抗干扰素-γ单克隆抗体AMG 811在无狼疮性肾炎或伴有狼疮性肾炎的系统性红斑狼疮受试者中的安全性、药代动力学和药效学
Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis.
作者信息
Boedigheimer Michael J, Martin David A, Amoura Zahir, Sánchez-Guerrero Jorge, Romero-Diaz Juanita, Kivitz Alan, Aranow Cynthia, Chan Tak Mao, Chong Yip Boon, Chiu Kit, Wang Christine, Sohn Winnie, Arnold Gregory E, Damore Michael A, Welcher Andrew A, Sullivan Barbara A, Kotzin Brian L, Chung James B
机构信息
Amgen Inc., Thousand Oaks, California, USA.
Amgen Inc., Seattle, Washington, USA.
出版信息
Lupus Sci Med. 2017 Sep 14;4(1):e000226. doi: 10.1136/lupus-2017-000226. eCollection 2017.
OBJECTIVE
To evaluate safety, pharmacokinetics and pharmacodynamics of anti-interferon (IFN)-γ monoclonal antibody AMG 811 in subjects with SLE without or with lupus nephritis (LN).
METHODS
In this phase Ib, randomised, multiple-dose escalation study (NCT00818948), subjects without LN were randomised to subcutaneous AMG 811 (6, 20 or 60 mg) or placebo and subjects with LN were randomised to subcutaneous AMG 811 (20, 60 or 120 mg) or placebo every four weeks for three total doses. Outcomes included incidence of adverse events (AEs); pharmacokinetics; levels of serum proteins (CXCL-10, interleukin 18, monocyte chemotactic protein-1); changes in gene transcript profiles and clinical parameters (Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores, proteinuria, anti-double-stranded DNA (anti-dsDNA) antibodies, C3 complement, C4 complement).
RESULTS
Fifty-six subjects enrolled (28 SLE without LN; 28 with LN). Baseline mean SELENA-SLEDAI scores were 2.2 and 12.0 for SLE subjects without and with LN, respectively. Most subjects reported an AE; no meaningful imbalances were observed between AMG 811 and placebo. Pharmacokinetic profiles were similar and mostly dose-proportional in subjects without or with LN. AMG 811 treatment reduced CXCL-10 protein levels and blood-based RNA IFN-γ Blockade Signature compared with placebo. Reductions were less pronounced and not sustained in subjects with LN, even at the highest dose tested, compared with subjects without LN. No effect on SELENA-SLEDAI scores, proteinuria, C3 or C4 complement levels, or anti-dsDNA antibodies was observed.
CONCLUSION
AMG 811 demonstrated favourable pharmacokinetics and acceptable safety profile but no evidence of clinical impact. IFN-γ-associated biomarkers decreased with AMG 811; effects were less pronounced and not sustained in LN subjects.
TRIAL REGISTRATION NUMBER
NCT00818948; results.
目的
评估抗干扰素（IFN）-γ单克隆抗体AMG 811在无狼疮性肾炎（LN）或伴有LN的系统性红斑狼疮（SLE）患者中的安全性、药代动力学和药效学。
方法
在这项Ib期随机、多剂量递增研究（NCT00818948）中，无LN的患者被随机分为皮下注射AMG 811（6、20或60mg）或安慰剂组，有LN的患者被随机分为皮下注射AMG 811（20、60或120mg）或安慰剂组，每四周一次，共注射三剂。观察指标包括不良事件（AE）发生率、药代动力学、血清蛋白水平（CXCL-10、白细胞介素18、单核细胞趋化蛋白-1）、基因转录谱变化以及临床参数（狼疮性红斑全国评估系统-系统性红斑狼疮疾病活动指数（SELENA-SLEDAI）评分、蛋白尿、抗双链DNA（抗dsDNA）抗体、C3补体、C4补体）。
结果
共纳入56例患者（28例无LN的SLE患者；28例有LN的患者）。无LN和有LN的SLE患者基线时SELENA-SLEDAI评分的平均值分别为2.2和12.0。大多数患者报告了AE；在AMG 811组和安慰剂组之间未观察到有意义的失衡。无LN和有LN的患者药代动力学特征相似，且大多呈剂量依赖性。与安慰剂相比，AMG 811治疗降低了CXCL-10蛋白水平和基于血液的RNA IFN-γ阻断特征。与无LN的患者相比，即使在测试的最高剂量下，有LN的患者中这种降低也不那么明显且未持续。未观察到对SELENA-SLEDAI评分、蛋白尿、C3或C4补体水平或抗dsDNA抗体有影响。
结论
AMG 811显示出良好的药代动力学和可接受的安全性，但无临床疗效证据。AMG 811使与IFN-γ相关的生物标志物降低；在有LN的患者中，这种作用不那么明显且未持续。
试验注册号
NCT00818948；结果
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