Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020.
Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020.
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DOI：
10.1128/aac.00054-22
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发表时间：
2022-05-17
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
--
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世界卫生组织（世卫组织）警告说，我们目前的抗生素库没有足够的创新来应对即将到来的传染病，特别是那些由多重耐药革兰氏阴性病原体引起的传染病。虽然目前的临床前管道中有大量的新候选药物，但美国食品和药物管理局（FDA）批准的最后一种具有针对革兰氏阴性菌的新作用机制的抗生素是在近60年前发现的。在2000年代启动研究性新药（IND）申请的所有抗生素候选药物中，17%在12年内获得了FDA的批准，而在这段时间内，绝大多数抗生素候选药物被停用。临床管道中的这些“泄漏”，即具有临床潜力的化合物在临床开发过程中被放弃，表明科学创新没有到达临床并为患者提供益处。这不仅适用于新的候选药物，也适用于具有临床验证靶点的现有抗生素类别的候选药物。通过识别临床管道中的泄漏源，未来的开发工作可以指向更有可能流入临床使用的策略。在这篇综述中，我们对过去十年中从临床管道中脱落的革兰氏阴性活性的临床候选药物进行了详细的失败分析。尽管受到从事抗生素开发的公司不完整数据披露的限制，我们试图提取每个被终止的候选人所面临的发展挑战。我们希望这种见解可以帮助降低抗生素开发的风险，并为临床带来新的有效抗生素。
The World Health Organization (WHO) has warned that our current arsenal of antibiotics is not innovative enough to face impending infectious diseases, especially those caused by multidrug-resistant Gram-negative pathogens. Although the current preclinical pipeline is well stocked with novel candidates, the last U.S. Food and Drug Administration (FDA)-approved antibiotic with a novel mechanism of action against Gram-negative bacteria was discovered nearly 60 years ago. Of all the antibiotic candidates that initiated investigational new drug (IND) applications in the 2000s, 17% earned FDA approval within 12 years, while an overwhelming 62% were discontinued in that time frame. These “leaks” in the clinical pipeline, where compounds with clinical potential are abandoned during clinical development, indicate that scientific innovations are not reaching the clinic and providing benefits to patients. This is true for not only novel candidates but also candidates from existing antibiotic classes with clinically validated targets. By identifying the sources of the leaks in the clinical pipeline, future developmental efforts can be directed toward strategies that are more likely to flow into clinical use. In this review, we conduct a detailed failure analysis of clinical candidates with Gram-negative activity that have fallen out of the clinical pipeline over the past decade. Although limited by incomplete data disclosure from companies engaging in antibiotic development, we attempt to distill the developmental challenges faced by each discontinued candidate. It is our hope that this insight can help de-risk antibiotic development and bring new, effective antibiotics to the clinic.
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