ， SVR12率为79 ％ ，治疗组和对照组的36％ 。

所有3项试验的次要终点包括SVR24和SVR 72 。以及相关的SVR12的主要终点的两个端点，但数据是不完整的，在60个数据截止的一周。

在高基线病毒载量，对肝脏组织学的先进的疾病（桥接纤维化和肝硬化）患者的SVR率较低，年龄较大，非洲裔美国人的种族和缺乏IL28B CC遗传多态性。

在基线HCV GT1a Q80K多态性（通常在在美国GT1a患者）的存在对simeprevir的疗效产生了重大影响。在汇集试验，其差异在SVR12率在GT1a患者与Q80K多态性治疗（58％ ）和对照组（55％）之间无统计学意义。 HPC3007 ， SVR12为那些与Q80K多态性率分别为47％ ，治疗组和对照组的30 ％ 。

在那些没有Q80K多态性， SVR12率分别为84 ％，治疗组与对照组的43％， 2个试验池， 78 ％，治疗组与对照组24％的relapser试验。委员会建议的Q80K病毒启动前simeprevir （联合聚乙二醇干扰素和利巴韦林） ，并考虑替代治疗方案，对于那些与此多态性多态性筛选所有患者与GT1a感染的。

SVR12率明显更高在simeprevir臂，与安慰剂组相比，在所有其他的亚组分析。

平均simeprevir浓度 - 时间曲线下面积24 -H的给药后（ AUC24h ）值分别为2.4和5.2倍，分别在HCV未感染者有中度或重度肝功能不全，健康对照组相比。平均simeprevir的AUC24h值约3.4倍，在HCV感染患者的东方人相比，与汇集的第3阶段的人口约91 ％的白人。出于这个原因，委员会希望看到更多的研究，患者的东亚起源。

安全

各治疗组共发生4人死亡，他们被判定为与治疗无关。

在汇总分析，有2％那些在simeprevir组有严重不良事件，与3％ ，在对照组在最初的12周。总共有3例（0.4％）在simeprevir组有显着的不良事件，被确定为相关simeprevir的研究者;经验丰富的抑郁症患者和2名经验丰富的光敏反应。

其他常见的不良反应为皮疹（218 [ 28％ ]治疗组79 ％ [20 ％ ]对照组），流感样病例（203 [ 26 ％]治疗组84 [21％ ]对照组） ，瘙痒（ 168 [ 22 ％ ]治疗组58 [15 ％]对照组） ，恶心（173 [22％ ]治疗组70 [18％ ]对照组） 。

投票权的成员阿曼达·科贝特，药学博士， BCPS ， FCCP ，北卡罗莱纳大学教堂山埃什尔尔曼药学院临床副教授“ ，说：”我认为这是一个很好的机会，在治疗HCV感染患者。

“解释说：”投票权的成员托马斯· P.佐丹奴， MD ， MPH在贝勒大学医学院的艾滋病防治服务的在哈里斯卫生系统，医疗主任，副教授，医学，和一个研究清楚地表明疗效和安全性显然是有利的，在高铁研发卓越中心，迈克尔·E·狄见贝基VA医疗中心，在休斯敦，得克萨斯州的科学家。

一些委员表示对种族和少数族裔的上市后研究的需要，患者同时感染HIV和其他弱势族群。一些委员建议，应用本品与制药行业更加积极主动，在临床试验过程的开始，更准确地反映人口的临床研究，以确保一个更加多样化的研究人口。