Harnessing potent next-generation diarylquinolines for long-acting injectable formulations to prevent and treat tuberculosis

项目摘要/摘要 结核病是艾滋病毒携带者过早死亡的最常见原因，以及 有效的结核病预防和治疗战略对于预防PLWH中与结核病相关的死亡至关重要。招待- 活动性肺结核的治疗要求每天服用多种药物至少6个月。尽管这是一种很有希望的养生法 对于结核病预防治疗(TPT)，只需要每天服用一个月的药物(异烟肼和利福喷丁或“1HP”)， 目前世界卫生组织(世卫组织)批准的方案需要4-9个月的日常治疗， 在高结核病负荷环境下，推荐连续服药(≥36个月)。有明确的证据表明 更短的方案与更高的完成率相关，对于TPT和活动性结核病来说，未能 完全治疗会降低治疗效果。长效注射(LAI)药物制剂的使用可 简化结核病防治方案，通过减轻负担提高完成率，两者 对于个人患者和公共卫生系统，与数月至数年的每日药片摄入量有关。最近， 二芳基喹啉(DAQ)贝达奎兰的LAI制剂显示出对A 世卫组织批准的方案(利福平单一疗法)在经验证的TPT小鼠模型中。下一代 作为口服药物，DARQS的TBAJ-876和TBAJ-587目前处于第一阶段试验，对分枝杆菌的作用更强 活动性结核病治疗小鼠模型中的结核病，并具有高度服从于 LAI配方。这个里程碑驱动的R61/R33项目的目标是开发LAI配方 用于TPT的下一代DAQ和DAQ与配伍试剂(pretomanid， Delamanid和/或利福布汀)，用于活动性结核病治疗的继续阶段。在R61公路上 阶段，研究将集中在开发和选择优化的下一代LAI配方 DAQ和/或DAQ PLUS配伍制剂的组合、基于生理学的药代动力学模型 和非临床药代动力学/药效学研究，以预测有效剂量和测试证据- 在经验证的TPT小鼠模型和具有良好特性的活动性结核病治疗小鼠模型中提出了这一概念。在……里面 R33阶段，研究将集中在研究性新药(IND)-使非临床特征 在R61阶段开发和选择的1-2个LAI配方，包括注射部位的安全性和耐受性； 以及相关的化学、制造和控制问题，包括热稳定性。此外，高级非 将在TPT和活动性结核病治疗的小鼠模型上进行临床疗效测试，以证实长期有效。 LAI方案的期限、灭菌活性。该项目的最终目标是开发和非临床应用 验证针对TPT的基于DAQ的“一次性”LAI治疗以及基于LAI的优化治疗 活动性结核病治疗继续阶段使用的战略。

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the most common cause of premature death among people living with HIV (PLWH), and effective TB prevention and treatment strategies are critical for preventing TB-related deaths in PLWH. Treat- ment of active TB requires the daily intake of multiple drugs for at least 6 months. Although a promising regimen for TB preventive therapy (TPT) requires only one month of daily drugs (isoniazid and rifapentine or “1HP”), current World Health Organization (WHO) approved regimens require 4-9 months of daily treatment, and for PLWH in high TB burden settings, continuous TPT (≥36 months) is recommended. There is clear evidence that shorter regimens are as associated with higher completion rates and, for both TPT and active TB, failure to complete therapy decreases treatment efficacy. The use of long-acting injectable (LAI) drug formulations may simplify regimens for TB prevention and treatment and increase completion rates by reducing the burdens, both for individual patients and for public health systems, associated with months to years of daily pill intake. Recently, an LAI formulation of the diarylquinoline (DARQ) bedaquiline demonstrated superior bactericidal activity to a WHO-approved regimen (rifampin monotherapy) in a validated mouse model of TPT. The next generation DARQs TBAJ-876 and TBAJ-587, now in phase 1 trials as oral drugs, are more potent against Mycobacterium tuberculosis in mouse models of active TB treatment and have physiochemical properties highly amenable to LAI formulation. The objective of this milestone-driven R61/R33 project is to develop LAI formulations of a next-generation DARQ for TPT and DARQ co-formulated with a companion agent (pretomanid, delamanid, and/or rifabutin), for use during the continuation phase of active TB treatment. In the R61 phase, research will focus on development and selection of optimized LAI formulations of a next-generation DARQ and/or a combination of a DARQ plus companion agent, physiologically-based pharmacokinetic modeling and non-clinical pharmacokinetic/pharmacodynamic studies to predict efficacious doses and testing proof-of- concept in a validated mouse model of TPT and a well-characterized mouse model of active TB treatment. In the R33 phase, research will focus on investigational new drug (IND)-enabling non-clinical characterization of 1-2 LAI formulations developed and selected in the R61 phase, including injection site safety and tolerability, and relevant chemistry, manufacturing, and control issues, including heat stability. In addition, advanced non- clinical efficacy testing will be conducted in mouse models of TPT and active TB treatment to confirm the long- term, sterilizing activity of LAI regimens. The ultimate goal of this project is to develop and non-clinically validate a “one-shot” DARQ-based LAI treatment for TPT as well as an optimized LAI-based treatment strategy for use in the continuation phase of active TB treatment.