Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis.
Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis.
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DOI：
10.1136/lupus-2017-000226
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发表时间：
2017
影响因子：
3.9
通讯作者：
Chung JB
中科院分区：
文献类型：
--
作者：
Boedigheimer MJ;Martin DA;Amoura Z;Sánchez-Guerrero J;Romero-Diaz J;Kivitz A;Aranow C;Chan TM;Chong YB;Chiu K;Wang C;Sohn W;Arnold GE;Damore MA;Welcher AA;Sullivan BA;Kotzin BL;Chung JB
评价抗干扰素（IFN）-γ单克隆抗体AMG 811在SLE（不伴或伴狼疮性肾炎（LN））受试者中的安全性、药代动力学和药效学。在这项Ib期、随机、多次剂量递增研究（NCT 00818948）中，无LN的受试者随机接受皮下注射AMG 811（6、20或60 mg）或安慰剂，LN受试者随机接受皮下注射AMG 811（20、60或120 mg）或安慰剂，每4周一次，共3次给药。结果包括不良事件（AE）的发生率;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）;基因转录谱和临床参数的变化雌激素在红斑狼疮中的安全性国家评估-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）。五十六例受试者入组（28例SLE无LN; 28例LN）。无LN和有LN的SLE受试者的基线平均SELENA-SLEDAI评分分别为2.2和12.0。大多数受试者报告了AE; AMG 811和安慰剂之间未观察到有意义的失衡。在无或有LN的受试者中，药代动力学特征相似，且大部分与剂量成比例。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的受试者相比，即使在最高剂量下，LN受试者的降低也不太明显且不持续。未观察到对SELENA-SLEDAI评分、蛋白尿、C3或C4补体水平或抗dsDNA抗体的影响。AMG 811表现出有利的药代动力学和可接受的安全性特征，但无临床影响的证据。AMG 811的IFN-γ相关生物标志物减少;在LN受试者中，效果不太明显且不持续。NCT 00818948;结果。
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). 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). 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. 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. NCT00818948; results.