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）为全球突发卫生事件；另一种疾病从未有过这种区别。全世界有20亿人感染结核分枝杆菌（Mtb），每年导致900多万新发结核病病例和近200万人死亡。结核病控制的一大障碍是耐药疾病的出现。耐多药结核分枝杆菌菌株（至少对异烟肼[INH]和利福平[RIF]具有耐药性）每年在41个国家造成44万例耐多药结核新病例。在许多低收入和中等收入国家环境中，在开始治疗之前通常不会确定耐药性，并且用一线药物进行不适当的治疗可能导致治疗失败和进一步的耐药性发展。一种全新的治疗方案，缩短结核病和耐多药结核病的治疗时间和活性，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蔓延使人们的注意力集中在迫切需要为结核病，特别是耐多药结核病开发新药和新的药物方案上。SQ109 （Sequella公司正在开发）和TMC207（强生公司Tibotec公司正在开发）是两种临床阶段的候选药物，目前正在或即将在人体进行2期疗效研究。两者在体外均对耐多药结核病临床菌株具有强效活性。TMC207和吡嗪酰胺（Pyrazinamide， PZA）是一种已建立的一线结核病药物，在体内具有协同作用，并在结核病小鼠模型中显示出良好的联合治疗方案疗效。然而，由于PZA不能阻止对TMC207的耐药性的发展，至少需要一种额外的药物才能将这种方案过渡到人类。SQ109和TMC207在体外也具有协同作用。我们推测SQ109可以通过一种全新的作用机制，与TMC207+PZA联合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个重要研究项目，两家公司都有正在临床开发的有趣药物，但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用药的疗效，并可能确定一种可以在临床评估的治疗方案。我们建议评估SQ109和TMC207在患有和不患有PZA的TB动物模型中的相互作用，以获得这3种药物相互作用的非临床数据。具体目标评估拟议联合治疗的药物-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。评估目标2中确定的最有效方案的小鼠复发率。

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.