Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension
Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension
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DOI：
10.1164/rccm.201607-1515pp
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发表时间：
2017-03-01
影响因子：
24.7
通讯作者：
Humbert, Marc
中科院分区：
文献类型：
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作者：
Bonnet, Sebastien;Provencher, Steeve;Humbert, Marc
肺动脉高压（PAH）是一种罕见且严重的疾病，以肺血管重构、血管收缩、内皮功能障碍、炎症和原位血栓形成为特征(2)。超过10种靶向内皮素、一氧化氮和前列环素途径的药物(3)已经被开发和商业化。目前，已有的治疗方法已被证明可以降低患者短期死亡(4)和临床恶化(5)的风险。然而，尽管现代治疗方式取得了这些进步，但大多数患者的生活质量仍然很差（6,7），长期预后仍然很差（8-10）。有趣的是，尽管发表了许多临床前研究，提出了治疗多环芳烃的新靶点（11），但很少有临床试验阶段（12），这些创新疗法目前都没有被批准用于临床应用。从潜在治疗靶点的发现到商业化的过程是漫长、复杂和昂贵的。这一系列的临床试验可能要花费数亿美元。此外，患者对当前和即将进行的PAH临床试验的时间承诺在几个月到几年的范围内，从而限制了PAH患者参加其他治疗试验的数量。此外，即使动物实验显示出有希望的结果，超过80%的这些疗法在人体试验时最终失败（13）。人类临床反应不可预测和药物开发延迟的潜在原因可能包括目前可用的模拟（部分）人类疾病谱的动物和体外模型的固有局限性，以及分析或报告结果的偏差和数据可重复性有限（14）。重要的是，这并非多环芳烃所独有，因为将研究转化为改善患者护理存在于各种疾病中（13,15）。然而，考虑到有限的财政资源、对改进PAH治疗的持续医疗需求以及临床试验的研究人群有限，有必要减少临床前研究中假阳性信号的数量，并通过基于更可靠的实验数据的临床试验来优化创新治疗靶点的开发。目前的综述讨论了临床前研究的挑战、缺陷和机遇，以促进PAH的药物开发。
We have witnessed significant advances in the management of pulmonary arterial hypertension (PAH)(1), a rare and severe condition characterized by intense pulmonary vascular remodeling, vasoconstriction, endothelial dysfunction, inflammation, and in situ thrombosis (2). More than 10 drugs targeting the endothelin, nitric oxide, and prostacyclin pathways (3) have been developed and commercialized. At present, available therapies have been shown to decrease patients’ risk of short-term mortality (4) and clinical worsening (5). However, despite these advances with modern treatment modalities, most patients continue to experience poor quality of life (6, 7), and long-term prognosis remains poor (8–10). Intriguingly, despite the publication of numerous preclinical studies proposing new therapeutic targets for PAH (11), few have reached clinical trial phases (12) and none of these innovative therapies are currently approved for clinical use. The journey from the discovery of a potential therapeutic target to its commercialization is long, complex, and costly. The series of clinical trials can cost hundreds of millions of dollars. Moreover, patient time commitment for current and upcoming PAH clinical trials is in the range of months to years, thus limiting the number of patients with PAH to be enrolled in trials testing for other therapies. In addition, even when animal studies show promising results, more than 80% of these therapies ultimately fail when tested in humans (13). Potential reasons for unpredicted clinical response in humans and delayed drug development may include the inherent limitations of the currently available animal and in vitro models that mimic (part of) the spectrum of the human disease, as well as bias in the analysis or reporting of findings and limited data reproducibility (14). Importantly, this is not unique to PAH, because translating research into improved patient care exists across diseases (13, 15). Nonetheless, given the limited financial resources, the persistent medical need for improved therapy in PAH, and the restricted study population available for clinical trials, there is a need to reduce the number of false positive signals in preclinical studies and to optimize the development of innovative therapeutic targets through performance of clinical trials based on more robust experimental data. The current review discusses the challenges, pitfalls, and opportunities in preclinical research to foster drug development in PAH.