Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials.
Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials.
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DOI：
10.1002/art.40186
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
van 't Klooster G
中科院分区：
文献类型：
--
作者：
Vanhoutte F;Mazur M;Voloshyn O;Stanislavchuk M;Van der Aa A;Namour F;Galien R;Meuleners L;van 't Klooster G
JAK抑制剂在类风湿性关节炎（RA）中显示出疗效。我们进行这项研究是为了验证我们的假设，即与选择性较低的JAK抑制剂相比，选择性抑制JAK-1将联合收割机良好的疗效与更好的安全性特征相结合。在两项为期4周的探索性、双盲、安慰剂对照IIa期试验中，127例对甲氨蝶呤（MTX）疗效不佳的RA患者接受了filgotinib治疗（GLPG 0634，GS-6034）口服胶囊（100 mg每日两次或30、75、150、200或300 mg每日一次）或安慰剂，添加到MTX的稳定方案中，以评价安全性、疗效，本发明涉及filgotinib的药代动力学（PK）和药效学（PD）。主要疗效终点是第4周时每个治疗组中符合美国流变学会20%改善标准（达到ACR 20应答）的患者数量和百分比。使用75-300 mg filgotinib治疗符合主要终点，并显示出早期起效的疗效。ACR 20反应率逐渐增加至第4周，使用C反应蛋白（CRP）水平的28个关节的疾病活动评分下降。观察到血清CRP水平和其他PD标志物的显著和持续改善。在30-300 mg范围内，filgotinib及其主要代谢产物的PK与剂量成比例。没有观察到用其他选择性较低的JAK抑制剂观察到的早期副作用（例如，贫血没有恶化[JAK-2抑制相关]，对肝转氨酶没有影响，低密度脂蛋白或总胆固醇没有增加）。中性粒细胞的有限减少（无中性粒细胞减少）与JAK-1抑制的免疫调节作用一致。无感染。总体而言，filgotinib耐受性良好。与研究药物相关的事件为轻度或中度，在治疗期间为一过性，最常见的此类事件为恶心。在这些探索性研究中，filgotinib选择性抑制JAK-1显示出在RA中的初步疗效和令人鼓舞的安全性特征。
JAK inhibitors have shown efficacy in rheumatoid arthritis (RA). We undertook this study to test our hypothesis that selective inhibition of JAK‐1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors. In two 4‐week exploratory, double‐blind, placebo‐controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS‐6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib. The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4. Treatment with filgotinib at 75–300 mg met the primary end point and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C‐reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers. The PK of filgotinib and its major metabolite was dose proportional over the 30–300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK‐2 inhibition related], no effects on liver transaminases, and no increase in low‐density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK‐1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea. Selective inhibition of JAK‐1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies.
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影响因子：
10.5
作者：
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