Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial
Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial
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DOI：
10.1016/s2213-2600(18)30181-4
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发表时间：
2018-08-01
影响因子：
76.2
通讯作者：
Wuyts, Wim
中科院分区：
文献类型：
--
作者：
Maher, Toby M.;van der Aar, Ellen M.;Wuyts, Wim
特发性肺纤维化（IPF）导致肺功能不可逆转的丧失。IPF患者肺组织中自身taxin浓度升高，支气管肺泡灌洗液和呼出冷凝水中溶血磷脂酸（LPA）浓度升高。GLPG1690 （Galapagos, Mechelen, Belgium）是一种新型的、有效的、选择性的自噬素抑制剂，具有良好的口服暴露性。我们探讨了GLPG1690在IPF患者中的作用。这是一项随机、双盲、安慰剂对照的2a期研究，在意大利、乌克兰和英国的17个中心进行。符合条件的患者年龄为40岁或以上，非吸烟者，未服用吡非尼酮或尼达尼布，并有中央确诊的IPF诊断。我们使用计算机生成的随机化计划，将患者1:3分配给安慰剂或600 mg口服GLPG1690，每天一次，持续12周。主要结局是安全性（不良事件）、耐受性、药代动力学和药效学。肺活量测定作为次要指标进行评估。该试验已在ClinicalTrials.gov注册，注册号NCT02738801。在2016年3月24日至2017年5月2日期间，对72例患者进行了筛查，其中49例不符合条件，23例入组于8个中心（6例在乌克兰，2例在英国）。6名患者接受安慰剂治疗，17名患者接受GLPG1690治疗。20名患者完成了研究，每组中有1名患者因不良事件而停止，GLPG1690组中有1名患者撤回同意。安慰剂组4名（67%）患者和GLPG1690组11名（65%）患者出现治疗后出现的不良事件，其中大多数为轻度至中度。GLPG1690组中最常见的事件是感染和感染（10个事件）以及呼吸、胸腔和纵隔疾病（8个事件），与安慰剂组无明显差异。GLPG1690组中有2例（12%）患者的事件被判断为与治疗相关。安慰剂组有2例患者出现严重不良事件（1例出现尿路感染、急性肾损伤和下呼吸道感染，另1例出现二级房室传导阻滞），GLPG1690组有1例患者出现严重不良事件（胆管癌导致停药）。没有患者死亡。GLPG1690的药代动力学和药效学特征与先前在健康对照中显示的相似。血浆中LPA C18:2浓度持续下降。第12周时，GLPG1690组强迫肺活量与基线相比的平均变化为25 mL (95% CI -75 - 124)，安慰剂组为-70 mL （-208 - 68 mL）。我们的研究结果支持进一步开发GLPG1690作为IPF的新治疗方法。爱思唯尔有限公司版权所有版权所有。
Background Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. People with IPF have increased concentrations of autotaxin in lung tissue and lysophosphatidic acid (LPA) in bronchoalveolar lavage fluid and exhaled condensate. GLPG1690 (Galapagos, Mechelen, Belgium) is a novel, potent, selective autotaxin inhibitor with good oral exposure. We explored the effects of GLPG1690 in patients with IPF.Methods This was a randomised, double-blind, placebo-controlled phase 2a study done in 17 centres in Italy, Ukraine and the UK. Eligible patients were aged 40 years or older, non-smokers, not taking pirfenidone or nintedanib, and had a centrally confirmed diagnosis of IPF. We used a computer-generated randomisation schedule to assign patients 1:3 to receive placebo or 600 mg oral GLPG1690 once daily for 12 weeks. The primary outcomes were safety (adverse events), tolerability, pharmacokinetics, and pharmacodynamics. Spirometry was assessed as a secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT02738801.Findings Between March 24, 2016, and May 2, 2017, 72 patients were screened, of whom 49 were ineligible and 23 were enrolled in eight centres (six in Ukraine and two in the UK). Six patients were assigned to receive placebo and 17 to receive GLPG1690. 20 patients completed the study after one in each group discontinued because of adverse events and one in the GLPG1690 group withdrew consent. Four (67%) patients in the placebo group and 11 (65%) in the GLPG1690 group had treatment-emergent adverse events, most of which were mild to moderate. The most frequent events in the GLPG1690 group were infections and infestations (ten events) and respiratory, thoracic, and mediastinal disorders (eight events) with no apparent differences from the placebo group. Two (12%) patients in the GLPG1690 group had events that were judged to be related to treatment. Serious adverse events were seen in two patients in the placebo group (one had a urinary tract infection, acute kidney injury, and lower respiratory tract infection and the other had atrioventricular block, second degree) and one in the GLPG1690 group (cholangiocarcinoma that resulted in discontinuation of treatment). No patients died. The pharmacokinetic and pharmacodynamic profiles of GLPG1690 were similar to those previously shown in healthy controls. LPA C18:2 concentrations in plasma were consistently decreased. Mean change from baseline in forced vital capacity at week 12 was 25 mL (95% CI -75 to 124) for GLPG1690 and -70 mL (-208 to 68 mL) for placebo.Interpretation Our findings support further development of GLPG1690 as a novel treatment for IPF. Copyright (C) 2018 Elsevier Ltd. All rights reserved.