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Sirturo tab(bedaquiline)

ID号：716 发布日期： 2014-08-24 截止日期：不限地区：全国浏览次数：213

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。
SIRTURO(BEDAQUILINE FUMARATE)
SIRTURO™ Is the First Medication for Pulmonary MDR-TB With a Novel Mechanism of Action in Over 40 Years
Indications
•SIRTURO™ (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (≥18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB).
•Reserve SIRTURO™ for use when an effective treatment regimen cannot otherwise be provided.
•SIRTURO™ should be administered by directly observed therapy (DOT).
•This indication is based on analysis of time to sputum culture conversion from two controlled Phase 2 trials in patients with pulmonary MDR-TB.
Limitations of Use
Use of SIRTURO™ in these settings is not recommended:
•The safety and efficacy of SIRTURO™ for the treatment of drug-sensitive TB (DS-TB), latent infection due to Mycobacterium tuberculosis and for the treatment of infections caused by non-tuberculous mycobacteria (NTM) have not been established.
•There are no data on the treatment with SIRTURO™ of extrapulmonary TB (e.g., central nervous system).
Mechanism of Action
•SIRTURO™ is the first anti-TB drug to interfere with bacterial energy metabolism.
•SIRTURO™ specifically inhibits mycobacterial ATP (adenosine 5'-triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis.
Download a comprehensive resource on SIRTURO™ (bedaquiline) tablets
..IMPORTANT SAFETY INFORMATION
WARNINGS:
•An increased risk of death was seen in the SIRTURO™ treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial. Only use SIRTURO™ when an effective treatment regimen cannot otherwise be provided.
•QT prolongation can occur with SIRTURO™. Use with drugs that prolong the QT interval may cause additive QT prolongation.
Warnings and Precautions
Increased Mortality: An increased risk of death was seen in the SIRTURO™ treatment group. The imbalance in deaths is unexplained.
QT Prolongation: SIRTURO™ prolongs the QT interval. An electrocardiogram (ECG) should be obtained before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO™. Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Discontinue SIRTURO™ and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of >500 ms (confirmed by repeat ECG).
The following may increase the risk for QT prolongation when patients are receiving SIRTURO™, and therefore ECGs should be monitored closely: use with other QT-prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine; a history of Torsade de Pointes; a history of congenital long QT syndrome; a history of hypothyroidism and bradyarrhythmias; a history of uncompensated heart failure; serum calcium, magnesium, or potassium levels below the lower limits of normal.
SIRTURO™ has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
Hepatic-related Adverse Drug Reactions: More hepatic-related adverse drug reactions were reported with the use of SIRTURO™ plus other drugs to treat TB compared to other drugs used to treat TB without the addition of SIRTURO™. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO™, especially in patients with diminished hepatic reserve. Monitor symptoms and liver-related laboratory tests. Discontinue SIRTURO™ if aminotransferase elevations are accompanied by total bilirubin elevation >2X ULN; aminotransferase elevations are >8x ULN; or aminotransferase elevations persist beyond 2 weeks.
Drug Interactions: Co-administration of strong systemic CYP3A4 inducers (e.g., rifamycins such as rifampin, rifapentine, and rifabutin) should be avoided. Co-administration with strong systemic CYP3A4 inhibitors for more than 14 consecutive days should be avoided. Appropriate clinical monitoring for SIRTURO™-related adverse reactions is recommended.
HIV-TB Co-infected Patients: There are no clinical data on the combined use of antiretroviral agents and SIRTURO™ in HIV/MDR-TB co-infected patients, and only limited clinical data on the use in HIV/MDR-TB co-infected patients who were not receiving antiretroviral therapy.
Treatment Failure: SIRTURO™ should be administered by directly observed therapy. SIRTURO™ should only be administered in combination with at least 3 drugs active against the patient’s TB isolate. Nonadherence to the treatment regimen could result in failure or resistance.
Adverse Reactions
The most common adverse drug reactions reported in greater than or equal to 10.0% of patients treated with SIRTURO™ compared to the placebo treatment group were nausea (38.0% vs. 32.1%), arthralgia (32.9% vs. 22.2%), headache (27.8% vs. 12.3%), and additional adverse events reported in greater than or equal to 10.0% of patients and with a higher frequency than the placebo treatment group were hemoptysis (17.7% vs. 11.1%) and chest pain (11.4% vs. 7.4%).
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References
CDC. Treatment of tuberculosis. MMWR 2003;52(No. RR-11).
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 .
Sensi P. History of the development of rifampicin. Rev Infect Dis 1983;5(Suppl 3):S402–6.
Food and Drug Administration. Drugs for the treatment of tuberculosis, including drug resistant tuberculosis. Washington, DC: Food and Drug Administration; 2012. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM188373.pdf .
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.
Diacon AH, Donald PR, Pym A, et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother 2012;56:3271–6 10.1128/AAC.06126-11.
Food and Drug Administration. FDA Pregnancy categories. Washington, DC: Food and Drug Administration; 2004. Available athttp://depts.washington.edu/druginfo/Formulary/Pregnancy.pdf .
Kurbatova EV, Gammino VM, Bayona J, et al. Predictors of sputum culture conversion among patients treated for multidrug‐ esistant tuberculosis. Int J Tuberc Lung Dis 2012;16:1335–43.
Kurbatova EV, Gammino VM, Bayona J, et al. Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment. Int J Tuberc Lung Dis 2011;15:1553–5.
CDC. Tuberculosis laboratory information. Atlanta, GA: US Department of Health and Human Services, CDC; 2013. Available athttp://www.cdc.gov/tb/topic/laboratory/default.htm.
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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