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

项目总结/摘要 结核病（TB）是艾滋病毒感染者（PLWH）过早死亡的最常见原因， 有效的结核病预防和治疗战略对于预防感染者和妇女健康者中结核病相关死亡至关重要。治疗- 活动性结核病的缓解需要每天摄入多种药物至少6个月。虽然一个很有前途的养生法 对于TB预防性治疗（TPT），仅需要一个月的每日药物（异烟肼和利福喷丁或“1HP”）， 目前世界卫生组织（WHO）批准的方案需要4-9个月的每日治疗， 在结核病高负担环境中，建议连续TPT（≥36个月）。有明确的证据表明 较短的治疗方案与较高的完成率相关，对于TPT和活动性结核病， 完全疗法降低治疗功效。长效可注射（LAI）药物制剂的使用可 简化结核病预防和治疗方案，通过减轻负担提高完成率， 对于个体患者和公共卫生系统，与数月至数年的每日药丸摄入量相关。最近， 二芳基喹啉（DARQ）贝达喹啉的LAI制剂显示出比二芳基喹啉（DARQ）制剂更上级的杀菌活性。 在经验证的TPT小鼠模型中采用WHO批准的方案（利福平单药治疗）。下一代 DARQs TBAJ-876和TBAJ-587，目前作为口服药物处于1期试验，对分枝杆菌更有效 在活动性结核病治疗的小鼠模型中， LAI制剂。这个里程碑式的R61/R33项目的目标是开发LAI制剂， 用于TPT的下一代DARQ和与伴随剂（pretomanid， 地拉马尼和/或利福昔单抗），用于在活性TB治疗的持续阶段期间使用。在R61 在第一阶段，研究将集中在开发和选择下一代的优化LAI配方 DARQ和/或DARQ加伴随剂的组合，基于生理学的药代动力学建模 和非临床药代动力学/药效学研究，以预测有效剂量，并检测 这一概念在经验证的TPT小鼠模型和充分表征的活动性TB治疗小鼠模型中得到证实。在 在R33阶段，研究将集中在研究性新药（IND）上，使非临床表征 1-2在R61阶段开发和选择的LAI制剂，包括注射部位安全性和耐受性， 以及相关的化学、制造和控制问题，包括热稳定性。此外，先进的非 将在TPT和活动性TB治疗的小鼠模型中进行临床疗效测试，以确认长期- 术语，LAI方案的灭菌活性。该项目的最终目标是开发和非临床 验证TPT的“一次性”基于DARQ的LAI治疗以及优化的基于LAI的治疗 在活动性结核病治疗的继续阶段使用的策略。

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.