强生（JNJ）3月7日宣布，结核病新药Situro（bedaquiline）获欧盟委员会（EC）有条件批准（conditional approval），作为组合疗法的一部分，用于因耐药性或耐受性使得一种有效治疗方案不能用于其临床治疗的肺部耐多药结核病（MDR-TB）成人患者的治疗。
此前，Sirturo被指定为孤儿药地位，并于2013年12月获欧盟CHMP建议批准的积极意见。CHMP认为，强生所提供的数据表明，Sirturo的临床利益大于其风险，该药可能有助于应对多耐药结核病在新治疗选择方面远未满足的医疗需求，但这些数据尚不全面，因此，应该就Sirturo的使用开展更多的研究。
在美国，Sirturo于2012年12月通过加速审批程序获FDA批准，该药是近40年来首个具有全新作用机制的TB药物，同时也是有史以来首个明确用于MDR-TB的TB药物。Sirturo具有独特的作用机制，通过靶向ATP合成酶来杀死结核分枝杆菌（M.tb），而ATP合成酶对能量的生成至关重要。
Sirturo的获批，是基于一项II期临床开发项目的24周数据。根据规定，强生将开展一项III期试验，进一步证实Sirturo的利益风险，并确定其最佳使用，包括需要联合用药的药物类型、数量及最佳治疗期。
结核病（tuberculosis）是由结核杆菌（Mycobacterium tuberculosis）引发的一种传染性疾病，主要影响肺部。在欧盟，结核病是一种罕见病，据2011年预计数据，结核病在欧盟的发病率约为万分之2.3。耐多药结核病是指至少对异烟肼（ isoniazid）和利福平（rifampicin）耐药的结核病，这2种药物是用于结核病标准治疗中的2种主要的抗结核药物。据估计，在全球范围内，每年发生约45万例耐多药结核病病例，相当于全球每年结核病的5%。
近年来，由于缺乏新的治疗选择，耐药性结核病所导致的公共健康问题迅速增加。耐多药结核病与高的死亡率相关，已构成了严重的公共健康威胁，因为感染了耐药菌株的患者无法获得充分的治疗，并有可能传播感染。
Sirturo则为那些没有其他治疗选择的患者带来了希望。但是，该药也有一些严重的风险，医生应确保合理应用该药物，只适用于对其他抗结核治疗无效的患者。
Beerse, Belgium, March 6, 2014 — Janssen-Cilag International NV (Janssen) announced today that the European Commission (EC) has granted conditional approval to SIRTURO® (bedaquiline) in the European union, for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients, when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.
The decision from the EC follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending the approval of bedaquiline on December 20, 2013.
“We are delighted that SIRTURO® has been approved for use in the European union, as it represents a significant step forward in helping address a very serious global public health issue,” said Wim Parys, Head R&D, Global Public Health at Janssen. “We will continue to work with partners and relevant authorities to ensure SIRTURO® is used correctly and appropriately, and we recognise the importance of educational efforts in informing physicians and patients about appropriate use."
SIRTURO® was discovered by scientists at Janssen and has a unique mechanism of action that inhibits mycobacterial ATP (adenosine 5’triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. The conditional approval by the EC is supported by 24-week data from the Phase 2 clinical development programme, which included a controlled, randomised trial that evaluated the safety and efficacy of SIRTURO® versus placebo in the treatment of patients with pulmonary MDR-TB in combination with a background regimen (TMC207-C208) and an open-label study (C209). The durability of effect was supported by 120-week data from the Phase 2 controlled, randomised trial.[1]
In Phase 2 studies, the SIRTURO® treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group. The median time to culture conversion was 83 days for the SIRTURO® treatment group, compared to 125 days for the placebo treatment group at week 24 (TMC207-C208). At week 120, treatment with SIRTURO® continued to result in a significantly improved culture conversion rate versus the placebo treatment group.
Furthermore, based on WHO-recommended treatment outcome definitions applied to week 120 final data, the proportion of patients defined as cured at 120 weeks was 57.6% in the SIRTURO® arm vs. 31.8% in the placebo arm (p=0.003).
“MDR-TB is associated with a high mortality rate and poses a significant public-health threat, as inpiduals infected with drug-resistant strains are often unable to receive adequate treatment and can potentially spread their infection,” said Professor Martin Grobusch, Head of the Center for Tropical Medicine and Travel Medicine, University of Amsterdam. “Today’s approval is a critical step forward in tackling this rapidly growing disease and speeding up patient access to much needed treatment.”
Under the provisions of the conditional approval, Janssen commits to support a Phase 3 study to further substantiate the benefit-risk for SIRTURO® and define its optimal use, with regards to the number and types of agents that are needed in combination, and its optimal treatment duration.
To date, SIRTURO® has received accelerated approval in the United States and has been registered in the Russian Federation by JSC Pharmstandard, the company Janssen signed a license agreement with in 2013 for Russia and the Commonwealth of Independent States. Regulatory filings have also been submitted in South Africa, China, India, Thailand, Vietnam, Colombia, and South Korea.
About Multi-Drug Resistant Tuberculosis (MDR-TB)
MDR-TB is a particularly complicated form of TB characterised by resistance to at least two of the standard four-drug, anti-TB drugs.[3] Inadequately treated patients are likely to increase selective pressure, allowing resistant bacteria to thrive and pose a significant transmission risk to the general population.[4] Without significant public health intervention, MDR-TB is projected to infect more than two million people between 2011 and 2015.[4]
About The Clinical Development Program
The clinical development program includes two Phase 2 studies in patients with MDR-TB. 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. Stage 2 compared time to culture conversion following the use of SIRTURO® (400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks) versus placebo in combination with a standardised background regimen for MDR-TB. The study enrolled 161 patients who received treatment for 24 weeks followed by continuation of the background therapy for an additional 12 to 18 months. Results were presented in 2010 at the 41st union World Conference on Lung Health in Berlin, Germany.[5] Results from Stage 1 were published in The New England Journal of Medicine [6] in 2009. The submission contains 120 week data from TMC207-C208 Stage 2, the results of which were published in 2013 at the 44th union World Conference of Lung Health in Paris, France.[1]
TMC207-C209 is a Phase 2 open-label trial in MDR-TB patients, in which SIRTURO® was administered as 400 mg once daily for two weeks followed by 200 mg three times weekly for 22 weeks in combination with an inpidualised background regimen for MDR-TB, followed by continued administration of the background regimen for 12 to 18 months. A total of 233 patients from 11 countries were enrolled in the trial, designed to evaluate the safety and efficacy of SIRTURO® in treatment-experienced patients, including 25% with pre-extensively drug-resistant TB (pre-XDR) and 21% with XDR-TB. Results were presented in 2011 at the 42nd union World Conference on Lung Health in Lille, France.[7]
Janssen will conduct a Phase 3 study to further substantiate the benefit-risk for SIRTURO® and define the optimal use of SIRTURO®, with regards to the number and types of agents that are needed in combination, and the optimal treatment duration.
European Commission grants conditional approval to Janssen's TB drug Sirturo
Published 07 March 2014
The European Commission (EC) has granted conditional approval to Janssen-Cilag International's (Janssen's) Sirturo (bedaquiline) in the European union (EU), for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients.
Sirturo is indicated when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.
The approval follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending the approval of bedaquiline in December 2013.
Janssen head of R&D, Global Public Health Wim Parys said the company is delighted that Sirturo has been approved for use in the EU, as it represents a significant step forward in helping address a very serious global public health issue.
"We will continue to work with partners and relevant authorities to ensure Sirturo is used correctly and appropriately, and we recognise the importance of educational efforts in informing physicians and patients about appropriate use," Parys said.
Scientists at Janssen have discovered Sirturo, which has a unique mechanism of action that inhibits mycobacterial ATP (adenosine 5'triphosphate) synthase, an enzyme that is necessary for the generation of energy in Mycobacterium tuberculosis.
The EC approval is based on 24-week data from the Phase II clinical development programme, which included a controlled, randomized trial that assessed the safety and efficacy of the drug versus placebo in the treatment of patients with pulmonary MDR-TB in combination with a background regimen (TMC207-C208) and an open-label study (C209).
The company said that the durability of effect was supported by 120-week data from the Phase II controlled, randomized trial.
Under the provisions of the approval, Janssen will support a Phase III trial to further substantiate the benefit-risk for Sirturo and define its optimal use, with regards to the number and types of agents that are needed in combination, and its optimal treatment duration.
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