Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Medizinische Klinik IV, LMU Klinikum, LMU, Munich, Germany.
BMC Nephrol. 2021 Jan 6;22(1):5. doi: 10.1186/s12882-020-02190-0.
Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor obtained through selective modifications to eculizumab, is efficacious in inhibiting complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. In this analysis, we report outcomes in a subgroup of patients from the 311 study who developed TMA postpartum.
This was a phase 3, multicenter trial evaluating efficacy and safety of ravulizumab in adults (≥18 years of age) with aHUS naïve to complement inhibitor treatment. The primary endpoint was complete TMA response (simultaneous platelet count normalization [≥150 × 10/L], lactate dehydrogenase normalization [≤246 U/L] and 25% improvement in serum creatinine) through the 183-day initial evaluation period. Additional efficacy endpoints included time to complete TMA response, hematologic normalization, and dialysis requirement status.
Eight patients presenting with TMA postpartum (median age of 37.7 [range; 22.1-45.2] years) were diagnosed with aHUS and received ≥1 dose of ravulizumab. Five patients (63%) were on dialysis at baseline. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 31.5 days. Hematologic normalization was observed in all patients. All patients on dialysis at baseline discontinued dialysis within 21 days after treatment with ravulizumab. All patients showed continued improvements in the estimated glomerular filtration rate from baseline to Day 183. Three possible treatment-related adverse events were observed in 2 patients (arthralgia and nasopharyngitis [both non-severe]; urinary tract infection). No deaths or meningococcal infections occurred.
Treatment with ravulizumab provided immediate and complete C5 inhibition, resulting in rapid clinical and laboratory improvements and complete TMA response through 183 days in patients with aHUS triggered by pregnancy. The safety profile observed in this subset of patients analysed is consistent with the 311 study investigating ravulizumab in patients with aHUS naïve to complement treatment.
Clinical trial identifier: NCT02949128 .
妊娠诱发的非典型溶血尿毒综合征（aHUS）是一种罕见疾病，由补体替代途径失调引起，在大约 1/25000 次妊娠中发生。311 期 3 试验（NCT02949128）表明，ravulizumab 是一种通过对 eculizumab 进行选择性修饰获得的长效 C5 抑制剂，可有效抑制 aHUS 患者的补体介导的血栓性微血管病（TMA）。在这项分析中，我们报告了来自 311 研究的一组在产后发生 TMA 的患者的结果。
这是一项 3 期、多中心试验，评估了 ravulizumab 在初次评估期 183 天内对既往未接受补体抑制剂治疗的 aHUS 成人（≥18 岁）的疗效和安全性。主要终点是完全 TMA 反应（血小板计数同时正常化[≥150×10/L]、乳酸脱氢酶正常化[≤246 U/L]和血清肌酐改善 25%）。其他疗效终点包括完全 TMA 反应时间、血液学正常化和透析需求状态。
8 例产后出现 TMA 的患者（中位年龄 37.7 [范围：22.1-45.2] 岁）被诊断为 aHUS，并接受了至少 1 剂 ravulizumab。基线时有 5 例患者（63%）接受透析。7/8 例患者（87.5%）在中位时间 31.5 天内达到完全 TMA 反应。所有患者均实现血液学正常化。所有基线时接受透析的患者均在接受 ravulizumab 治疗后 21 天内停止透析。所有患者在基线至第 183 天的肾小球滤过率均有持续改善。2 例患者观察到 3 例可能与治疗相关的不良事件（关节痛和鼻咽炎[均为非严重]；尿路感染）。无死亡或脑膜炎奈瑟菌感染发生。
ravulizumab 的治疗立即且完全抑制了 C5，导致妊娠诱发的 aHUS 患者在 183 天内迅速出现临床和实验室改善及完全 TMA 反应。在该亚组患者中观察到的安全性概况与 311 研究一致，该研究调查了既往未接受补体治疗的 aHUS 患者使用 ravulizumab 的情况。
临床试验标识符：NCT02949128。
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