A New Therapeutic Regimen for MDR-TB

描述(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；这一区别从未给予其他疾病。全世界有20亿人感染结核分枝杆菌(Mtb)，每年导致900多万新结核病病例和近200万人死亡。结核病控制的一个相当大的障碍是出现抗药性疾病。耐多药的结核分枝杆菌菌株(至少对异烟肼和利福平耐药)每年在41个国家导致44万例新的耐多药结核病病例。在许多中低收入国家，在开始治疗之前，通常不会进行耐药性测定，不适当的一线药物治疗可能导致治疗失败和更多的耐药性发展。一种针对结核病和耐多药结核病的治疗时间和活动都更短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。耐多药结核病的全球传播将注意力集中在开发治疗结核病，尤其是耐多药结核病的新药和新药方案的迫切需要上。SQ109(由Sequella公司开发)和TMC207(由强生公司旗下的Tibotec公司开发)是两种临床候选药物，目前或即将进入人体第二阶段疗效研究。两者在体外对耐多药结核临床菌株均具有较强的抗多药耐药性。TMC207和已确定的一线结核病药物吡津酰胺(PZA)在体内具有协同作用，并在小鼠结核病模型的联合治疗方案中显示出出色的疗效。然而，至少需要一种额外的药物才能将这种方案过渡到人类身上，因为PZA不能阻止对TMC207的耐药性的发展。SQ109和TMC207在体外也具有协同作用。我们推测，具有全新作用机制的SQ109可以与TMC207 PZA联合使用，进一步提高治疗效果，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，该公司拥有临床开发中感兴趣的药物，这些药物都没有注册用于人类。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，并可能确定一种可以在临床上进行评估的方案。我们建议评估SQ109和TMC207在结核病动物模型中的相互作用，包括使用和不使用PZA，以产生关于这三种药物相互作用的非临床数据。具体目的1.评价拟议联合治疗的药物-药物相互作用。具体目的2.评价这些药物联合治疗方案的疗效。具体目标3.评估目标2中确定的最有效方案(S)小鼠的复发率。 公共卫生相关性：迫切需要治疗耐多药结核病(MDR-TB)的新药和用药方案。目前正在进行临床试验的两种药物SQ109和TMC207对耐多药结核病具有出色的活性，当它们与目前用于治疗结核病的药物吡嗪酰胺(PZA)联合使用时，似乎具有更好的性能。在这项申请中，我们建议进一步描述这一前景看好的新药组合的特征，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.