Objectives To characterize the relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with moderate to severe SLE despite standard therapy, using pooled data from two phase 3 trials. Methods TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks). For the exposure–response analysis, BILAG-based Composite Lupus Assessment (BICLA) or SLE Responder Index [SRI(4)] response rates at week 52 in each quartile/tertile of average anifrolumab serum concentration (Cave) were compared for anifrolumab and placebo in all-comers, patients who completed treatment, and IFN gene signature (IFNGS)-high patients who completed treatment, using average marginal effect logistic regression. Relationships between exposure and key safety events were assessed graphically. Results Of patients in TULIP-1/TULIP-2 who received anifrolumab (150 mg, n = 91; 300 mg, n = 356) or placebo (n = 366), 574 completed treatment, of whom 470 were IFNGS high. In the exposure–efficacy analyses, BICLA and SRI(4) treatment differences favouring anifrolumab 300 mg vs placebo were observed across Cave subgroups and all analysis populations. Logistic regression identified Cave as a significant covariate for predicted BICLA response, as higher anifrolumab Cave predicted greater efficacy. There was no evidence of exposure-driven incidence of key safety events through week 52 in patients receiving anifrolumab 150 or 300 mg. Conclusion While higher Cave predicted greater efficacy, consistent positive benefit favouring anifrolumab 300 mg vs placebo was observed in BICLA and SRI(4) responses across Cave subgroups in the TULIP trials. There was no evidence of exposure-driven safety events. ClinicalTrial.gov numbers NCT02446912, NCT02446899

中文翻译：

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Anifrolumab 药代动力学与系统性红斑狼疮患者疗效和安全性的关系

目的 使用来自两项 3 期试验的汇总数据，表征 anifrolumab 药代动力学与中度至重度 SLE 患者的疗效和安全性之间的关系，尽管标准治疗。方法 TULIP-1 和 TULIP-2 是随机、安慰剂对照、为期 52 周的静脉注射 anifrolumab 试验（每 4 周一次，共 48 周）。对于暴露-反应分析，比较了 anifrolumab 和安慰剂在平均 anifrolumab 血清浓度 (Cave) 的每个四分位数/三分位数的第 52 周时基于 BILAG 的综合狼疮评估 (BICLA) 或 SLE 反应者指数 [SRI(4)] 反应率在所有患者中，完成治疗的患者和完成治疗的 IFN 基因特征 (IFNGS) 高的患者，使用平均边际效应逻辑回归。以图形方式评估暴露与关键安全事件之间的关系。结果 在接受 anifrolumab（150 mg，n = 91；300 mg，n = 356）或安慰剂（n = 366）的 TULIP-1/TULIP-2 患者中，574 人完成了治疗，其中 470 人 IFNGS 高。在暴露-功效分析中，在 Cave 亚组和所有分析人群中观察到 BICLA 和 SRI(4) 治疗差异有利于 anifrolumab 300 mg 与安慰剂。逻辑回归将 Cave 确定为预测 BICLA 反应的重要协变量，因为更高的 anifrolumab Cave 预测更大的疗效。在接受 anifrolumab 150 或 300 mg 的患者中，在第 52 周内没有证据表明暴露驱动的关键安全事件发生率。结论 虽然较高的 Cave 预示着更高的疗效，但在 TULIP 试验中的 Cave 亚组的 BICLA 和 SRI(4) 反应中观察到有利于 anifrolumab 300 mg 与安慰剂的一致积极益处。没有证据表明暴露驱动的安全事件。ClinicalTrial.gov 编号 NCT02446912、NCT02446899