强生旗下Sirturo在欧洲获得批准，成为几十年来进入欧洲市场的新类型结核病(TB)治疗药物之一。欧盟已授予Sirturo (bedaquiline)上市许可，做为肺多重耐药(MDR) TB合并治疗方案的一部分，该病症属孤儿适应症，在欧洲影响大约万分之二的人口。
这次的批准基于一项2期临床试验，强生下属子公司杨森制药正在开展一项3期临床试验，以确证这款药物的风险和收益。Sirturo于2012年年底在美国获得批准，它是TB治疗的一项重要科学进展，因为这款药物是首款抑制分枝杆菌三磷酸腺苷合酶的药物，分枝杆菌三磷酸腺苷合酶是结核菌能量产生所必需的一种酶。
对强生来说，这款药物销售未有很大的预期，因这它用于不能耐受其它药物或感染了耐药菌株的患者，但据分析师们的预测，这款药物全球年销售峰值可能会达到约3亿美元。然而，从公共健康的角度来看，这款药物的重要性怎么强调都不过分，尽管其标签中需要添加一项罕见心血管副作用(QT间期延长)的警告。
“MDR-TB与高死亡率相关，对公共健康造成明显威胁，作为感染了耐药菌株的个人，通常不能获得充分的治疗，并将他们的感染进行传播，”阿姆斯特丹大学热带医学和旅行医学中心主管Martin Grobusch教授评论说。Bedaquiline的批准“是应对这种快速增长疾病迈出的关键一步，加快了患者获取急需的治疗药物，”他补充说。
治疗多药耐药结核病完全新颖的药物一直寥寥无几，去年欧洲批准了一连串的新药，有日本大冢的Deltyba (delamanid)，这款药物去年9月获得有条件批准，另外还有Pharma SA的对氨水杨酸。近年来，TB对至少包括异烟肼和利福平在内的一线治疗药物耐药的负担因缺乏新的治疗选择而迅速增长，异烟肼和利福平是两款重要的抗结核病治疗药物。
References
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Francis J. Curry National Tuberculosis Center, California Department of Health Service. Drug-resistant tuberculosis: a survival guide for clinicians. 2nd ed. San Francisco, CA: Francis J. Curry National Tuberculosis Center, California Department of Public Health; 2011.
World Health Organization. Global tuberculosis report 2012. Geneva, Switzerland: World Health Organization; 2012.
World Health Organization. Multidrug and extensively drug-resistant tuberculosis (M/XDR-TB). 2010 global report on surveillance and response. Geneva, Switzerland: World Health Organization; 2010.
Wells CD. Tuberculosis among HIV-infected and other immunocompromised hosts: epidemiology, diagnosis, and strategies for management. Curr Infect Dis Rep 2010;12:192–7
Johnston JC, Shahidi NC, Sadatsafavi M, Fitzgerald JM. Treatment outcomes of multidrug-resistant tuberculosis: a systematic review and meta-analysis. PLoS ONE 4[9]:e6914.doi:10.1371/journal.pone.0006914
Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006;368:1575–80.
Food and Drug Administration. SIRTURO (bedaquiline) tablets label. Washington, DC: Food and Drug Administration; 2012. Available athttp://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf .
Food and Drug Administration. Briefing package: Sirturo. Washington, DC: Food and Drug Administration; 2012. Available athttp://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329258.pdf .
Food and Drug Administration. Briefing package: TMC207 (bedaquiline). Treatment of patients with MDR-TB. Washington, DC: Food and Drug Administration; 2012. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329260.pdf .
Cox EM. FDA accelerated approval letter to Janssen Research and Development. Washington, DC: Food and Drug Administration; 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/204384Orig1s000ltr.pdf .
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Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009;360:2397–405 10.1056/NEJMoa0808427.
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Information
Generic Name: bedaquiline
Trade Name: Sirturo
Synonym: TMC 207
Entry Type: New molecular entity
Developmental Status
UK: Launched
EU: Launched
US: Approved (Licensed)
UK launch Plans: Available only to registered users
Actual UK launch date: 01/06/2014
Comments
Jun 14: Launched in the UK [10].
09/06/2014 15:51:37
Mar 14: Approved in the EU [9].
13/03/2014 09:19:53
Dec 13: EU CHMP recommends granting conditional approval of bedaquiline for use as part of an appropriate combination regimen for pulmonary multidrug-resistant TB in adults when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability [8].
23/12/2013 08:40:43
Dec 12: Approved in the US as part of combination therapy to treat adults with multi-drug resistant pulmonary TB when other alternatives are not available [7].
02/01/2013 15:47:41
Nov 12: an FDA advisory committee voted 18-0 in favour of efficacy of bedaquiline, for combating multidrug-resistant pulmonary TB, but voted 11-7 in support of safety data; concerns about the effects of the treatment on the liver and heart have been raised [6].
29/11/2012 22:27:07
Sep 12: Granted priority review in the US [5].
11/09/2012 17:00:52
Aug 12: Marketing Authorisation Application submitted to the European Medicines Agency seeking conditional approval for the use of bedaquiline (TMC207) as an oral treatment, to be used as part of combination therapy for pulmonary, multi-drug resistant tuberculosis (MDR-TB) in adults. [4]
03/09/2012 08:29:11
July 12: New Drug Application submitted to the US FDA seeking accelerated approval for the use of the bedaquiline as an oral treatment, to be used as part of combination therapy for pulmonary, multi-drug resistant tuberculosis (MDR-TB) in adults. If approved by the FDA, bedaquiline would be the first drug with a new mechanism of action for TB in more than 40 years and the first and only one specifically indicated for MDR-TB. [1]
05/07/2012 16:53:58
Trial or other data
July 12: Phase III trial TMC207-C210 a double-blind study comparing nine months of treatment with bedaquiline versus placebo (both with a background regimen) is planned to start recruiting in Q4 2012. This study will eva luate a new regimen of seven drugs for a shorter treatment duration (nine months of treatment) than the current 18 to 24 months WHO standard of care. [1]
05/07/2012 16:59:17
July 12: Two Phase II studies in patients with MDR-TB. (1) TMC207-C208 was conducted in two independent stages: stage 1 was a controlled, randomised, exploratory trial and stage 2 was a controlled, randomised superiority trial in MDR-TB patients. 161 patients received treatment for 24 weeks followed by continuation of the background therapy for an additional 12 to 18 months. (2) TMC207-C209 was an open-label trial in MDR-TB patients, in which bedaquiline was administered as 400 mg once daily for two weeks followed by 200 mg three times weekly for 22 weeks in combination with an individualised background regimen for MDR-TB, followed by continued administration of the background regimen for 12 to 18 months (n=233). [1]
05/07/2012 16:58:52
Evidence Based eva luations
EPAR http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002614/human_med_001730.jsp&mid=WC0b01ac058001d124
Other http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf
FDA doc http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329258.pdf
References
Available only to registered users
Category
BNF Category: Antituberculous drugs (05.01.09)
Pharmacology: diarylquinolone compound that inhibits ATP synthase (ATPase) in Mycobacterium tuberculosis
Epidemiology: According to the Health Protection Agency’s annual TB report, the number of drug resistant cases of TB (when a patient fails to respond to 1 of the 4 main antibiotics used to treat the infection) continue to rise, with 431 reports in 2011, up from 342 in 2010 – an increase of 26%. Overall, 8963 new cases of TB were reported to the Agency in 2011, up from 8410 cases in 2010. [3]
Indication: Tuberculosis
Additional Details: multi-drug resistant
Method(s) of Administration
Oral
Company Information
Name: Janssen-Cilag
US Name: Johnson & Johnson
NICE Information
In timetable: No
When: /
PBR Likely Healthcare Resource Group included.
Service
Implications Available only to registered users
Prescribing
Outlook: Available only to registered users
Sirturo（Bedaquiline）能显著提高耐药肺结核治愈率
杨森制药的Sirturo(Bedaquiline)治疗多耐药肺结核的长期跟踪结果。这是一个二期临床，共有160人参加。用药组和对照组都以标准疗法作为背景治疗。用药组前两周使用每日一次400mg Sirturo，然后使用22周每周3次200mg的维持剂量。结果在第120周用药组治愈率为58%，而对照组为32%，但用药组有10人死亡而对照组只有2人死亡。
肺结核是世界第二传染病杀手，2012年有860万病人，其中130万人死于这个疾病。这是比ALS和Ebola严重得多的疾病，但没有人为肺结核药物研发泼冰水，因为肺结核的发病区使不起冰水，甚至连干净的饮用水都是奢侈品。正所谓“石壕村里夫妻别，泪比长生殿上多”。这样严重的大病种40年来只有Sirturo一个全新机理药物上市。肺结核一般需联合多种药物长期治疗，可达2年用药时间，所以Sirturo的半年用药时间算短的。
美国约有1万患者，Sirturo因此在FDA获得孤儿病药权利。Sirturo抑制ATP合成酶，适用人群为对多种药物耐药肺结核病人。这种病人死亡率高达15%，2008年共有15万人死于该病。2012年9月FDA给予Sirturo优先审批，11月FDA专家组以18-0支持其疗效，以11-7支持其安全性。Sirturo有延长QT的副作用，可以导致严重的心脏副作用甚至死亡。在这个实验的79名用药组中有10例死亡，其中1人死于车祸，不算数，但仍有5例和结核病失控有关。另外4例死亡发生在停药较长时间以后，所以难以推断是否是药物造成。据FDA讲Sirturo的超长半衰期（5个月）也无法解释滞后死亡。FDA称多耐药肺结核死亡率高，病人没有其它选择，并如果不及时治愈可能继续传播给他人，所以权衡利弊值得使用，但有黑框警告。
因为Sirturo目前的数据显示有可能致死，所以这个产品只能用于对已有药物耐药的病人。现在进行的3期临床会更加准确定义Sirturo的疗效和安全性。这个实验的主要病人来源是非洲，疗效能否外推到其他人种需要更多实验证实。Sirturo一个疗程在发达国家卖30000美元，中等发达国家买3600美元，低收入国家卖900美元。很多东南亚国家和中国都被列为中等发达国家，但得这个病都是这些国家的穷人，能否支付的起3600美元的药费也是个问题。不管怎样多耐药肺结核是个非常致命的疾病，Sirturo作为40年来第一个全新机理药物是对这个领域的一个重要贡献。
