C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab.
C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab.
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DOI：
10.1002/ajh.25960
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发表时间：
2020-11
影响因子：
12.8
通讯作者：
Francois C
中科院分区：
文献类型：
--
作者：
de Castro C;Grossi F;Weitz IC;Maciejewski J;Sharma V;Roman E;Brodsky RA;Tan L;Di Casoli C;El Mehdi D;Deschatelets P;Francois C
阵发性睡眠性血红蛋白尿症（PNH）是一种获得性、危及生命的血液病，以慢性补体介导的溶血和血栓形成为特征。尽管使用C5抑制剂eculizumab治疗，72%的人仍然贫血。Pegcetacoplan（APL-2）是一种聚乙二醇化C3抑制剂，有可能为PNH患者提供更全面的溶血控制。这项开放标签、Ib期研究旨在评估pegcetacoplan在接受依库珠单抗治疗期间仍然贫血的PNH受试者中的安全性、耐受性和药代动力学。药效学终点也作为本研究的探索性目的进行了评估。提供了队列4中接受治疗长达2年的6例受试者的数据。共报告了427起治疗后出现的不良事件（TEAE），其中68起可能与研究药物相关。2例受试者发生8起严重TEAE;其中3起事件被认为可能与研究药物相关。重复给药后，Pegcetacoplan药代动力学浓度蓄积，在约6 - 8周时达到稳态。基线时，依库珠单抗可良好控制乳酸脱氢酶水平。在所有6例受试者中，Pegcetacoplan升高血红蛋白水平，降低网织红细胞计数和总胆红素。观察到慢性疾病治疗疲劳评分的功能评估改善。2例受试者因与pegcetacoplan无关的原因停药。完成研究的所有4例受试者在依库珠单抗停药后转为pegcetacoplan单药治疗，并避免输血。在这项小型研究中，pegcetacoplan治疗通常耐受性良好，并通过实现广泛的溶血控制改善血液学应答，使依库珠单抗停药。
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life‐threatening hematologic disease characterized by chronic complement‐mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL‐2), a PEGylated C3 inhibitor, has the potential to provide more complete hemolysis control in patients with PNH. This open‐label, phase Ib study was designed to assess the safety, tolerability, and pharmacokinetics of pegcetacoplan in subjects with PNH who remained anemic during treatment with eculizumab. Pharmacodynamic endpoints were also assessed as an exploratory objective of this study. Data are presented for six subjects in cohort 4 who received treatment for up to 2 years. In total, 427 treatment‐emergent adverse events (TEAEs) were reported, 68 of which were possibly related to the study drug. Eight serious TEAEs occurred in two subjects; three of these events were considered possibly related to the study drug. Pegcetacoplan pharmacokinetic concentrations accumulated with repeated dosing, and steady state was reached at approximately 6‐8 weeks. Lactate dehydrogenase levels were well controlled by eculizumab at baseline. Pegcetacoplan increased hemoglobin levels and decreased both reticulocyte count and total bilirubin in all six subjects. Improvements were observed in Functional Assessment of Chronic Illness Therapy Fatigue scores. Two subjects discontinued for reasons unrelated to pegcetacoplan. All four subjects who completed the study transitioned to pegcetacoplan monotherapy following eculizumab discontinuation and avoided transfusions. In this small study, pegcetacoplan therapy was generally well‐tolerated, and resulted in an improved hematological response by achieving broad hemolysis control, enabling eculizumab discontinuation.
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影响因子：
20.3
作者：
Hillmen, Peter;Muus, Petra;Young, Neal S.
通讯作者：
Young, Neal S.
DOI：
10.1182/asheducation-2016.1.208
发表时间：
2016-12-01
影响因子：
3
作者：
Parker, Charles J.
通讯作者：
Parker, Charles J.
影响因子：
3.6
作者：
Webster K;Cella D;Yost K
通讯作者：
Yost K
影响因子：
1.5
作者：
Rudmann, Daniel G.;Alston, James T.;Heidel, Shawn
通讯作者：
Heidel, Shawn
DOI：
10.4049/jimmunol.1203200
发表时间：
2013-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ricklin D;Lambris JD
通讯作者：
Lambris JD