A New Therapeutic Regimen for MDR-TB

描述（由申请人提供）：世界卫生组织（WHO）宣布结核病（TB）为全球卫生紧急情况;从未给予其他疾病的区别。全世界有20亿人感染结核分枝杆菌（Mtb），每年导致900多万新发结核病例和近200万人死亡。结核病控制的一个重大障碍是抗药性疾病的出现。耐多药结核分枝杆菌菌株（至少对异烟肼[INH]和利福平[RIF]耐药）每年在41个国家导致440，000例新的耐多药结核病例。在许多中低收入国家，在开始治疗前通常不确定耐药性，一线药物治疗不当可能导致治疗失败和产生更多耐药性。一种治疗时间更短、对结核病和耐多药结核病都有效的全新方案将减少这一问题，为大多数结核病病例提供适当的治疗。耐多药结核病在全球的蔓延使人们的注意力集中在开发结核病新药和新药治疗方案的迫切需要上，特别是针对耐多药结核病。SQ 109（由Sequella开发）和TMC 207（由约翰逊和约翰逊公司的Tibotec开发）是两种临床阶段的候选药物，目前或不久将进入人体2期疗效研究。两者在体外对耐多药结核临床菌株都具有有效的活性。TMC 207和吡嗪酰胺（PZA）（一种已确立的一线TB药物）在体内具有协同作用，并在TB小鼠模型的联合治疗方案中表现出优异的疗效。然而，至少需要一种额外的药物将这种方案过渡到人类，因为PZA不能阻止对TMC 207的耐药性的发展。SQ 109和TMC 207的组合在体外也是协同的。我们假设SQ 109具有全新的作用机制，可以与TMC 207 +PZA联合使用，以进一步提高治疗效果并减少复发。该提案概述了两家公司之间的一项重要研究计划，这些公司在临床开发中具有令人感兴趣的药物，但均未注册用于人类。这些研究的结果将使两家公司更好地了解联合药物的疗效，并可能确定一个方案，可以在临床上进行评估。我们建议评估SQ 109和TMC 207在结核病动物模型中的相互作用，有和没有PZA，以产生这3种药物相互作用的非临床数据。具体目标1。评价拟定联合治疗的药物相互作用。具体目标2。评价这些药物联合治疗方案的疗效。具体目标3。评价目标2中确定的最有效方案的小鼠复发率。 公共卫生相关性：迫切需要治疗耐多药结核病（MDR-TB）的新药和药物方案。目前正在进行临床试验的两种药物，SQ 109和TMC 207，对耐多药结核病具有优异的活性，并且在相互联合使用以及与目前用于结核病治疗的药物吡嗪酰胺（PZA）联合使用时，似乎具有增强的特性。在本申请中，我们建议进一步表征这种有前途的新药组合，目的是获得必要的信息，使我们能够推进临床试验。

DESCRIPTION (provided by applicant): World Health Organization (WHO) declared tuberculosis (TB) a global health emergency; a distinction never accorded another disease. Two billion people are infected with Mycobacterium tuberculosis (Mtb) worldwide, leading to over 9 million new TB cases each year and nearly 2 million deaths. A considerable obstacle to TB control is the emergence of drug-resistant disease. Multidrug-resistant strains of Mtb (resistant to at least isoniazid [INH] and rifampicin [RIF]) result in 440,000 new cases of MDR-TB each year in 41 countries. Determination of drug resistance is not routinely made prior to the start of treatment in many low-to-middle income country settings, and inappropriate treatment with the 1st-line drugs can lead to treatment failure and additional resistance development. An entirely new regimen with a shorter treatment time and activity against both TB and MDR-TB would reduce this problem, providing appropriate therapy for the majority of TB cases. MDR-TB global spread focused attention on the critical need to develop new drugs, and new drug regimens, for TB, but especially for MDR-TB. SQ109 (in development by Sequella) and TMC207 (in development by Tibotec, a Johnson & Johnson company) are two clinical stage drug candidates that are now or will shortly be in Phase 2 efficacy studies in humans. Both have potent activity against MDR-TB clinical strains in vitro. TMC207 and Pyrazinamide (PZA), an established 1st-line TB drug, are synergistic in vivo and demonstrate excellent efficacy in a combination treatment regimen in a mouse model of TB. However, at least one additional drug will be needed to transition this regimen to humans, since PZA does not prevent the development of drug resistance to TMC207. The combination of SQ109 and TMC207 is also synergistic in vitro. We hypothesize that SQ109, with a completely novel mechanism of action, can be combined with TMC207+PZA to further improve treatment efficacy and reduce relapse. This proposal outlines an important research program between 2 companies with interesting drugs in clinical development, neither registered for use in humans. The results of these studies will give both companies a better understanding of combination drug efficacy and may identify a regimen that could be evaluated in the clinic. We propose to evaluate interaction of SQ109 and TMC207 in animal models of TB, with and without PZA, to generate nonclinical data on the interaction of these 3 drugs. Specific Aim 1. Evaluate drug-drug interactions of proposed combination treatments. Specific Aim 2. Evaluate efficacy of combination treatment regimens with these drugs. Specific Aim 3. Evaluate relapse rate of mice for the most effective regimen(s) identified in Aim 2. PUBLIC HEALTH RELEVANCE: New drugs and drug regimens to treat multidrug-resistant tuberculosis (MDR-TB) are desperately needed. Two drugs currently in clinical trials, SQ109 and TMC207, have excellent activity against MDR-TB and appear to have enhanced properties when used in combination with each other and with Pyrazinamide (PZA), a drug currently used for TB treatment. In this application, we propose to further characterize this promising new drug combination, with the goal of obtaining the necessary information to allow us to move forward with clinical trials.