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首页> 外文期刊>Biochemical Pharmacology >A Translational Medicine perspective of the development of torcetrapib: Does the failure of torcetrapib development cast a shadow on future development of lipid modifying agents, HDL elevation strategies or CETP as a viable molecular target for atherosclerosis? A case study of the use of biomarkers and Translational Medicine in atherosclerosis drug discovery and development.
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A Translational Medicine perspective of the development of torcetrapib: Does the failure of torcetrapib development cast a shadow on future development of lipid modifying agents, HDL elevation strategies or CETP as a viable molecular target for atherosclerosis? A case study of the use of biomarkers and Translational Medicine in atherosclerosis drug discovery and development.

机译：转化医学对Torcetrapib发育的观点：Torcetrapib发育的失败是否为脂质修饰剂，HDL升高策略或CETP作为动脉粥样硬化的可行分子靶标的未来发展蒙上阴影？在动脉粥样硬化药物发现和开发中使用生物标志物和转化医学的案例研究。

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Although the relationship between HDL (high density lipoprotein) function and cardiovascular (CV) risk has been extensively explored, the premise that HDL elevation is linked to reduced CV risks and that high HDL cholesterol (HDL-C) might be a potential surrogate biomarker for reduced CV risk remains controversial. Substantial genetic, molecular, biochemical and preclinical evidence have raised the hope that HDL-C elevation via CETP inhibition might generate clinical benefits. However, four large-scale clinical trials with the CETP inhibitor torcetrapib failed to demonstrate benefits on CV clinical outcomes. Likewise, biomarkers that were supposed to predict vascular risk reduction provided disappointing results. The sad tale of torcetrapib development emphasizes the need for a paradigm shift from the conventional drug development mode to a biomarker-based Translational Medicine (TMed) strategy. Emergence of further CETP inhibitors encourage continued development of such compounds for cardiovascular risk management. However, there is a need to adopt biomarker-driven TMed strategies in target validation, target-compound interaction, pharmacodynamic activities, disease modification and patient selection to guide future drug development efforts. This commentary analyzes the issues surrounding the demise of torcetrapib and proposes a TMed-based road map towards successful development of new CETP inhibitors.
机译：尽管已经广泛研究了HDL（高密度脂蛋白）功能与心血管（CV）风险之间的关系，但前提是HDL升高与降低CV风险有关，而高HDL胆固醇（HDL-C）可能是潜在的替代生物标志物降低简历风险仍存在争议。大量的遗传，分子，生化和临床前证据已使人们希望，通过CETP抑制作用升高HDL-C可能产生临床益处。但是，使用CETP抑制剂torcetrapib进行的四项大规模临床试验未能证明对CV临床结局具有益处。同样，原本可以预测降低血管风险的生物标志物也令人失望。 Torcetrapib开发的悲惨故事强调了从传统药物开发模式到基于生物标记物的转化医学（TMed）策略的范式转变的必要性。进一步的CETP抑制剂的出现促进了此类化合物在心血管风险管理中的持续开发。但是，有必要在目标验证，目标化合物相互作用，药效学活性，疾病修饰和患者选择中采用生物标志物驱动的TMed策略，以指导未来的药物开发工作。该评论分析了Torcetrapib灭亡的相关问题，并提出了基于TMed的成功开发新型CETP抑制剂的路线图。

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