2014年3月12日讯 /生物谷BIOON/ --葛兰素史克（GSK）3月12日宣布，美泊利单抗（mepolizumab）III期项目2个关键性III期研究（MEA115588和MEA115575）均达到了主要终点。该项目的全部数据，将提交至未来的科学会议。GSK计划于今年年底提交mepolizumab的监管文件。mepolizumab是一种实验性白介素5（IL-5）拮抗剂，有望为严重失控性难治性哮喘群体提供一个重要的治疗选择。
MEA115588研究评估了mepolizumab 2种剂量方案用于严重嗜酸性粒细胞哮喘（eosinophilic asthma）的疗效。在整个研究过程中，患者仍保持其当前的哮喘维持治疗，并随机接受每4周一次mepolizumab 75mg静脉注射（IV）、100mg皮下注射（SC）或安慰剂。研究数据表明，与安慰剂组相比，mepolizumab 2个治疗组临床显著病情加重的发作频率得到了统计学意义的显著降低（75mg IV, 47%, p<0.001; 100mg SC, 53%, p<0.001），达到了研究的主要终点。该项研究中，不良事件在所有治疗组相似。最常见的不良反应为鼻咽炎、头痛、上呼吸道感染和哮喘。不良事件发生率，安慰剂组为83%，75mg IV组为84%，100mg SC组为78%。严重不良事件发生率，安慰剂组为14%，75mg IV组为7%，100mg SC组为8%。
MEA115575研究评估了每4周一次100mg皮下注射（SC）mepolizumab作为辅助疗法，相对于安慰剂对每日口服皮质类固醇剂量的降低作用。该项研究中中，患者同时接受当前的哮喘维持治疗。研究数据表明，在20-24周，100mg SC mepolizumab能够更大幅度地降低维持性疗法中口服糖皮质激素的剂量（p=0.008），并能够维持哮喘控制，达到了研究的主要终点。该项研究中，不良事件在各治疗组相似。最常见的不良反应为头痛、鼻咽炎、支气管炎、鼻窦炎、疲劳和哮喘。不良事件发生率，安慰剂组为92%，mepolizumab治疗组为84%。严重不良事件发生率，安慰剂组为18%，mepolizumab治疗组为1%。
关于mepolizumab，葛兰素史克有一个雄心勃勃的开发计划。就在上个月，该公司宣布启动一项关键性III期研究MEA115921，调查mepolizumab用于治疗嗜酸细胞性肉芽肿性多血管炎（EGPA）的疗效和安全性。
EPGA即Churg-Strauss综合征，是一种罕见的全身性炎症性疾病，特征是小血管内壁广泛的炎症（血管炎，vasculitis），该病可累及多个器官，包括心脏、肺、皮肤、胃肠道、肾脏及神经系统。EGPA临床治疗的主要目标是诱导和维持缓解，同时减少糖皮质激素等免疫疗法的使用。
关于III期项目：
mepolizumab III期项目包括2个关键性研究：MEA115588和MEA115575。
MEA115588是一项32周、双盲、双模拟（double-dummy）、安慰剂对照、平行组多中心研究，在576例既往经高剂量吸入性糖皮质激素（ICS）及至少一种其他控制药物治疗后仍经历频繁病情加重的哮喘患者中开展。在治疗开始时，血液嗜酸性粒细胞计数高于150个细胞/微升的预先指定水平或在过去12个月内曾经嗜酸性粒细胞计数≥300个/微升的患者才有资格参与该项研究。研究的主要终点是，调查每4周1次75mg静脉注射（IV）和100mg皮下注射（SC）mepolizumab相较于安慰剂，对临床显著病情加重频率的改善。
MEA115575是一项24周、双盲、安慰剂对照、平行组多中心研究，在135例正接受口服糖皮质激素、高剂量ICS及一种额外的控制药物常规治疗的严重患者中开展。在治疗开始时，血液嗜酸性粒细胞计数高于150个细胞/微升的预先指定水平或在过去12个月内曾经嗜酸性粒细胞计数≥300个/微升的患者才有资格参与该项研究。研究的主要终点是，调查每4周接受1次100mg皮下注射mepolizumab作为辅助治疗，对类固醇使用剂量的减少。
关于mepolizumab：
mepolizumab是一种实验性全人源化单克隆抗体，特异靶向于白介素5（IL-5），开发用于经高剂量吸入性（ICS）或口服皮质类固醇激素（OCS）和长效β2激动剂治疗后病情仍无法控制的严重难治性哮喘患者。IL-5是一种细胞因子，能够调节嗜酸性粒细胞（白细胞）的生长、活化、存活，并能够为嗜酸性粒细胞从骨髓迁移至肺部提供重要的信号。mepolizumab与人IL-5的结合，能够阻断IL-5与嗜酸性粒细胞表面受体的结合。以这种方式抑制IL-5对受体的结合作用，能够降低血液、组织、痰液中的嗜酸性粒细胞水平，这反过来又能够降低哮喘急性发作的频率。目前mepolizumab还未获任何监管批准。（生物谷bioon.com）
英文原文：GSK announces positive results from phase III studies for mepolizumab in severe eosinophilic asthma
Issued: Wednesday 12 March 2014, London UK – LSE Announcement
GlaxoSmithKline plc (LSE/NYSE: GSK) today announced that a pivotal phase III study of mepolizumab, an investigational IL-5 antagonist monoclonal antibody, met its primary endpoint of reduction in the frequency of exacerbations, in patients with severe eosinophilic asthma.
The study (MEA115588) evaluated the efficacy of two dose regimens of mepolizumab in the treatment of patients with severe eosinophilic asthma. Patients remained on their current asthma maintenance therapy throughout the study and were randomised to receive either mepolizumab 75mg intravenous (IV), 100mg subcutaneous (SC), or placebo every four weeks.
For the primary end point, both mepolizumab treatment arms showed statistically significant reductions in the frequency of clinically significant exacerbations of asthma compared to placebo (75mg IV, 47%, p<0.001; 100mg SC, 53%, p<0.001).
Adverse events reported in the study were similar across all treatment groups. The most common reported adverse events across all treatment groups were nasopharyngitis, headache, upper respiratory tract infection and asthma. The frequency of adverse events was 83% in the placebo group, 84% in the mepolizumab 75mg IV and 78% in the mepolizumab 100mg SC group. The frequency of serious adverse events was 14% in the placebo group, 7% in the mepolizumab 75mg IV and 8% in the mepolizumab 100mg SC group.
Dave Allen, Head, GSK Respiratory Therapy Area Unit, R&D, said: “We are really pleased to have generated further positive data on mepolizumab, consistent with the findings from our earlier exacerbation study. We now have two studies showing a reduction in exacerbations in a specific group of patients with a severe form of asthma who continue to exacerbate despite treatment with high doses of their current maintenance therapies. This is very positive news for patients. For GSK it is exciting that this is the first non-inhaled treatment for severe asthma and we will be progressing towards global filings at the end of the year.”
In addition, a second phase III study (MEA115575) designed to evaluate the use of mepolizumab 100mg SC, every 4 weeks in comparison to placebo in reducing daily oral corticosteroid use while maintaining asthma control also met its primary endpoint. The study showed that patients on mepolizumab 100mg SC were able to achieve greater reductions in their maintenance oral corticosteroid dose during weeks 20-24 compared to patients on placebo (p =0.008), while maintaining asthma control.
In this study adverse events were similar across treatment groups. The most common reported adverse events in the two treatment groups were headache, nasopharyngitis, bronchitis, sinusitis, fatigue and asthma. The frequency of adverse events was 92% in the placebo and 84% in the mepolizumab treatment group. Frequency of serious adverse events was 18% in the placebo group and 1% in the mepolizumab group.
The full results of these studies will be posted onto the GSK clinical study register, clinicaltrials.gov and presented at a future scientific meeting.
About the studies:
Study MEA115588 was a 32-week double-blind, double-dummy, placebo-controlled, parallel group multicentre study that randomised and treated 576 patients with severe asthma, who had experienced frequent exacerbations despite treatment with high dose inhaled corticosteroids (ICS) plus at least one other controller medication. All patients were also required to have a blood eosinophil count above a pre-specified threshold of ≥150 cells/μl at initiation of treatment or who have had blood eosinophils ≥300 cells/μl in the past 12 months to be eligible for the study.
Study MEA115575 was a 24-week double-blind, placebo-controlled, parallel group multicentre study that randomised and treated 135 patients. To be eligible for the study patients had severe asthma and were on regular treatment with oral corticosteroids, high dose ICS plus an additional controller medication. All patients were also required to have a blood eosinophil count above a pre-specified threshold of ≥150 cells/μl at initiation of treatment or who have had blood eosinophils ≥300 cells/μl in the past 12 months to be eligible for the study.
About severe eosinophilic asthma and mepolizumab
The presence of eosinophils may represent a subtype of severe asthma. Although asthma is a heterogeneous disease it is often characterised by an accumulation of eosinophils (white blood cells) in lung tissues and in general, raised eosinophils correlate with severity and frequency of exacerbations. Interleukin-5 (IL-5) is the main promoter of eosinophil growth, activation and survival and provides an essential signal for the movement of eosinophils from the bone marrow into the lung.
Mepolizumab is an investigational fully humanised IgG1 monoclonal antibody specific for IL-5, which binds to IL-5, stopping it from binding to its receptor on the surface of eosinophils. Inhibiting IL-5 binding in this way reduces blood, tissue and sputum eosinophil levels.
Mepolizumab is in development for severe eosinophilic asthma in patients who exacerbate despite high-dose oral or inhaled corticosteroids (ICS) and an additional controller such as long-acting beta-2 agonist. In addition, mepolizumab is being investigated in COPD and Eosinophilic Granulomatosis with Polyangiitis (EGPA).
Mepolizumab is not approved anywhere in the world.
关键词：葛兰素史克,单抗,IL-5拮抗剂,mepolizumab,嗜酸性粒细胞哮喘
信息来源:生物谷
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