辉瑞潜在重磅药物tofacitinib 2个III期研究达主要终点

辉瑞潜在重磅药物tofacitinib 2个III期研究达主要终点
来源：　2013-10-11 08:30:14
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　　关键词：辉瑞,tofacitinib,银屑病,JAK抑制剂

　　2013年10月10日讯 /生物谷BIOON/ --辉瑞(Pfizer)10月9日公布了有关口服Janus激酶(JAK)抑制剂tofacitinib的2项III期研究的顶级数据：OPT Compare (A3921080)和OPT Retreatment (A3921111)，这些研究是III期OPT(口服治疗银屑病)项目5个III期研究中的前2个研究，旨在调查tofacitinib治疗中度至重度慢性斑块牛皮癣成人患者的疗效和安全性。OPT项目是迄今为止在中度至重度慢性斑块型银屑病中开展的全球最大的临床试验项目。OPT Pivotal 1(A3921078)和OPT Pivotal 2(A3921079) 研究的顶级数据预计将于2014年第二季度获得，这4个研究，以及一项长期扩展研究，将组成tofacitinib监管文件的数据包。
　　OPT Compare (A3921080)是一项为期12周、非劣性研究，在中度至重度慢性斑块型银屑病患者中开展，将tofacitinib 5mg和10mg每日2次(BID)疗法，与高剂量Enbrel(etanercept，依那西普)50mg每周2次(BIW)疗法及安慰剂进行了疗效和安全性比较。研究数据表明，与高剂量Enbrel BIW相比，10mg BID剂量tofacitinib达到了非劣性的主要终点，5mg BID剂量tofacitinib未达到非劣性标准。研究中，各积极治疗组重要安全事件率相似。
　　OPT Retreatment (A3921111)是一项为期56周的研究，在中度至重度慢性斑块型银屑病成人患者中开展，比较了tofacitinib 5mg和10mg BID疗法撤出(withdrawal)和复治(retreatment)相对于安慰剂的疗效和安全性。研究数据表明，在停药期间(withdrawal phase)，与切换至安慰剂治疗的患者组相比，继续接受tofacitinib治疗的患者组有更大比例的患者维持了治疗反应。该项研究中，5mg和10mg BID剂量均达到了主要疗效终点。此外，在失去足够治疗反应的患者中，在接受tofacitinib复治(retreatment)后，许多患者能够重新获得治疗反应。OPT Retreatment研究的数据将为医生在临床实践中提供相关资料，因为在临床治疗中，患者停止和重新治疗现象很常见。
　　关于tofacitinib：
　　tofacitinib是一种新颖的口服Janus激酶(JAK)抑制剂，目前正在调查用于中度至重度慢性斑块型银屑病成人患者的治疗。该药由辉瑞科学家发现和开发，具有一种新颖的作用机制，旨在抑制JAK通路，这些通路被认为在银屑病慢性炎症反应中发挥了重要作用。通过抑制这些JAK通路，tofacitinib能够降低细胞因子信号传导、细胞因子诱导的基因表达及细胞的激活。(Bioon.com)
　　英文原文：Pfizer Announces Top-Line Results Of The First Two Of Five Phase 3 Clinical Trials Of Tofacitinib In Adults With Moderate-To-Severe Chronic Plaque Psoriasis
　　Wednesday, October 9, 2013 - 8:00am EDT
　　Pfizer Inc. (NYSEFE) announced today top-line results from two Phase 3 clinical trials of tofacitinib, a novel, oral Janus kinase (JAK) inhibitor that is being investigated for the treatment of adults with moderate-to-severe chronic plaque psoriasis: OPT Compare (A3921080) and OPT Retreatment (A3921111). These are the first two of five studies in the Phase 3 Oral Psoriasis Treatment (OPT) Program, one of the largest global clinical trial programs in moderate-to-severe chronic plaque psoriasis to date. Top-line results for the OPT Pivotal 1 and OPT Pivotal 2 trials (A3921078 and A3921079) are anticipated in the second quarter of 2014, and these four studies, in addition to a long-term extension study, will form the potential psoriasis submission package to regulatory authorities.
　　“We are excited to see progress in our development program in psoriasis,” said Dr. Steven Romano, senior vice president and the head of the Medicines Development Group for Pfizer Specialty Care. “The OPT Compare and OPT Retreatment studies provide information that is consistent with our expectations based on the Phase 2 data in psoriasis. We look forward to the results of our remaining Phase 3 trials in order to fully evaluate tofacitinib in psoriasis and how it may fit into clinical practice for patients and physicians.”
　　OPT Compare is a 12-week, non-inferiority study comparing the efficacy and safety of tofacitinib 5 and 10 mg twice-daily (BID) to high-dose ENBREL? (etanercept) 50 mg twice-weekly (BIW), the approved starting dose for ENBREL for the first twelve weeks, and placebo for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis. Top-line results from the OPT Compare study showed that tofacitinib met the primary endpoint of non-inferiority to high-dose ENBREL at the 10 mg BID dose. Tofacitinib did not meet the non-inferiority criteria to high-dose ENBREL at the 5 mg BID dose. The dose-response relationship observed for tofacitinib in this trial is consistent with the findings from the Phase 2 trial. Additionally, rates of important safety events were similar across the active treatment arms.
　　OPT Retreatment is a 56-week study comparing the efficacy and safety of withdrawal and retreatment with tofacitinib 5 and 10 mg BID to placebo for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis. The OPT Retreatment study met its primary efficacy endpoints at the 5 and 10 mg BID doses by demonstrating that a greater proportion of patients continuing tofacitinib treatment maintained their response during the treatment withdrawal phase compared to patients who switched to placebo. Additionally, among patients who lost an adequate response, many were able to recapture their response upon retreatment with tofacitinib. The results of OPT Retreatment will provide relevant information to physicians in clinical practice, as it is common for patients with psoriasis to stop and restart therapy.
　　No new safety signals for tofacitinib were observed in these studies, and the efficacy and safety profile of tofacitinib in psoriasis remains consistent with that seen in the Phase 2 clinical trial. Full analyses of the OPT Compare and OPT Retreatment data, including additional efficacy and safety data, will be submitted for presentation at a future scientific meeting.
　　About OPT Compare (A3921080)
　　OPT Compare was a Phase 3 randomized, double-blind, placebo-controlled 12-week non-inferiority study comparing the efficacy and safety of tofacitinib 5 and 10 mg BID to ENBREL (etanercept) 50 mg BIW and placebo for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis who had an inadequate response to, intolerance to, or contraindication to systemic therapy. There were 1106 patients enrolled in this study. The primary objectives of the study were to compare the efficacy of tofacitinib to ENBREL and placebo for the reduction in severity of plaque psoriasis as measured by the proportion of patients achieving a Physician’s Global Assessment (PGA) response of “clear” or “almost clear,” and the proportion of patients achieving at least a 75 percent reduction in Psoriasis Area and Severity Index (PASI75) relative to baseline, two commonly used measures of efficacy in psoriasis.
　　About OPT Retreatment (A3921111)
　　OPT Retreatment was a Phase 3 randomized, mixed-blind, three-period, parallel group, placebo-controlled study evaluating the efficacy and safety of the withdrawal and retreatment with tofacitinib 5 and 10 mg BID to placebo in adult patients with moderate-to-severe chronic plaque psoriasis. There were 674 patients enrolled in the study. During period A (24 weeks), patients were treated with tofacitinib at a dose of 5 or 10 mg BID in a blinded manner. To qualify for period B, patients had to achieve both a PASI75 and a PGA response of “clear” or “almost clear”. In period B, patients were randomized to either continue tofacitinib or switch to placebo for 16 weeks or until they lost half of their original PASI response to treatment from Period A, whichever occurred first. In period C, all patients resumed their original tofacitinib dose until week 56. One of the primary objectives of the study was to compare the maintenance of response (period B, withdrawal) with tofacitinib relative to placebo at various time points during the 16 week double-blind active or placebo treatment period. The second primary objective of the study, evaluated in period C (retreatment), was to assess the percentage of patients who regained responses with tofacitinib retreatment after having lost adequate responses during period B. The data announced today are from the planned final analysis at 56 weeks.
　　About the OPT Clinical Trial Program
　　The Phase 3 OPT clinical trial program consists of five studies, including one open-label, long-term extension study evaluating oral tofacitinib 5 and 10 mg BID in adults with moderate-to-severe chronic plaque psoriasis. It is a global, multi-study, comprehensive clinical development program that includes 3,600 patients in 39 countries. The OPT Program is designed to specifically evaluate tofacitinib in moderate-to-severe chronic plaque psoriasis, and to support an independent assessment of the benefit:risk profile of tofacitinib in psoriasis patients.

之前听说北京10月开始临床实验，今天去医院询问了一下，得知大概在12月前后才开始。

有两种现在正在进行III期临床试验的药物可能会使中度银屑病患者受益。它们是辉瑞公司的tofacitinib（即枸橼酸托法替尼， FDA2012年11月批准用于用于类风湿关节炎）和塞尔基因制药的apremilast。这两种药物均为小分子化疗药物，故成本比生物制剂更便宜。不像生物制剂必须通过注射，这两种药物可以口服。Tofacitinib为酪氨酸激酶（JAKs）分子。敲除JAKs，即不产生银屑病相关细胞因子受体位点。而Apremilast是通过阻滞细胞因子合成所必需的磷酸二酯酶4（PDE4）而发挥作用。Papp希望，这些小分子可以以口服或局部应用的剂型用于治疗非重度银屑病患者。

这两种药物的II期临床数据并不像生物制剂那样令人印象深刻。在tofacitinib的研究数据中，有67%患者达到PASI 75缓解，apremilast为41%。不过因为两种药物都未出现明显的副作用，可以用于非重症银屑病患者的治疗。特别是 Apremilast，尤其适于治疗中度活动的银屑病患者。Apremilast很可能是匹黑马。虽然apremilast无法达到生物制剂那样好的疗效，但是有很好的安全性。尽管JAK阻滞剂的长期安全性尚不明确，但最终这种药物也可以在治疗中度银屑病中占得一席之地。

然而，对大多数银屑病患者来说，他们病情过于温和而无法得到系统的治疗。对他们来说，新的小分子药物软膏剂就是一个好消息。例如，辉瑞已将tofacitinib制成外用剂型，并取得了振奋人心的结果。

好消息很多，可惜真正能为P友所用而又能解决问题的基本没有

这个药好像要开始实验了。

这几年新药层出不穷，好消息不断，可接地气的没几个，都不亲民，出一个就是天价来一个就是高消费，钱真有用。