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

利用强效的下一代二芳基喹啉制备长效注射制剂来预防和治疗结核病

• 批准号: 10631987
• 负责人: ERIC L NUERMBERGER
• 金额: $ 61.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-25 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631987
• 关键词: Antitubercular Agents; Cause of Death; Cessation of life; Chemistry; Collaborations; Companions; Data; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Drug resistance in tuberculosis; Evaluation; Failure; Formulation; Goals; Good Manufacturing Process; HIV; Health system; In Vitro; Injectable; Injections; Intake; Investigational Drugs; Investigational New Drug Application; Kinetics; Libraries; Modeling; Mus; Mycobacterium tuberculosis; Oral; Oral Administration; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiological; Plasma; Prevention; Prevention strategy; Preventive therapy; Preventive treatment; Property; Public Health; Rationalization; Recommendation; Regimen; Relapse; Research; Rifabutin; Rifampin; Rifamycins; Safety; Series; Site; Solid; Techniques; Testing; Therapeutic; Treatment Efficacy; Tuberculosis; Universities; Work; World Health Organization; active method; bactericide; candidate selection; comparative efficacy; design; efficacy study; efficacy testing; follow-up; in vivo; individual patient; isoniazid; manufacture; member; mouse model; nanoengineering; nanoparticle drug; next generation; novel; pharmacokinetic model; pharmacokinetics and pharmacodynamics; phase I trial; pill; premature; prevent; rifapentine; scale up; technology platform; treatment strategy; tuberculosis treatment

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.

项目概要/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，并且 有效的结核病预防和治疗策略对于预防艾滋病毒感染者与结核病相关死亡至关重要。 治疗活动性结核病需要每天服用多种药物至少六个月。 结核病预防治疗 (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) 批准的治疗方案需要 4-9 个月的每日治疗，并且 结核病高负担环境下的感染者，建议持续 TPT（≥36 个月） 有明确证据表明。 较短的治疗方案与较高的完成率相关，并且对于 TPT 和活动性结核病而言，未能 完整治疗可能会降低治疗效果。 简化结核病预防和治疗方案，并通过减轻负担来提高完成率 对于个体患者和公共卫生系统来说，与数月至数年的每日服用药物有关。 二芳基喹啉 (DARQ) 贝达喹啉的 LAI 制剂表现出比 WHO 批准的治疗方案（利福平单一疗法）用于经过验证的下一代 TPT 小鼠模型。 DARQ TBAJ-876 和 TBAJ-587 作为口服药物目前正处于 1 期试验，对分枝杆菌更有效 在积极结核病治疗的小鼠模型中发现结核病，并且具有高度适合的理化特性 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和DARQ的下一代DARQ与同伴代理（pretomanid， 德拉马尼和/或利福布丁），用于活动性结核病治疗的持续阶段。 该阶段的研究重点是开发和选择下一代优化的 LAI 配方。 DARQ 和/或 DARQ 与伴随药物的组合，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，以预测有效剂量并测试证明- 已验证的 TPT 小鼠模型和特征明确的活动性结核病治疗小鼠模型中的概念。 R33阶段，研究将集中于研究性新药（IND）的非临床表征 1-2 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。 将在 TPT 和活动性结核病治疗的小鼠模型中进行临床疗效测试，以确认长期疗效 术语，LAI方案的灭菌活性是开发和非临床的。 验证基于 DARQ 的“一次性”LAI 治疗 TPT 以及优化的基于 LAI 的治疗 用于活动性结核病治疗持续阶段的策略。

项目成果

Potential Impact of Long-Acting Products on the Control of Tuberculosis: Preclinical Advancements and Translational Tools in Preventive Treatment.

长效产品对结核病控制的潜在影响：预防性治疗的临床前进展和转化工具。

• 发表时间: 2022-11-21
• 作者: Ammerman, Nicole C;Nuermberger, Eric L;Owen, Andrew;Rannard, Steve P;Meyers, Caren Freel;Swindells, Susan
• 通讯作者: Swindells, Susan