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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02829-7

摘要内容如下：

需要新的结核病治疗方法来解决耐药性、治疗时间过长和现有药物的不良反应。GSK3036656（Ganfeborole）是抑制结核分枝杆菌亮氨酰-tRNA合成酶的第一类苯并氧杂硼杂环戊烯。在这项2A期、单中心、开放标签、随机试验中，我们评估了甘非罗勒在未经治疗的利福平敏感肺结核患者中的早期杀菌活性（主要目标）、安全性和药代动力学（次要目标）。总共有75名男性接受了甘非泊罗（1/5/15/30mg）或标准治疗（Rifafour E-275或通用替代药物），每天一次，持续14天。我们观察到，每天一次服用5、15和30mg甘非洛尔的参与者的每日痰液衍生集落形成单位较基线减少，而服用1mg甘非洛尔的参与者则没有减少。不良事件发生率在各组间具有可比性；所有事件均为1级或2级。在参与者亚组中，对18F-氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描结果的事后探索性计算分析显示，在第14天接受30mg Ganfeborole的患者中，几种病变类型均有可测量的治疗反应。对第14天接受30mg Ganfeborole的全血转录治疗反应的分析显示，与中性粒细胞主导的转录模块密切相关。证实的杀菌活性和可接受的安全性表明甘非硼是联合治疗肺结核的潜在候选药物。ClinicalTrials.gov标识符：NCT03557281。

英文原文如下：

Abstracts

New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.ClinicalTrials.gov identifier: NCT03557281 .

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