Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate.
Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate.
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DOI：
10.1002/art.39808
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发表时间：
2016-12
影响因子：
13.3
通讯作者：
Jungerwirth, Steven
中科院分区：
文献类型：
--
作者：
Genovese, Mark C.;Smolen, Josef S.;Weinblatt, Michael E.;Burmester, Gerd R.;Meerwein, Sebastian;Camp, Heidi S.;Wang, Li;Othman, Ahmed A.;Khan, Nasser;Pangan, Aileen L.;Jungerwirth, Steven
评价ABT-494（一种选择性JAK-1抑制剂）在对甲氨蝶呤（MTX）反应不充分的中重度类风湿关节炎（RA）患者中的疗效和安全性。300名接受稳定剂量MTX的RA患者被随机平均分配接受速释ABT-494 3、6、12或18 mg每日2次，24 mg每日1次或安慰剂治疗12周。主要疗效终点为第12周时符合美国流变学会20%改善标准（达到ACR 20应答）的患者比例，采用末次观察值结转法测定。第12周时，ABT-494组的ACR 20应答比例（3、6、12、18和24 mg剂量组分别为62%、68%、80%、64%和76%）高于安慰剂组（46%）（使用非应答者插补）（6、12和24 mg剂量组P <0.05）。所有ABT-494剂量之间存在显著的剂量反应关系（P <0.001）。所有ABT-494剂量组达到ACR 50和ACR 70缓解的患者比例（ACR 70缓解的12 mg剂量除外）均显著高于安慰剂组，使用C反应蛋白水平（DAS 28-CRP）测定的28个关节的疾病活动性评分变化也是如此。第2周（首次基线后访视）时，所有剂量组与安慰剂组相比，ACR 20应答率和DAS 28-CRP变化的显著差异证明了快速改善。各组不良事件的发生率相似;大多数是轻度的，感染是最常见的。ABT-494 12 mg组发生1例严重感染（社区获得性肺炎）。高密度脂蛋白（HDL）和低密度脂蛋白（LDL）胆固醇呈剂量依赖性增加，但LDL胆固醇：HDL胆固醇比在第12周内保持不变。平均血红蛋白水平在较低剂量下保持稳定，但在较高剂量下观察到降低。本研究在MTX疗效不佳的RA患者中评价了ABT-494的广泛剂量范围。ABT-494证明了疗效，其安全性和耐受性特征与其他JAK抑制剂相似。
To evaluate the efficacy and safety of ABT‐494, a selective JAK‐1 inhibitor, in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate‐release ABT‐494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method. At week 12, the proportion of ACR20 responses was higher with ABT‐494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose‐response relationship among all ABT‐494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT‐494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28‐CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community‐acquired pneumonia) occurred with ABT‐494 at 12 mg. There were dose‐dependent increases in high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses. This study evaluated a broad range of doses of ABT‐494 in RA patients with an inadequate response to MTX. ABT‐494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.
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影响因子：
4.9
作者：
Isaacs JD;Harari O;Kobold U;Lee JS;Bernasconi C
通讯作者：
Bernasconi C
影响因子：
4.9
作者：
Aletaha D;Nell VP;Stamm T;Uffmann M;Pflugbeil S;Machold K;Smolen JS
通讯作者：
Smolen JS
影响因子：
32.4
作者：
Stark GR;Darnell JE Jr
通讯作者：
Darnell JE Jr
影响因子：
27.4
作者：
Huizinga TW;Fleischmann RM;Jasson M;Radin AR;van Adelsberg J;Fiore S;Huang X;Yancopoulos GD;Stahl N;Genovese MC
通讯作者：
Genovese MC
影响因子：
158.5
作者：
Lee, Eun Bong;Fleischmann, Roy;van Vollenhoven, Ronald F.
通讯作者：
van Vollenhoven, Ronald F.