药品名称:Bedaquiline
生产厂家：强生
适应症：
Bedaquiline就是通过靶向作用于结核分枝杆菌的ATP合成酶抑制细菌产能而发挥作用的。
FDA批准Bedaquiline用于耐药性结核
美国强生制药有限公司Janssen研发中心近日宣布该公司已向美国食品药品监管局提交了抗结核药物TMC207的使用申请，期待尽快得到这种试验性药物的使用批准，据悉，TMC207作为一种口服药物，可用于肺结核及耐多药结核病的联合治疗。若美国食品药品监管局批准了Bedaquiline的使用，Bedaquiline将会成为40多年以来第一种以新机制抗结核的药物，也是第一种及唯一一种治疗耐多药结核病的药物。

强生公司的全球董事长Paul Stoffels说：“结核病耐多药菌株的出现影响着全世界人民并越来越受关注，这将引发对这种严重疾病治疗新方法研究的挑战。”“全世界每年大约有140万人死于结核病，目前现有的治疗方法不能有效抑制耐药菌株，且在过去40年内没有治疗结核病的新方法。我们坚信Bedaquiline药物申请的批准将会是抗结核新药研发发展过程中的一个里程碑。”

Bedaquiline是由强生制药公司Janssen研发中心的科学家们发现的。结核病是由结核分枝杆菌感染引起的，在结核分枝杆菌生存过程中需要自身产生能量以维持细菌的生命，Bedaquiline就是通过靶向作用于结核分枝杆菌的ATP合成酶抑制细菌产能而发挥作用的。

Bedaquiline药物的评估证据需要来源于24周的数据分析，这些数据来自随机的、双盲的、安慰剂对照的第二期临床试验。耐多药肺结核病人均服用Bedaquiline及其他基础抗结核药。

在传染性疾病中，结核病是导致全球成人死亡的第二大病因。世界卫生组织统计，全世界大概每年大约有1/3人口感染结核分枝杆菌且每天约有3800人死于结核病。耐多药结核病即至少对现有的2种强效抗结核药物耐药，对于药物敏感性结核病，至少对4中药物耐药。鉴于全球范围抗菌药物耐药率的增加及治疗难度的加大，我们应该对耐多药结核病引起足够的重视。据统计，2010年大约有65万人患有多耐药结核病，2008年，全球约有15万人死于多耐药结核病。由于多耐药结核病日渐引起的公众健康威胁，世界卫生组织于2009年在北京发出行动呼吁。在美国，结核病是一种孤儿性疾病，每年大约有100-130个孤儿患有多耐药结核病。
Janssen研发中心感染性疾病治疗部门负责人WimParys博士表示：“Bedaquiline的研发是一个重要的里程碑，并且是我们研究治疗结核病跨出的重要的一步。”“它见证了我们致力于发现及研发新药物及解决严重不足的医学需求的努力，我们希望这种新的药物成为多耐药结核病患者治疗的首选药物。

Bedaquiline (TMC-207), a diarylquinolone, is an anti-TB drug based on a novel mode of action (inhibition of ATP synthase). Initial results from a phase 2 randomised, double blind, placebo-controlled trial were reported in the New England Journal of Medicine in 2009. A new article published ahead of print in Antimicrobial Agents and Chemotherapy provides longer term follow-up data on efficacy and safety up to 104 weeks.

This was a multicentre trial within South Africa, enrolling individuals with pulmonary MDR-TB, most of whom were HIV negative (87%). All were treated with an individualised background drug regimen consisting at least of kanamycin, ethionamide, ofloxacin (all except one patient), in combination with other selected second-line TB drugs. Patients were randomised to the inclusion of bedaquiline or placebo in the regimen, administered only for the first eight weeks of therapy. Participants then continued on the background regimen and were followed up for two years (104 weeks).

In total 47 patients were included in the trial (23 treated with bedaquiline, 24 with placebo). Two patients with XDR-TB at baseline were excluded from the efficacy analysis as was one patient with negative pre-treatment culture.

The key findings were:

- Time to 50% sputum conversion was 78 days in the bedaquiline arm vs 129 days in the placebo arm

- At 24 weeks, 81.0% in the bedaquiline arm had culture conversion vs 65.2% in the placebo arm

- Treatment success at 104 weeks was not substantially different between the two groups (52.4% for bedaquiline vs 47.8% for placebo). The precise definition of this outcome is not stated in the paper but it is presumed to represent standard WHO definitions, i.e. cure or completion

Rates of discontinuation in the study were very high, with 49% of all study subjects discontinuing, over half of those within the first 24 weeks. It should be noted that many of these were discontinuation from study follow-up rather than necessarily discontinuation of treatment and that many study subjects were culture negative at the time of discontinuation.

There was evidence that the accumulation of additional drug resistance was more frequent in the placebo arm (6 patients developed additional resistance vs one subject in the bedaquiline arm). Of particular concern was the emergence of fluoroquinolone resistance in four patients in the placebo arm.

In the safety analysis, there was excess nausea in the bedaquiline arm (26.1% vs nil) but no other significant difference between the two arms. This is of concern given that nausea is a symptom that might affect adherence to therapy, especially outside the trial setting with less rigorous monitoring and follow-up. Having said that it is surprising that no nausea was reported in the placebo arm given the drug regimens used in this group and the frequency of this symptom in routine practice. It will be important to assess the frequency, severity, and effect on adherence of nausea in the continuing trials of bedaquiline.

The second stage of the phase 2 trial (an open label trial comparing 24 weeks of bedaquiline vs placebo in combination with a background regimen for MDR-TB patients) has now completed recruitment and the results are awaited with much interest. It is expected that regulatory approval will be sought on the basis of these results. Furthermore, a phase 3 trial is planned, evaluating the use of bedaquiline as part of a 9-month treatment regimen for MDR-TB.

References

Diacon AH, Pym A, Grobusch M, et al. The diarylquinolone TBC207 for multidrug-resistant tuberculosis. N Engl J Med 2009; 360: 2397-2405

Diacon AH, Donald PR, Pym A, et al. Randomised pilot trial of 8 weeks of bedaquiline (TMC207) for MDR-TB: long-term outcome, tolerability and effect on emergence of drug resistance. Antimicrob Agents Chemother 2012 (published ahead of print)