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FDA panel backs bronchodilator combo for COPD, with precautions FDA专家组支持支气管扩张复合制剂治疗COPD并提出注意事项  

2013-11-01 09:00:33|  分类: 呼吸科 |  标签: |举报 |字号 订阅

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network


SILVER SPRING, MD. – A fixed-dose combination of umeclidinium bromide, a new long-acting antimuscarinic agent (LAMA), and vilanterol, a relatively new long-acting beta agonist (LABA), in an inhaled powder formulation, should be approved for treatment of chronic obstructive pulmonary disease, with a recommendation for a postmarketing safety study, according to the majority of a Food and Drug Administration advisory panel.


At a meeting on Sept. 10, the FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 11-2 that the safety and efficacy data on the combined treatment, administered once a day, supported approval for the proposed indication: the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. The daily dose is 62.5 mcg of umeclidinium and 25 mcg of vilanterol (UMEC/VI 62.5/25), provided in one inhalation.


In another vote, the panel unanimously agreed that treatment with UMEC/VI 62.5/25 provided clinically meaningful benefits for this indication, based on the clinical trial results provided by GlaxoSmithKline. However, all the panelists were concerned about potential safety issues in patients with severe heart disease. There was also concern over the generalizability of the use of the combination because of a cardiovascular safety signal in the studies and the types of patients excluded in the research.


Those voting in favor of approval recommended a postmarketing study to evaluate the safety signal further, and a statement in the precautions and warnings section of the label about possible risks. The two panelists voting against approval said that the study should be done before approval.


If approved, this would be the first LAMA/LABA combination product to become available in the United States. Umeclidinium is not yet available in any product, although the FDA is currently reviewing the 62.5-mcg dose as monotherapy. Vilanterol is available only as the LABA component in Breo Ellipta, the combination of vilanterol with the inhaled corticosteroid fluticasone, which was approved in May 2013 for COPD. The same device is used to deliver UMEC/VI 62.5/25, which, if approved, will be marketed as Anoro Ellipta, by GSK and Theravance.


Research details


The four main safety and efficacy studies compared two doses of umeclidinium (125 mcg and 62.5 mcg) combined with 25 mcg of vilanterol to the separate components alone and to placebo (in two studies) or to the approved long-acting antimuscarinic agent tiotropium (two studies) in about 4,700 patients – most of whom were male and white – with moderate to severe COPD. Their mean age was 63 years, almost half were still smoking, and almost 30% had had at least one exacerbation during the previous year that required treatment with corticosteroids and/or antibiotics; about 10% said they had been hospitalized for an exacerbation during the previous year (25% were enrolled in the United States).


In the two placebo-controlled studies, the combination and the two separate components (UMEC and vilanterol) were associated with statistically significant improvements in mean trough forced expiratory volume in 1 second (FEV1) from baseline at 24 weeks (the primary endpoint), compared with placebo. Improvements were also statistically significant for the two combinations over the individual components. In the active controlled study, the two combinations showed improvements in trough FEV1 that were superior to vilanterol alone and to tiotropium alone. The results with the higher dose of umeclidinium and vilanterol were similar to the 62.5-mcg dose, the proposed dose for approval.


The mortality rate and nonfatal serious adverse events were even in the treatment arms, in the four primary efficacy studies, and in long-term safety studies, and adverse events were consistent with those associated with the LAMAs and LABAs, according to GSK. The total number of cardiovascular-related events was fairly low in the safety database that included the four main studies and a long-term safety study. But there were numerical imbalances in ischemia-related events in the primary efficacy studies that were not seen in the long-term safety study, an issue raised by the FDA, although the overall number of events was low, according to the agency.


Panelists raised several safety issues, including the generalizability of the cardiac safety data to patients with more severe cardiac disease, because of exclusion criteria that may have eliminated these patients.


The panel chair, Dr. David Jacoby, professor of medicine in the division of pulmonary and critical care medicine at Oregon Health and Science University, Portland, supported approval but recommended that safety should be studied further in patients with COPD who have more severe cardiac disease.


Also voting for approval, Dr. Nizar Jarjour, professor and head of the section of allergy, pulmonary, and critical care at the University of Wisconsin, Madison, said the data indicated that the product was reasonably safe. But if it were to be used outside the parameters studied in the trials, such as for patients with recent exacerbations of COPD, or severe heart disease, he said he have would "no real confidence" that it would have the same safety profile as seen in the trials.


The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but that was unnecessary at this meeting.


马里兰州银泉市——美国食品药品管理局(FDA)顾问小组多数成员支持批准一种固定剂量复合制剂用于慢性阻塞性肺病(COPD)的治疗,这种复合制剂包含umeclidinium bromide[一种新型长效抗毒蕈碱制剂(LAMA)]和维兰特罗[一种相对较新的长效β受体激动剂(LABA)],复合制剂的剂型为吸入性粉末剂。


在9月10日的会议上,FDA的肺病-过敏药物顾问委员会以11-2的投票结果认可这种联合治疗每日应用1次的安全性和疗效数据,支持批准将其用于建议的适应证:对COPD患者气流阻塞的每日1次支气管扩张剂长期维持治疗,包括慢性支气管炎和/或肺气肿患者。每日剂量为umeclidinium 62.5 mcg和维兰特罗25 mcg(UMEC/VI 62.5/25),在一次吸入中提供。


在另一项投票中,专家小组全体一致认同,基于葛兰素史克公司(GSK)提供的临床试验结果,对于这一适应证,UMEC/VI 62.5/25治疗可提供有临床意义的效益。但所有专家小组成员对重度心脏病患者中的潜在安全性问题表示忧虑。另外,由于研究中显示的心血管安全性信号和排除的患者类型,还存在对于联合应用可推广性的担忧。


上述投票结果支持批准该药物,并建议开展一项上市后研究以进一步评估安全性信号,以及在说明书的注意事项与警告部分对潜在风险作出声明。专家小组中有两位成员投票反对批准,认为应在批准前开展该研究。


如获得批准,这将成为首个在美国上市的LAMA/LABA复合产品。Umeclidinium尚未以任何形式上市,但FDA目前正在审查62.5 mcg剂量单药治疗。维兰特罗目前仅作为Breo Ellipta中的LABA成分上市,后者是一种维兰特罗与吸入性皮质类固醇激素氟替卡松的复合制剂,这种制剂于2013年5月获准用于治疗COPD。UMEC/VI 62.5/25的给药装置与之相同,如经核准,将以Anoro Ellipta的商品名上市,由GSK和治疗先锋公司负责销售。


研究详细介绍


4项主要的安全性和疗效研究在大约4,700例患者中对两种剂量的umeclidinium(125 mcg和 62.5 mcg)联合维兰特罗25 mcg与单一成分、安慰剂(两项研究)或已获准的长效抗毒蕈碱药物噻托溴铵(两项研究)进行了比较,多数患者为男性和白人,患有中至重度COPD。患者平均年龄为63岁,接近半数仍在吸烟,接近30%在之前1年内发生至少1次COPD加重,需要皮质类固醇激素和/或抗生素治疗;约10%自述在之前1年内因COPD加重而住院(25%的患者是在美国招募的)。


在两项安慰剂对照的研究中,与安慰剂相比,联合治疗和两种单一成分(UMEC和维兰特罗)治疗与24周时较基线的平均谷值1秒用力呼气量(主要终点)显著改善相关,两种成分联合治疗较单一成分治疗的改善也具有统计学意义。在活性对照研究中,显示两种成分联合治疗谷值FEV1 的改善优于维兰特罗和噻托溴铵单药治疗。较高剂量的umeclidinium与维兰特罗治疗的结果与62.5 mcg剂量相似,建议的核准剂量为62.5 mcg。


据GSK报告,在4项主要疗效研究和长期安全性研究中,各治疗组的死亡率和非致死性严重不良事件发生率分布均衡,并且不良事件与LAMAs和 LABAs相关的不良事件一致。包含4项主要研究和1项长期安全性研究的安全性数据库中的心血管相关事件总数相当低。但主要疗效研究中显示缺血相关事件的数量不均衡,而长期安全性研究的结果与之不一致,尽管事件总数很低。


专家小组成员提出了数个安全性问题,包括心血管安全性数据是否可推广至更严重的心脏病患者,因为根据研究的排除标准,已将这些患者排除在外。


专家小组主席波特兰市俄勒冈医科大学肺病与重症医学科的医学教授David Jacoby医生支持对这一制剂的核准,但建议对于合并更严重心脏病的COPD患者做进一步的安全性研究。


威斯康辛大学过敏、肺病与重症医学科的Nizar Jarjour医生也投票支持核准,并指出,数据提示该产品相当安全。但如将其用于试验研究之外的参数,如近期有COPD加重或重度心脏病患者,那么他对能否得出与试验中相同的安全性结果“缺乏足够信心”。


FDA通常会采纳其顾问小组的建议。已确定小组成员无与会议主题相关的潜在利益冲突。偶尔会要求小组成员弃权,但在这次会议上没有发生这种情况。


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