A New Therapeutic Regimen for MDR-TB

耐多药结核病的新治疗方案

• 批准号: 8250158
• 负责人: Carol A. Nacy
• 金额: $ 26.74万
• 依托单位: SEQUELLA, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8250158
• 关键词: Affect; Animal Model; Attention; Cessation of life; Chronic; Clinic; Clinical; Clinical Trials; Colony-forming units; Combined Modality Therapy; Country; Data; Development; Disease; Disease Resistance; Dose; Drug Combinations; Drug Interactions; Drug resistance; Emergency Situation; Goals; Human; In Vitro; Income; Individual; Investigational Drugs; Lead; Lung; Modeling; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mutation; Mycobacterium tuberculosis; Pharmaceutical Preparations; Phase; Plasma; Property; Public Health; Pyrazinamide; Regimen; Relapse; Research; Resistance; Resistance development; Rifampin; Signal Transduction; Small Business Innovation Research Grant; Spleen; Staging; Structure of parenchyma of lung; Time; Tissues; Treatment Efficacy; Treatment Failure; Treatment Protocols; Tuberculosis; Withholding Treatment; World Health Organization; drug candidate; drug efficacy; global health; improved; in vivo; innovation; interest; isoniazid; mouse model; novel; novel therapeutics; phase 1 study; prevent; programs; research study; resistant strain; standard of care; tuberculosis drugs; tuberculosis treatment; willingness

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.

描述（由申请人提供）：世界卫生组织（WHO）宣布结核病（TB）全球卫生紧急情况；区别从未染上另一种疾病。全球有20亿人感染结核分枝杆菌（MTB），每年导致超过900万例新的结核病病例，死亡近200万例。结核病控制的一个巨大障碍是耐药性疾病的出现。 MTB的多药抗性菌株（至少对ISONIAZID [INH]和RIFAMPICIN [RIF]具有抗性），每年在41个国家 /地区每年有44万例MDR-TB病例。在许多低到中型收入的国家环境开始治疗之前，通常不常规地确定耐药性的确定，而一线药物的不当治疗可以导致治疗失败和额外的抵抗力发展。一种全新的方案，具有较短的治疗时间和针对结核病和MDR-TB的活性，将减少此问题，为大多数结核病病例提供适当的治疗。 MDR-TB Global扩散关注针对结核病的新药和新药方案的关键需求，尤其是对于MDR-TB。 SQ109（在Sequella的开发中）和TMC207（约翰逊公司（Johnson＆Johnson Company）的Tibotec在开发中）是两个临床阶段药物候选者，现在或不久将在人类的第二阶段效力研究中进行。两者在体外具有对MDR-TB临床菌株的有效活性。 TMC207和吡嗪酰胺（PZA）是一种已建立的第一线结核病药物，在体内具有协同作用，在TB小鼠模型中在组合治疗方案中表现出极好的功效。但是，由于PZA不能阻止对TMC207的耐药性发展，因此至少需要另外一种药物将该方案转变为人类。 SQ109和TMC207的组合在体外也是协同的。我们假设具有完全新颖的作用机理的SQ109可以与TMC207+PZA结合使用，以进一步提高治疗功效并降低复发。该提案概述了两家在临床开发中具有有趣药物的公司之间的重要研究计划，均未注册用于人类。这些研究的结果将使两家公司都能更好地了解联合药物疗效，并可能确定可以在诊所进行评估的方案。我们建议评估在有或没有PZA的TB动物模型中SQ109和TMC207的相互作用，以生成有关这三种药物相互作用的非临床数据。具体目的1。评估拟议组合处理的药物与药物相互作用。具体目的2。评估组合治疗方案使用这些药物的功效。特定目标3。评估AIM 2中最有效方案的小鼠复发率。 公共卫生相关性：迫切需要新的药物和药物治疗多药结核病（MDR-TB）的新药和药物方案。目前正在临床试验中的两种药物SQ109和TMC207对MDR-TB具有出色的活性，并且在彼此结合使用时，与吡嗪酰胺（PZA）（PZA）（一种目前用于TB治疗的药物）似乎具有增强的性质。在此应用中，我们建议进一步表征这种有希望的新药组合，目的是获取必要的信息，以使我们能够继续进行临床试验。