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首页> 外文期刊>Pulmonary therapy. >A Phase 1b Study of Vismodegib with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis
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A Phase 1b Study of Vismodegib with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

机译：具有特发性肺纤维化患者的PIRFENIDONE对vismodegib的第1B期研究

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IntroductionComponents of the hedgehog signaling pathway are upregulated in patients with idiopathic pulmonary fibrosis (IPF). Vismodegib, a small-molecule inhibitor of hedgehog signaling, when used in combination with currently available antifibrotic therapy, may be more efficacious than antifibrotics alone. The objective of this study was to evaluate the safety and tolerability of vismodegib plus pirfenidone in patients with IPF. MethodsTwenty-one patients were enrolled in a phase 1b open-label trial to receive vismodegib 150?mg plus pirfenidone 2403?mg/day once daily. Key endpoints were safety, tolerability, and pharmacokinetics. Exploratory endpoints included change from baseline to week 24 in % predicted forced vital capacity (FVC) and University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) scores, as well as pharmacodynamic changes in hedgehog biomarker C-X-C motif chemokine ligand 14 (CXCL14). ResultsAll patients reported at least one treatment-emergent adverse event (AE), most frequently muscle spasms (76.2%). Serious AEs were reported in 14.3% of patients; one event of dehydration was considered related to vismodegib. One patient died due to IPF progression, unrelated to either treatment. More patients discontinued vismodegib than pirfenidone (42.9% vs. 33.3%, respectively). Changes from baseline to week 24 in % predicted FVC and UCSD-SOBQ scores were within known endpoint variability. In contrast to findings in basal cell carcinoma, vismodegib had no effect on circulating CXCL14 levels. ConclusionThe safety profile was generally consistent with the known profiles of both drugs, with no new safety signals observed in this small cohort. There was no pharmacodynamic effect on CXCL14 levels. Future development of vismodegib for IPF may be limited due to tolerability issues. Trial RegistrationClinicalTrials.gov NCT02648048. Plain Language SummaryPlain language summary available for this article. FundingF. Hoffmann-La Roche Ltd. and Genentech, Inc.
机译：特发性肺纤维化（IPF）的患者上调刺猬信号通路的引入信息。当与当前可用的抗纤维化疗法组合使用时，Vismodegib，刺猬信号的小分子抑制剂可能比单独的抗纤维体更有效。本研究的目的是评估VISModegib加上Pirfenidone在IPF患者中的安全性和耐受性。方法患者在1B期开放标签试验中注册，以接收Vismodegib 150？Mg加上Pirfenidone 2403？Mg /天每天一次。关键终点是安全性，耐受性和药代动力学。探索性终点包括从基线到第24周的变化，以％预测强制生命能力（FVC）和加州大学，圣地亚哥呼吸问卷（UCSD-Sobq）得分，以及刺猬生物标志物CXC MOTIF趋化因子配体14的药效变化（ cxcl14）。结果持有患者报告至少有一个治疗 - 紧急的不良事件（AE），最常肌肉痉挛（76.2％）。 14.3％的患者报告了严重的AES;考虑了一个脱水事件与Vismodegib有关。一名患者因IPF进展而死亡，与任何一种治疗无关。更多的患者停止Vismodegib而不是Pirfenidone（分别为42.9％，分别为33.3％）。在％预测的FVC和UCSD-SobQ分数中从基线到第24周的变化在已知的端点变异中。与基底细胞癌中的结果形成鲜明对比，Vismodegib对循环CXCL14水平没有影响。结论安全性型材通常与两种药物的已知型材一致，在该小队列中没有观察到的新安全信号。对CXCL14水平没有药物动力学作用。由于耐受性问题，可能有限地限制VISMODEGIB的未来发展。试用registageClinicalTrials.gov NCT02648048。普通语言SummaralPlain语言摘要可用于本文。资金。 Hoffmann-La Roche Ltd.和Genentech，Inc。

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