Two New Drugs Poised to Replace Interferon in HCV Treatment

StephenW

http://www.medscape.com/viewarticle/753865
Two New Drugs Poised to Replace Interferon in HCV Treatment

Neil Canavan

                                                       
                                                                                                                                                                                                                                                                                                        November 18, 2011 (San Francisco, California) — Two new compounds — a protease inhibitor and a polymerase inhibitor — have the potential to replace pegylated interferon in standard treatment regimens for hepatitis C virus (HCV), according to late-breaking data reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.
In an interim analysis of the open-label phase 2b SOUND-C2 study, investigators looked at the novel protease inhibitor BI 201335 (BI35, Boehringer Ingelheim) and the novel polymerase inhibitor BI 207127 (BI27, Boehringer Ingelheim).
The analysis involved 362 treatment-naïve patients with HCV genotype 1. In the cohort, 52% were male, 98% were white, 85% had an HCV RNA viral load of at least 800,000 IU/mL at baseline, 39% had HCV genotype 1a, 10% showed evidence of compensated cirrhosis, and 26% carried the interleukin (IL)28B polymorphism C/C genotype.
The 5 treatment groups, which all received BI35 120 mg once daily, were:

• BI27 600 mg 3 times a day plus ribavirin for 16 weeks, for 28 weeks, or for 40 weeks (thrice-daily groups)
• BI27 600 mg twice daily plus ribavirin for 28 weeks (twice-daily group)
• BI27 600 mg 3 times daily without ribavirin for 28 weeks (no-ribavirin group).
  

"Having 2 investigational compounds in 1 trial is a bit unusual," noted Federico Mensa, MD, from the division of clinical research in virology at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut.
"The idea is to take interferon out of the regimen equation. That treatment is associated with so many adverse events that many patients don't even want to start treatment," Dr. Mensa noted. It's thought that the combination of 2 of the so-called direct-acting antiviral agents will also prevent the emergence of resistance prior to sustained virologic response, he added.
The interim analysis was performed after all patients completed 12 weeks of treatment. Data for the 238 patients in the 16-week and 28-week thrice-daily groups were combined, since those patients received the same treatment for the first 12 weeks.
Results at week 4 show that response to antiviral treatment (HCV RNA viral load below the lower limit of quantification) ranged from 88% for the thrice-daily groups to 72% for the no-ribavirin group.
At week 12, responses ranged from 76% for the twice-daily group to 57% for the no-ribavirin group.
At weeks 4 and 8, virologic failure occurred in 3.4%, 1.3%, and 4.3% of patients in the thrice-daily, twice-daily, and no-ribavirin groups, respectively.
Virologic breakthrough at 12 weeks occurred in 13.4%, 20.5%, and 32.6% of patients in the twice-daily, thrice-daily, and no-ribavirin groups, respectively.
Patients infected with HCV genotype 1a had a lower response rate than others in the study, particularly those in the no-ribavirin group. The lowest rate of response was for IL28B non-C/C patients in the no-ribavirin group (22%); it was 100% in patients with the C/C genotype in the no-ribavirin group. Excellent response was seen in genotype 1b patients, regardless of IL28B status.
"Viral response rates at 12 weeks of up to 76% were comparable to complete early virologic responses achieved with first-generation protease inhibitors plus pegylated interferon," said Dr. Mensa.
How do low response rates observed for patients with HCV genotype 1a, IL28B non-C/C stack up? "This is an important question. Right now my understanding is that we have not seen that data published — the response rates for genotype 1a patients with the unfavorable C/C IL28b variant are not available, to my knowledge, for boceprevir or telaprivir. So it is hard to make a comparison," said Dr. Mensa.
There were some early discontinuations recorded for reasons other than virologic failure, including adverse events and patients lost to follow-up — 17% in the thrice-daily groups, 6% in the twice-daily group, and 13% in the no-ribavirin group. The most common adverse events were mild to moderate gastrointestinal or skin events.
Discussions are ongoing regarding the treatment protocol for a planned phase 3 study using these agents.
                        What Took So Long?                    
"Clearly, the protease inhibitors have shot ahead of the nonnukes [polymerase inhibitors], especially because the structural chemistry was understood earlier," said David R. Nelson, MD, associate dean for clinical research in the division of gastroenterology, hepatology, and nutrition at the University of Florida College of Medicine in Gainesville. "Protease inhibitors have also been much more potent than the typical nonnukes. There were some in development prior to protease inhibitors, but the potency of these drugs early on is what limited clinical trial results."
Dr. Nelson is the lead investigator of the ZENITH trial, in which the polymerase inhibitor VX-222 (Vertex Pharmaceuticals) is being combined with the recently approved protease inhibitor telaprevir in a population of treatment-naïve patients infected with HCV genotype 1.
The ZENITH trial is looking at the efficacy and tolerability of VX-222, telaprevir, and ribavirin with and without pegylated interferon. Response rates for the pegylated-interferon-free group will be reported at the 2012 meeting of the European Association of the Study of the Liver.
                        Dr. Mensa reports being an employee of Boehringer Ingelheim. Dr. Nelson reports being a consultant for Bayer HealthCare, Biolex, and Roche; and receiving grants and research support from Abbott, Anadys Pharmaceuticals, Bayer HealthCare, BMS, Gilead Sciences, Human Genome Sciences, Merck, Novartis, Roche, and Vertex Pharmaceuticals.                     
The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Late-breaking abstract 15, presented November 7, 2011. Abstract 14, presented November 9, 2011.

StephenW

将取代干扰素在HCV治疗新药

尼尔Canavan



2011年11月18日（旧金山，加利福尼亚州） - 两个新的化合物 - 一种蛋白酶抑制剂和聚合酶抑制剂 - 有可能取代聚乙二醇干扰素治疗丙型肝炎病毒（HCV）的标准治疗方案，根据最新的数据报告肝会议2011年美国肝病研究协会（AASLD）第62届年会。

在一个开放标签相2B声音C2研究的中期分析，调查研究在新的蛋白酶抑制剂的BI 201335（BI35，勃林格殷格翰）和小说聚合酶抑制剂BI 207127（BI27，勃林格殷格翰）。

该分析涉及了与丙型肝炎病毒基因型1 362治疗过的病人。在队列中，52％为男性，98％是白人，85％的丙型肝炎病毒RNA病毒载量至少80万IU / mL的基线时，39％的丙型肝炎病毒基因型1A，10％呈代偿性肝硬化的证据，和26％携带白细胞介素（IL）的28B多态性C / C基因型。

5治疗组，所有收到的BI35 120毫克，每天一次，分别为：

    BI27 600毫克，每日3次每天加利巴韦林为16周，28周或40周（每天三次团体）
    BI27 600毫克，每天两次加利巴韦林28周（每天两次组）
    BI27 600毫克，每日3次没有病毒唑，每日28周（无利巴韦林组）。

费德里科食堂，医学博士，从病毒学的临床研究，勃林格殷格翰制药公司在康涅狄格州Ridgefield分工“指出，”2 1试验研究的化合物，是有点不寻常。

“我们的想法是，采取的方案​​方程干扰素。食堂博士指出：”有这么多的不良事件，很多病人甚至不希望开始治疗，治疗不。他补充说，它认为所谓的直接作用抗病毒药物的组合也将持续病毒学应答之前防止出现抗药性。

中期分析后，所有患者完成12周的治疗。 238例患者在16周和28周每天三次群体的数据相结合，因为这些患者接受了第12周的同等待遇。

在第4周的结果表明，反应的抗病毒治疗（丙型肝炎病毒RNA病毒载量低于定量下限）为每日三班群体无利巴韦林组为72％，88％不等。

在第12周，无利巴韦林组为每日两次组从76％至57％不等的反应。

4和8周时，病毒学失败发生在3.4％，1.3％和4.3％的患者每天三次，每天两次，并没有利巴韦林组，分别。

12周时的病毒学突破发生在13.4％，20.5％，32.6％的患者每天两次，三次，每天和无利巴韦林组，分别。

与丙型肝炎病毒基因型1A感染的患者比他人的研究，特别是那些无利巴韦林组的反应率较低。 IL28B非C / C无利巴韦林组（22％）患者的反应率最低的是，它是在无利巴韦林组与C / C基因型患者100％。出色的响应1b型患者，无论IL28B地位。

博士说：“门萨”病毒反应率高达76％，在12个星期完成第一代蛋白酶抑制剂加聚乙二醇干扰素所取得的早期病毒学反应相媲美。

如何答复率较低与丙型肝炎病毒基因型1A的患者观察，IL28B非C / C叠起来呢？ “这是一个重要的问题，现在我的理解是，我们还没有看到，公布的数据 - 1A与不利的C / C + + IL28b变异基因型患者的反应率是不提供的，据我所知boceprevir或telaprivir，所以。食堂博士说：“很难做出比较。

有记录病毒学失败以外的原因，一些早期停药，包括失去了后续的不良事件和患者 - 在每日三班群体的17％，每天两次组的6％，13％没有，病毒唑组。最常见的不良事件为轻度至中度胃肠道或皮肤事件。

讨论正在进行的治疗方案，有计划第3期使用这些药物的研究。

为什么花了这么长时间？

“显然，提前出手的蛋白酶抑制剂的nonnukes [聚合酶抑制剂]，特别是因为结构化学的理解，说：”戴维R ·纳尔逊，医学博士，临床研究的副院长在胃肠病，肝病分工，和营养在Gainesville佛罗里达大学医学院的大学。 “蛋白酶抑制剂也已远远超过典型nonnukes有力有一些蛋白酶抑制剂之前在发展，但早在这些药物的药性是什么有限的临床试验结果。”

尼尔森博士的ZENITH试验的首席研究员，聚合酶抑制剂VX - 222（Vertex制药）正在与人口感染丙型肝炎病毒基因1型的治疗过的病人最近批准的蛋白酶抑制剂telaprevir结合。

中天试验是在VX - 222，telaprevir，和利巴韦林的疗效和耐受性和不聚乙二醇干扰素。的聚乙二醇化干扰素无组的反应率将在2012年欧洲肝脏研究协会会议上报告。

门萨博士报告，勃林格殷格翰公司的雇员。尼尔森博士的报告，是一个Biolex，拜耳医药保健有限公司和罗氏公司的顾问;和接收来自雅培，Anadys制药，拜耳医药保健，拜耳，Gilead Sciences公司，人类基因组科学，默克，诺华，罗氏，和Vertex制药赠款和研究的支持。

肝会议2011年美国肝病研究协会（AASLD）第62届年会。 15晚打破抽象，2011年11月7日。摘要14，2011年11月9日。

幸福永恒