Bromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE.
Bromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE.
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DOI：
10.1016/j.ejca.2021.01.018
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发表时间：
2021-02
影响因子：
8.4
通讯作者：
A. Pearson;S. DuBois;Vickie Buenger;M. Kieran;K. Stegmaier;P. Bandopadhayay;K. Bennett;F. Bourdeaut;P. Brown;L. Chesler;Jessica Clymer;E. Fox;C. French;E. Germovsek;F. Giles;J. Bender;M. Hattersley;Donna Ludwinski;K. Luptakova;J. Maris;Joe McDonough;Z. Nikolova;Malcolm A. Smith;A. Tsiatis;Rajeev Vibhakar;S. Weiner;Joanna S. Yi;Fred Zheng;G. Vassal
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文献类型：
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作者：
A. Pearson;S. DuBois;Vickie Buenger;M. Kieran;K. Stegmaier;P. Bandopadhayay;K. Bennett;F. Bourdeaut;P. Brown;L. Chesler;Jessica Clymer;E. Fox;C. French;E. Germovsek;F. Giles;J. Bender;M. Hattersley;Donna Ludwinski;K. Luptakova;J. Maris;Joe McDonough;Z. Nikolova;Malcolm A. Smith;A. Tsiatis;Rajeev Vibhakar;S. Weiner;Joanna S. Yi;Fred Zheng;G. Vassal
基于生物学和临床前数据，溴结构域和末端外（BET）抑制剂在儿科恶性肿瘤中至少有三种潜在作用：NUT（睾丸核蛋白）癌、MYC/MYCN驱动的癌症和融合驱动的恶性肿瘤。然而，目前至少有10种BET抑制剂正在开发中，用于评价这些药品的相关儿科人群有限。因此，召开了一次会议，具体目的是在相关生物制药公司、学术研究人员以及患者和家庭倡导者之间就BET抑制剂的开发达成共识，包括优先顺序及其在儿童中的具体作用。尽管BET抑制剂自2012年以来一直在成人中进行临床试验，但它在临床试验中的作用仍然存在。首次儿童研究（BMS-986158）仅于2019年开始。将来，当一类药品在儿科中具有强有力的机制原理或临床前活性时，应优先考虑并在儿科人群中快速执行该类药物的早期临床评价（包括嵌入式相关研究）。在儿科中评价BET抑制剂具有强有力的机制和生物学原理，并得到大量但不普遍的临床前数据的支持。然而，大多数泛BET抑制剂在成人中给药具有挑战性，因为单药治疗仅产生适度的抗肿瘤活性，并且由于血小板减少症而提供狭窄的治疗指数。得出的结论是，在儿科同时进行所有泛BET抑制剂的早期临床试验既不科学合理也不可行，但是，临床上需要在全球范围内获得用于NUT癌患者的BET抑制剂，NUT癌是一种由溴结构域融合驱动的非常罕见的恶性肿瘤，并在接受BET抑制剂治疗的患者子集中证明临床获益的概念。除NUT癌外，建议其他泛BET抑制剂在儿童中的进一步临床开发应等待BMS-986158的首次儿科临床试验结果，除非基于特定药物有令人信服的理由。BDII选择性抑制剂、中枢神经系统渗透性BET抑制剂（例如CC-90010）和那些双重靶向BET/p300溴结构域是特别令人感兴趣的，并且需要进一步的临床前研究。多个公司在开发一类化合物的早期与学术研究人员达成共识，然后与监管机构合作的多利益相关者方法将提高效率，生产力，节约资源并最大限度地提高癌症儿童的潜在利益。
Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas,MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children.Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations.There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors.However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults.Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system–penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation.This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.