SQ109 for treatment of MDR-TB

SQ109用于治疗耐多药结核病

基本信息

批准号：
7911350
负责人：
Leo Einck
金额：
$ 30万
依托单位：
SEQUELLA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911350
关键词：
Amikacin Animals Antitubercular Agents Antitubercular Antibiotics Bacterial Infections Capromycin Cessation of life Chronic Clinical Clinical Research Clinical Trials Collaborations Combination Drug Therapy Communicable Diseases Cycloserine Data Disease Dose Drug Combinations Drug Exposure Drug Kinetics Drug Resistant Tuberculosis Drug resistance Drug usage Drug-sensitive Ethambutol Ethionamide Evaluation Extreme drug resistant tuberculosis Genus Mycobacterium Health Human In Vitro Incidence Infection Kanamycin Laboratories Lung Moxifloxacin Multi-Drug Resistance Multidrug-Resistant Tuberculosis Mus Mycobacterium tuberculosis National Institute of Allergy and Infectious Disease Natural Resistance Patients Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacotherapy Phase Phenotype Population Predisposition Procedures Pulmonary Tuberculosis Pyrazinamide Regimen Reporting Resistance Rifampicin resistance Rifampin Safety Small Business Innovation Research Grant Spleen Time Toxicology Treatment Protocols Tuberculosis Work World Health Organization antimicrobial base chemotherapy design drug candidate drug efficacy improved in vitro activity in vivo isoniazid killings microorganism mouse model p-Aminosalicylic Acid particle pre-clinical public health relevance resistant strain response safety study small molecule standard care standard of care therapy development tuberculosis drugs tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): SQ109 is a small molecule, orally active drug and is a new drug candidate in clinical development for the treatment of all forms of tuberculosis (TB), including multi-drug resistant (MDR) and extreme drug resistant (XDR) TB. SQ109 has a unique pharmacological profile, and is safe and well-tolerated in animals (90-day dosing) and humans administered a single dose up to 300 mg. SQ109 ability to kill Mtb in vitro is exactly the same for the laboratory strain or clinical isolates, regardless of drug susceptibility phenotype. This suggests that the target of SQ109 is well conserved among Mtb that cause disease. SQ109 also has remarkable synergy with both of the most important first-line antitubercular drugs, Isoniazid (INH) and Rifampin (RIF). Small amounts of SQ109 in combination with standard amounts of RIF actually made RIF-resistant clinical isolates susceptible to RIF again in vitro. In this SBIR Phase 1 application, we will explore the potential of SQ109 for treatment of MDR TB when used in combinations with first- and second-line anti-TB drugs. We will investigate two approaches: In the first approach, which is based on the remarkable synergy between SQ109 and RIF to kill Mtb in both RIFs and RIFR strains, we will evaluate whether or not we can salvage the use of RIF in treatment of RIFR strains of Mtb when combined with SQ109. In second more traditional approach, we will determine the efficacy of SQ109-based drug combinations with second-line drugs that are currently used by clinicians for treatment of patients with MDR TB. SQ109 has completed IND-directed preclinical toxicology, safety, and pharmacology studies, and a Phase 1A human safety study. In collaboration with NIAID, a Phase 1B clinical study to evaluate safety and pharmacokinetics of SQ109 administered daily for 2 weeks began in May 2009 and will conclude in March 2010. Following the successful completion of the Phase 1B trial, SQ109 will enter multinational clinical trials to evaluate efficacy of SQ109 in drug-sensitive pulmonary TB and MDR-TB. PUBLIC HEALTH RELEVANCE: SQ109 is an orally active drug and a new drug candidate in clinical development for the treatment of all forms of tuberculosis (TB), including multi-drug resistant (MDR) and extreme drug resistant (XDR) TB. TB is a contagious bacterial infection caused by Mycobacterium tuberculosis (MTB) transmitted from person to person by airborne particles. TB kills more people than any other single etiologic agent, and yet the drugs used to treat this infectious disease are so ineffective that a combination of drugs given for six months is the standard treatment regimen for uncomplicated drug-sensitive TB. The National Institute of Allergy and Infectious Diseases (NIAID) and World Health Organization (WHO) recognize TB as one of the most serious health problems in the world. Two billion (one third) of the world's population are infected with TB. The estimated incidence of TB disease was more than 9 million worldwide in 2007, and these newly identified active infections resulted in nearly 2 million deaths. WHO reports that over 450,000 of these TB cases had MDR-TB. The WHO and the U.S. FDA are encouraging pharmaceutical companies to develop new TB drugs for MDR-TB, citing the rising numbers of patients and the critical need for new effective drugs for MDR-TB. A clinical trial to establish new drug efficacy for treating MDR-TB will compare a group of MDR-TB patients treated with a standard of care dose regimen selected from the 2nd line TB drugs with a seconf group of MDR-TB patients treated with the new drug plus the same standard of care regimen used in the first group. To correctly design a new regimen for MDR-TB, the clinical trials will benefit from an understanding of how well the drugs work together in humans (pharmacokinetics, interactions) and how efficacious the new regimen is (antimicrobial efficacy of drug combinations). This study proposes to examine the interaction of SQ109 with selected 1st and 2nd line TB drugs.

描述（申请人提供）：SQ109是一种小分子、口服活性药物，是临床开发中的新候选药物，用于治疗所有形式的结核病（TB），包括多重耐药（MDR）和极端耐药（ XDR）结核病。 SQ109 具有独特的药理学特征，在动物（90 天给药）和人类中单剂量高达 300 mg 时是安全且耐受性良好的。无论药物敏感性表型如何，SQ109 体外杀灭 Mtb 的能力对于实验室菌株或临床分离株来说是完全相同的。这表明 SQ109 的靶标在引起疾病的 Mtb 中高度保守。 SQ109还与最重要的一线抗结核药物异烟肼（INH）和利福平（RIF）具有显着的协同作用。少量的 SQ109 与标准量的 RIF 组合实际上使 RIF 耐药的临床分离株在体外再次对 RIF 敏感。在本次 SBIR 1 期申请中，我们将探索 SQ109 与一线和二线抗结核药物联合使用时治疗耐多药结核病的潜力。我们将研究两种方法：第一种方法基于 SQ109 和 RIF 之间显着的协同作用，可杀死 RIF 和 RIFR 菌株中的 Mtb，我们将评估是否可以挽救 RIF 在治疗 RIFR 菌株中的使用与 SQ109 结合使用时的 Mtb。在第二种更传统的方法中，我们将确定基于 SQ109 的药物与目前临床医生用于治疗耐多药结核病患者的二线药物组合的疗效。 SQ109已完成IND指导的临床前毒理学、安全性和药理学研究以及1A期人体安全性研究。与 NIAID 合作，一项 1B 期临床研究于 2009 年 5 月开始，为期 2 周，每天给药，评估 SQ109 的安全性和药代动力学，将于 2010 年 3 月结束。在 1B 期试验成功完成后，SQ109 将进入多国临床试验，以评估 SQ109 的安全性和药代动力学。评估 SQ109 在药物敏感肺结核和耐多药结核中的疗效。公共卫生相关性：SQ109是一种口服活性药物，也是临床开发中的新候选药物，用于治疗所有形式的结核病（TB），包括多重耐药（MDR）和极端耐药（XDR）结核。结核病是由结核分枝杆菌 (MTB) 引起的传染性细菌感染，通过空气中的颗粒在人与人之间传播。结核病造成的死亡人数比任何其他单一病原体都要多，但用于治疗这种传染病的药物却非常无效，因此六个月的药物组合是无并发症的药物敏感结核病的标准治疗方案。美国国家过敏和传染病研究所 (NIAID) 和世界卫生组织 (WHO) 认为结核病是世界上最严重的健康问题之一。世界上有二十亿（三分之一）人口感染了结核病。据估计，2007 年全球结核病发病率超过 900 万，这些新发现的活动性感染导致近 200 万人死亡。世界卫生组织报告称，这些结核病病例中有超过 45 万患有耐多药结核病。世界卫生组织和美国 FDA 鼓励制药公司开发治疗耐多药结核病的新结核病药物，理由是患者数量不断增加，并且迫切需要治疗耐多药结核病的新有效药物。一项旨在确定新药治疗耐多药结核病疗效的临床试验将比较一组接受选自二线结核病药物的标准护理剂量方案治疗的耐多药结核病患者与另一组接受新药治疗的耐多药结核病患者。药物加上与第一组相同的护理方案标准。为了正确设计耐多药结核病的新治疗方案，临床试验将受益于了解药物在人体中的协同作用（药代动力学、相互作用）以及新治疗方案的有效性（药物组合的抗菌功效）。本研究旨在检查 SQ109 与选定的第一线和第二线结核病药物的相互作用。