【转】诺华单抗药omalizumab III期ASTERIA I研究取得积极数据

仲夏秋夜云

诺华（Novartis）10月5日公布了实验性单抗药物奥马珠单抗（omalizumab）III期ASTERIA I研究的最新数据，表明omalizumab能够安全和有效地治疗慢性自发性荨麻疹（CSU）。ASTERIA I研究是有关omalizumab治疗CSU的最后一个关键性注册研究。目前，omalizumab还未获任何监管批准用于CSU的治疗。
ASTERIA I研究的数据，支持了此前已报道的2项关键性III期注册研究（ASTERIA II和GLACIAL）的积极且一致性数据。
诺华于2013年第三季度分别向FDA和欧洲药品管理局（EMA）提交了omalizumab治疗CSU的监管申请文件。
具体来说，ASTERIA I研究表明，omalizumab治疗组在1周时即表现出治疗反应，安慰剂组则在第4周出现（p＜0.0001）。在12周时，在改善患者每周瘙痒严重程度评分（ISS）方面，omalizumab 3个剂量组（300mg，150mg，75mg）均显著优于安慰剂组，达到了研究的主要终点。同时，这一临床益处在整个积极治疗周期（24周）中能够维持。
此外，研究还表明，在12周时，omalizumab 300mg 剂量组生活质量改善约为安慰剂组的2倍（p＜0.0001），52%的患者CSU症状（痒，荨麻疹）得到良好控制，36%的患者无症状（p＜0.0001）。
该项研究中，与安慰剂相比，omalizumab 300mg剂量和150mg剂量达到了所有的既定次要疗效终点，仅150mg剂量 12周生活质量测定未实现统计学显著差异。
CSU又名慢性特发性荨麻疹（CIU），是一种严重的皮肤疾病，特征是皮肤红肿、痒、时而出现荨麻疹。在世界范围内，CSU的患病率为0.5%至1.0%，超过50%的患者对获批剂量的抗组胺药物治疗无反应。
omalizumab是一种实验性单克隆抗体，靶向结合免疫球蛋白E（IgE），该药可能通过减少IgE和细胞激活机制的下游效应，来抑制组胺诱导的皮肤反应。
目前，omalizumab已获全球90多个国家批准，以品牌名素雷尔（Xolair）上市，用于治疗中度至重度持续性过敏性哮喘，该药由诺华和罗氏旗下基因泰克（Genentech）合作开发。
英文原文：Novartis announces positive results from final Phase III omalizumab registration study in severe form of chronic skin disease CSU
-Omalizumab significantly reduced itch and hives caused by chronic spontaneous urticaria (CSU) as early as Week 1; benefit sustained over 24 weeks of active treatment[1]
-Omalizumab 300 mg was nearly twice as effective in improving patients' quality of life within 12 weeks of treatment versus placebo[1]
-ASTERIA I is the final omalizumab CSU registration study to be presented; regulatory applications were filed with EU and US authorities in Q3 2013
-CSU is a debilitating form of hives and chronic itch; more than 50% of patients do not respond to approved doses of antihistamines, the only licensed treatment
Basel, October 5, 2013 - Novartis announced today new results from the Phase III ASTERIA I study showing omalizumab was effective and safe in the treatment of chronic spontaneous urticaria (CSU)[1], a chronic and debilitating form of hives. ASTERIA I is the final pivotal registration study for omalizumab in CSU to be announced, and results were presented today for the first time at the 22nd Congress of the European Association of Dermatology and Venereology (EADV) in Istanbul, Turkey. Omalizumab is currently not approved for the treatment of CSU.
The ASTERIA I data support the positive and consistent results from two previously reported pivotal Phase III registration studies of omalizumab in CSU (ASTERIA II and GLACIAL), which were presented at major medical congresses earlier this year[2],[3]. Regulatory applications for omalizumab in CSU were filed with US and EU health authorities in the third quarter of 2013, based on data from nearly 1,000 patients included in these Phase III studies.
"The positive new data clearly show the potential of omalizumab to treat CSU, a disease where more than 50% of patients don't respond to approved doses of antihistamines, the only licensed treatment option," said Tim Wright, Global Head of Development, Novartis Pharmaceuticals. "With submissions to EU and US regulatory authorities now completed, we are on track to bring omalizumab to people suffering from this chronic and debilitating disease."
Specifically, the ASTERIA I study showed that patients treated with omalizumab responded as early as Week 1 (300 mg dose), compared to Week 4 in the placebo group (p=<0.0001)[1]. By Week 12 all three omalizumab doses (300 mg, 150 mg and 75 mg) were significantly superior to placebo in improving patients' weekly Itch Severity Score (ISS), which was the primary endpoint of the study[1]. This benefit was maintained throughout active treatment (Week 24)[1].
The study also showed patients treated with omalizumab 300 mg experienced nearly twice the improvement in their quality of life compared to those taking placebo by Week 12 (p<0.0001)[1]. Quality of life measures are critical to assessing CSU treatments, because the disease can frequently lead to other negative consequences such as sleep deprivation, depression and anxiety[4].
In addition, by Week 12 more than half (52%) of omalizumab 300 mg patients in the study had their CSU symptoms (itch, hives) well controlled and 36% had no symptoms at all (p<0.0001)[1]. At the same time point, omalizumab 300 mg treated patients also experienced a significant increase in the proportion of days free of deep tissue swelling, also known as angioedema (p<0.0001)[1].
The study met all pre-specified secondary efficacy endpoints for omalizumab 300 mg and 150 mg compared to placebo, except the 150 mg group did not reach statistical significance versus placebo for the quality of life measurement at Week 12.
The incidence and severity of adverse events (AEs) was similar across all ASTERIA I treatment groups. Five omalizumab patients experienced serious AEs during the treatment period (75 mg group n=2, 150 mg group n=3, 300 mg group n=0), compared to four patients in the placebo group[1]. No deaths were reported during this study[1].
CSU is also known as chronic idiopathic urticaria (CIU) in the US, and is a severe and distressing skin condition characterized by red, swollen, itchy and sometimes painful hives or wheals on the skin[5],[6] that spontaneously present and re-occur for more than six weeks[2]. At any given time, the prevalence of CSU is 0.5% to 1% worldwide[4].
Omalizumab is being jointly developed by Novartis and Genentech, Inc. for CSU.
About the ASTERIA I Study
ASTERIA I was a 40-week, global, multi-center, randomized double-blind study that evaluated the efficacy and safety of omalizumab compared to placebo. It involved 318 patients between the ages of 12 and 75 with moderate-to-severe CSU who remained symptomatic despite prior treatment with H1 antihistamine treatment. Patients were randomized to omalizumab 300 mg, 150 mg, 75 mg or placebo (1:1:1:1), given subcutaneously every four weeks for a total period of 24 weeks, and subsequently monitored during a 16 week follow-up period when there was no active treatment[1].
The primary endpoint, ISS at Week 12, was assessed via a 21-point scale at Week 12[1]. Omalizumab significantly improved the mean weekly ISS from baseline by 9.4 in the 300 mg treatment arm (p<0.0001), 6.7 in the 150 mg treatment arm (p=0.0012) and 6.5 in the 75 mg treatment arm (p=0.0010), compared to a 3.6 improvement in patients on placebo[1].
Health-related quality of life was assessed using the Dermatology Life Quality Index (DLQI) questionnaire (range of 0-30, with a higher score representing greater impairment)[1]. Control of CSU symptoms was assessed by a measure of itch and hives called the weekly urticaria activity score (UAS7), where any score of 6 or less out of a 42 point score is considered to represent a well-controlled disease and a score of zero represents a complete resolution of symptoms[1]. In addition, time to response was measured by the median time to Minimally Important Difference (MID)[1].
About Omalizumab (Xolair&#174;)
Omalizumab is a targeted therapy unique in binding to immunoglobulin E (IgE). It is currently not approved for the treatment of CSU. Omalizumab suppresses histamine-induced skin reactions, probably through its reduction of IgE and downstream effects on cellular activation mechanisms[7]. Research is ongoing to understand the mechanism of action of omalizumab in CSU, which could lead to deeper understanding of how the disease develops[8].
Omalizumab is approved for the treatment of moderate to severe persistent allergic asthma under the brand-name Xolair&#174; in more than 90 countries, including the US since 2003 and the EU since 2005. In the EU it is approved for the treatment of severe persistent allergic asthma in children (aged six and above), adolescents, and adults. Following approval in the EU, a liquid formulation of Xolair in pre-filled syringes has been launched in most European countries. In the US, Xolair (omalizumab) for subcutaneous use in appropriate allergic asthma patients is co-promoted by Novartis Pharmaceuticals Corporation and Genentech, Inc.

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