Eculizumab (ECU) Inhibits Thrombotic Microangiopathy (TMA) and Improves Renal Function In Adult Patients (Pts) With Atypical Hemolytic Uremic Syndrome (aHUS)
Eculizumab (ECU) Inhibits Thrombotic Microangiopathy (TMA) and Improves Renal Function In Adult Patients (Pts) With Atypical Hemolytic Uremic Syndrome (aHUS)
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依库丽单抗 (ECU) 可抑制非典型溶血性尿毒症综合征 (aHUS) 成年患者 (Pts) 的血栓性微血管病 (TMA) 并改善肾功能
DOI：
10.1182/blood.v122.21.2179.2179
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发表时间：
2013
期刊：
影响因子：
20.3
通讯作者：
C. Legendre
中科院分区：
文献类型：
--
作者：
F. Fakhouri;M. Hourmant;S. Cataland;M. Espinosa;A. Gaber;J. Menne;E. Minetti;F. Provôt;E. Rondeau;P. Ruggenenti;L. Weekers;M. Ogawa;C. Bedrosian;C. Legendre
阿胡斯是一种罕见的、遗传性的、危及生命的疾病，其不受控制的和慢性的补体激活，导致全身性TMA和严重的终末器官损伤。尽管进行了血浆置换/血浆输注（PE/PI），但高达65%的患者仍会遭受永久性肾损伤，进展为终末期肾病，或在诊断后一年内死亡。Ecu是一种终末补体抑制剂，已被批准用于治疗阿胡斯，并在一项回顾性研究中显示其在儿科患者中安全有效。以前的研究表明，早期干预与Ecu导致显着的，时间依赖性的改善血液学和肾脏的结果。在这里，我们报告了第一个前瞻性试验的安全性和有效性结果与阿胡斯在26周（wks）的儿科患者。
方法这是一项开放标签、单臂、2期试验，在阿胡斯儿科患者中进行Ecu治疗。入选标准包括筛选时和基线（BL）时血小板计数<正常值下限（LLN），当前阿胡斯表现开始时LDH ≥1.5倍正常值上限（ULN），以及筛选时血清肌酐（Cr）升高。不需要确定的补体基因突变。STEC-HUS患者（滋贺毒素+大肠杆菌）。大肠杆菌）或ADAMTS 13严重缺陷（<5%）。主要终点为26周时的完全TMA缓解（血小板和LDH正常化，连续2次测量（间隔≥4周）时Cr较BL改善≥25%）。给药基于体重队列。
结果22例患者（1个月至17岁）入组，19例完成了26周的治疗。16例（73%）患者为新诊断，从诊断到首次使用ECU的中位时间为6天。12例患者（55%）在当前表现期间没有PE/PI。在第26周，14例患者（64%）达到了TMA完全缓解的主要终点（[表][1]）。从BL至26周研究期间，血小板（[图1][2]）和eGFR（[图2][3]）显著增加。在BL接受透析的11例患者中有9例（82%）停止透析。在BL时未接受透析的11例患者中，100%的患者在第26周时仍未接受透析。至第26周，eGFR平均增加64 mL/min/1.73m2。所有10例接受PE/PI的患者在BL时均停止PE/PI。QoL显著改善。Ecu是安全的，耐受性良好。1例患者因SAE（激越）退出研究。无患者发生脑膜炎球菌感染或死亡。
! [图][4]
图1：26周内血小板计数改善。
! [图][4]
图2：26周内eGFR改善。
查看此表：
表
结论：在本研究中，首次对阿胡斯儿童患者进行前瞻性试验，早期Ecu干预改善了血液学和肾脏参数。在26周研究期间，82%的患者停止透析，无患者开始透析。推荐使用Ecu作为阿胡斯儿童的一线治疗。该试验证实，Ecu抑制补体介导的TMA，并且在批准的剂量方案下作为阿胡斯儿科患者的一线治疗是安全有效的。本临床试验的治疗正在进行中。
披露：Greenbaum：Alexion制药：咨询，酬金，研究资金。Ardissino：Alexion制药公司：正式咨询活动其他，酬金。Henning：Alexion Pharmaceuticals：Grant Support Other，Research Funding。论文：诺华制药，Alexion制药：赠款支持其他，酬金，研究资金，发言人局。Kar：Alexion Pharmaceuticals：国际咨询委员会成员阿胡斯其他。Vande Walle：Alexion Pharmaceuticals：Ferring安全委员会、安斯泰来索非那新安全和研究者委员会、三菱安全委员会、Alexion注册审查委员会其他、研究基金、发言人局。小川：Alexion制药：就业。Bedrosian：Alexion Pharmaceuticals：就业。
[1]：#T1
[2]：#F1
[3]：#F2
[4]：待定：是
Introduction aHUS is a rare, genetic, life-threatening disease of uncontrolled and chronic complement activation, leading to systemic TMA and severe end-organ damage. Despite plasma exchange/plasma infusion (PE/PI), up to 65% of all pts sustain permanent renal damage, progress to end-stage renal disease, or die within a year of diagnosis. Ecu, a terminal complement inhibitor, is approved for the treatment of aHUS, and was shown to be safe and effective in pediatric pts in a retrospective study. Previous studies have shown that early intervention with Ecu leads to significant, time-dependent improvements in hematologic and renal outcomes. Here, we report safety and efficacy results from the first prospective trial of pediatric pts with aHUS at 26 weeks (wks).
Methods This was an open-label, single-arm, Phase 2 trial of Ecu in pediatric pts with aHUS. Admission criteria included platelet count < the lower limit of normal (LLN) at screening and at baseline (BL), LDH ≥1.5 times the upper limit of normal (ULN) at the start of the current aHUS manifestation, and elevated serum creatinine (Cr) at screening. An identified complement gene mutation was not required. Pts with STEC-HUS (shiga toxin + E. coli ) or severe ADAMTS13 deficiency (<5%) were excluded. The primary endpoint was complete TMA response at 26 wks (normalization of platelets and LDH, and ≥25% improvement in Cr from BL on 2 consecutive measurements ≥4 wks apart). Dosing was based on weight cohorts.
Results 22 pts (1 month to 17 yrs) were enrolled and 19 completed 26 wks. 16 pts (73%) were newly diagnosed, with a median of 6 days from diagnosis to the first dose of ECU. 12 pts (55%) had no PE/PI during the current manifestation. At wk 26, 14 pts (64%) achieved the primary endpoint of complete TMA response ([Table][1]). Platelets ([Fig 1][2]) and eGFR ([Fig 2][3]) increased significantly from BL through the 26-wk study period. 9 of 11 pts (82%) on dialysis at BL discontinued dialysis. 100% of the 11 pts not on dialysis at BL remained off dialysis through wk 26. Mean increase in eGFR through wk 26 was 64 mL/min/1.73m2. All 10 pts on PE/PI at BL discontinued PE/PI. QoL significantly improved. Ecu was safe and well tolerated. 1 pt withdrew due to an SAE (agitation). No pts had meningococcal infection or died.
![Figure][4]
Figure 1: Platelet count improvement through 26 weeks.
![Figure][4]
Figure 2: eGFR improvement through 26 weeks.
View this table:
Table
Conclusions In this, the first prospective trial of pediatric pts with aHUS, early intervention with Ecu improved hematologic and renal parameters. 82% of pts discontinued dialysis, and no pt initiated dialysis during the 26-wk study. Use of Ecu has been recommended as first-line therapy in children with aHUS. This trial confirms that Ecu inhibits complement-mediated TMA, and is safe and effective as first-line therapy at the approved dose regimen in pediatric pts with aHUS. Treatment in this clinical trial is ongoing.
Disclosures: Greenbaum: Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding. Ardissino: Alexion Pharmaceuticals: Formal Advisory Activities Other, Honoraria. Henning: Alexion Pharmaceuticals: Grant Support Other, Research Funding. Pape: Novartis Pharmaceuticals, Alexion Pharmaceuticals: Grant Support Other, Honoraria, Research Funding, Speakers Bureau. Kar: Alexion Pharmaceuticals: Member of the Int. Advisory Board aHUS Other. Vande Walle: Alexion Pharmaceuticals: Ferring Safety Board, Astellas Safety and Investigator Board for Solifenacin, Mitsubishi Safety Board, Alexion Registry Review Board Other, Research Funding, Speakers Bureau. Ogawa: Alexion Pharmaceuticals: Employment. Bedrosian: Alexion Pharmaceuticals: Employment.
[1]: #T1
[2]: #F1
[3]: #F2
[4]: pending:yes