新的噻托溴铵制剂即将获准用于治疗COPD

马里兰州银泉——基于大型随机TIOSPIR研究的心血管安全性数据，食品药品管理局（FDA）咨询专家组的大部分组员（10票赞成3票反对）支持批准通过新型给药装置（含30剂）给予吸入式噻托溴铵液体喷雾制剂（5 μg/d，每天1次）用于慢性阻塞性肺病（COPD）相关支气管痉挛的长期维持治疗和减少COPD加重。

如果FDA批准该产品，勃林格殷格翰公司计划以商品名Spiriva Respimat进行销售。该药自2007年起在美国以外的国家上市，目前在超过85个国家有售。

Spiriva Respimat获批治疗的适应证与单剂量噻托溴铵干粉制剂Spiriva HandiHaler相同，后者于2004年获得FDA批准，其给药方式是在每次给药时将胶囊插入呼吸启动的HandiHaler装置进行给药。

勃林格殷格翰公司表示，Respimat装置的给药剂量为5μg，HandiHaler装置的给药剂量为18μg，两者的药代动力学作用和全身暴露相似。专家组一致认为没有数据显示使用Respimat装置进行治疗比使用HandiHaler更有效，并且该研究没有任何数据表明患者对Respimat装置的依从性更佳。

TIOSPIR为随机、双盲、平行组研究，入选超过17,000例COPD患者，随访至少2年，目的是探讨噻托溴铵Respimat 5 μg 1次/d和Respimat 2.5 μg 1次/d在全因死亡率方面是否非劣效于噻托溴铵HandiHaler 18 μg 1次/d。结果显示所有3组的全因死亡率相似。3组的致死性MACE（主要不良心血管事件）发生率相似，但在2个致死性MACE成分（心脏障碍和致死性心肌梗死）方面存在数值上的轻微差异。

专家组表示致死性心肌梗死发生率方面的差异可能是随机结果，不足以支持投反对票。然而，一些专家表示在不同研究中观察到的心血管安全性信号一直是个值得担心的问题，这包括投了赞成票的国立过敏和传染病研究所生物统计学家Erica H. Brittain医生。Brittain医生对全因死亡率结果和明确疗效持肯定态度，但认为如果Respimat吸入器的易用特征对患者而言不重要的话，其可能建议使用HandiHaler产品。

与其他投了赞成票的专家一样，辛辛那提大学肺、重症监护和睡眠医学科主任Francis McCormack医生认同研究数据达到批准所需的安全性和疗效标准，并且新噻托溴铵产品Spiriva Respimat与现有的Spiriva HandiHaler产品具有可比性，其对使用Spiriva Respimat治疗患者持热衷态度。

旧金山心脏安全研究联盟科学项目委员会主席Philip Sager医生表示研究数据令人放心，并且该产品在治疗COPD患者方面的总体安全性、心血管安全性和明确疗效已得到证实。按亚组来进一步分析MACE终点变得有点复杂，心肌梗死结果可能是统计噪声。

投了反对票的费城宾夕法尼亚大学药物流行病学研究和培训中心的药学博士Sean Hennessy表示仍担心心脏安全性并且没有数据表明Respimat的获益大于HandiHaler。他表示多项随机临床研究均一致观察到致死性心肌梗死发生率增加。

FDA预期在9月21日前作出有关批准的决定。FDA通常遵循其咨询专家组的建议。专家组成员声明无相关经济利益冲突。TIOSPIR研究于2013年10月发表(N. Engl. J. Med. 2013;369:1491-501)。

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By: ELIZABETH MECHCATIE, Cardiology News Digital Network

SILVER SPRING, MD. – Reassured by the cardiovascular safety data in a large randomized study, the majority of a Food and Drug Administration advisory panel supported the approval of an inhaled liquid spray formulation of tiotropium bromide in a new delivery device for the long-term maintenance treatment of chronic obstructive pulmonary disease.

At the Aug. 14 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee, the panel voted 10-3 that the safety and efficacy data supported the approval of tiotropium bromide inhalation spray, at a dose of 5 mcg/day, administered via a device that contains 30 doses, for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

If the FDA approves the product, Boehringer Ingelheim plans to market it as Spiriva Respimat. It has been available outside of the United States since 2007 and is now available in more than 85 countries, according to the company.

The panel unanimously voted that the available data supported the efficacy of the Respimat device for the indication. This is the same indication approved for the dry powder formulation of tiotropium in the single dose, breath-actuated HandiHaler device, marketed as Spiriva HandiHaler by Boehringer Ingelheim, approved in 2004 by the FDA. A capsule is inserted into the HandiHaler device for each dose.

Like others voting for approval, Dr. Francis McCormack agreed the data had met the criteria for safety and efficacy required for approval and that the new tiotropium product, Spiriva Respimat, was comparable to the existing Spiriva HandiHaler product. “I’m enthusiastic about being able to offer this delivery device to my patients,” commented Dr. McCormack, professor of medicine and director of the division of pulmonary, critical care, and sleep medicine at the University of Cincinnati.

The Respimat device delivers a 5-mcg dose, and the HandiHaler device delivers an 18-mcg dose, with similar pharmacokinetic effects and systemic exposure, according to the company. Panelists agreed that treatment with the Respimat device was not shown to be more effective than with the HandiHaler, and the company did not have any data showing that compliance was better with the Respimat device.

Those voting in favor of approval were reassured by the results of a large study that addressed concerns about a cardiovascular mortality signal in earlier studies associated with tiotropium Respimat.

Boehringer Ingelheim filed for approval of tiotropium Respimat almost 7 years ago. At that time, the FDA requested more data from the company to support the exacerbation claim and to address the mortality imbalance among those treated with tiotropium Respimat in 48-week, placebo-controlled studies, and concerns over cardiovascular safety raised during the review.

The randomized, double-blind, parallel group study, the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial of more than 17,000 patients with COPD followed for at least 2 years adjudicated the cause of deaths, comparing 2.5 mg and 5 mg of tiotropium in the Respimat device to the tiotropium HandiHaler device. All-cause mortality in the three groups was similar.

Fatal MACE (major adverse cardiovascular events) rates were similar between the treatment groups, noted Dr. Robert Lim, a clinical reviewer in the FDA’s division of pulmonary, allergy, and rheumatology products. While there were numerical differences in two fatal MACE components – cardiac disorders and fatal myocardial infarction – the differences were small.

Panelists said that the imbalance in fatal MIs could be a random finding and was not strong enough to vote against approval. However, some panelists cited lingering concerns about a cardiovascular safety signal in different studies.

Although she voted in favor of approval, Erica H. Brittain, Ph.D., a biostatistician at the National Institute of Allergy and Infectious Diseases, Bethesda, Md., said that she had “lingering unease” about a cardiovascular safety signal cropping up in several studies. But she was confident with the all-cause mortality finding and the “clear-cut” efficacy. However, if the ease-of-use feature of the Respimat inhaler was not important to a patient, Dr. Brittain noted that she would probably recommend the HandiHaler product.

A cardiologist on the panel, Dr. Philip Sager, said that he was reassured by the data, and that overall safety, cardiovascular safety, and “clear efficacy in treating patients with COPD has been demonstrated.” Breaking the MACE endpoint down by subgroups gets complicated, and the MI finding could be “statistical noise,” added Dr. Sager, chair of the scientific programs committee of the Cardiac Safety Research Consortium, San Francisco.

Voting against approval, Sean Hennessy, Pharm.D., director of the Center for Pharmacoepidemiology Research and Training, University of Pennsylvania, Philadelphia, said he remained concerned about cardiac safety and the absence of data showing Respimat provided benefits over the HandiHaler. He referred to the consistent finding of an increased rate of fatal MIs in multiple randomized clinical trials.

The FDA is expected to make a decision on approval by Sept. 21. The agency usually follows the recommendations of its advisory panels. Panel members had no relevant conflicts of interest to disclose.

The TIOSPIR study was published in October 2013 (N. Engl. J. Med. 2013;369:1491-501).