Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; Haematology and Bone Marrow Transplant Unit, AORN Moscati, Avellino, Italy.
West German Cancer Center, Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany.
Lancet Haematol. 2021 May;8(5):e344-e354. doi: 10.1016/S2352-3026(21)00028-4. Epub 2021 Mar 23.
The haematological benefit of standard-of-care anti-C5 treatment for haemolytic paroxysmal nocturnal haemoglobinuria is limited by residual intravascular haemolysis or emerging C3-mediated extravascular haemolysis. Therefore, the aim of this phase 2 study was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics, and activity of the new complement factor B inhibitor, iptacopan, in patients with paroxysmal nocturnal haemoglobinuria who have active haemolysis despite anti-C5 therapy.
In this multicentre, open-label, single-arm, phase 2 trial, we enrolled adult patients (aged 18-80 years) with paroxysmal nocturnal haemoglobinuria who showed signs of active haemolysis despite receiving eculizumab treatment. Patients were enrolled at Federico II University Hospital (Naples, Italy), Hôpital Saint-Louis (Paris, France), and University Hospital Essen (Essen, Germany). For enrolment, patients were required to show lactate dehydrogenase more than 1·5-times the upper limit of normal and a paroxysmal nocturnal haemoglobinuria type 3 erythrocyte or granulocyte clone size of 10% or greater. Patients with bone marrow failure, on systemic steroid or immunosuppressive drugs, or with severe comorbidities were excluded from the study. Iptacopan was given orally as an add-on therapy at a dose of 200 mg twice daily. The primary endpoint was the effect of iptacopan on the reduction of chronic residual intravascular haemolysis measured as change in lactate dehydrogenase from baseline value to week 13. At 13 weeks, patients could opt into a long-term study extension (ongoing), allowing for modifications of standard treatment. This trial is registered at ClinicialTrials.gov, NCT03439839.
Between May 31, 2018, and April 9, 2019, ten patients had twice daily 200 mg iptacopan. Iptacopan resulted in marked reduction of lactate dehydrogenase from baseline versus at week 13 (mean 539 IU/L [SD 263] vs 235 IU/L [44], change from baseline -309·2 IU/L [SD 265·5], 90% CI -473·77 to -144·68, p=0·0081), associated with significant improvement of haemoglobin concentrations (mean 97·7 g/L [SD 10·5] vs 129·5 g/L [18·3] change from baseline 31·9 g/L [14·5], 90% CI 23·42-40·28, p<0·0001). All biomarkers of haemolysis improved on iptacopan treatment. Observed haematological benefits were maintained longer than the 13-week study period, throughout the study extension, including seven patients who stopped concomitant standard-of-care treatment and continued iptacopan as monotherapy. There were no deaths or treatment-related serious adverse events during the study period. Of three non-related serious adverse events, two occurred in the same patient (one during run-in and before exposure to iptacopan).
Iptacopan at a chronic dose of 200 mg twice daily was well tolerated without any major drug-related safety findings and shows lactate dehydrogenase reduction and haemoglobin normalisation in most patients with paroxysmal nocturnal haemoglobinuria at week 13 and beyond, even in monotherapy. On the basis of these data, iptacopan will be tested as monotherapy in pivotal trials investigating its haematological benefit in a broader paroxysmal nocturnal haemoglobinuria population.
Novartis Institutes for Biomedical Research.
标准治疗抗 C5 治疗对溶血性阵发性夜间血红蛋白尿症的血液学益处受到残余血管内溶血或新出现的 C3 介导的血管外溶血的限制。因此，本 2 期研究的目的是评估新型补体因子 B 抑制剂伊普可潘在接受抗 C5 治疗后仍有溶血活动的阵发性夜间血红蛋白尿症患者中的安全性、耐受性、药代动力学和药效学以及活性。
在这项多中心、开放标签、单臂、2 期试验中，我们招募了有溶血病活动迹象的成年阵发性夜间血红蛋白尿症患者（年龄 18-80 岁），尽管接受了依库珠单抗治疗。患者在那不勒斯费德里科二世大学医院（意大利那不勒斯）、圣路易斯医院（法国巴黎）和埃森大学医院（德国埃森）入组。入组需要乳酸脱氢酶比正常值高 1.5 倍以上，并且阵发性夜间血红蛋白尿症 3 型红细胞或粒细胞克隆大小为 10%或更大。骨髓衰竭、全身类固醇或免疫抑制药物或严重合并症患者被排除在研究之外。伊普可潘作为附加治疗，每日口服两次，剂量为 200mg。主要终点是伊普可潘对慢性残留血管内溶血减少的影响，以乳酸脱氢酶从基线值到第 13 周的变化来衡量。在第 13 周时，患者可以选择进入长期研究扩展（正在进行），允许修改标准治疗。这项试验在 ClinicialTrials.gov 上注册，NCT03439839。
在 2018 年 5 月 31 日至 2019 年 4 月 9 日期间，10 名患者每天两次服用 200mg 伊普可潘。伊普可潘使乳酸脱氢酶从基线值显著降低至第 13 周（平均 539IU/L[263]与 235IU/L[44]，与基线相比变化-309.2IU/L[265.5]，90%CI-473.77 至-144.68，p=0.0081），血红蛋白浓度显著改善（平均 97.7g/L[10.5]与 129.5g/L[18.3]，与基线相比变化 31.9g/L[14.5]，90%CI23.42-40.28，p<0.0001）。所有溶血生物标志物在伊普可潘治疗后均得到改善。在研究扩展期间，观察到的血液学益处持续时间长于 13 周的研究期，包括 7 名停止标准治疗并继续伊普可潘单药治疗的患者。在研究期间没有死亡或与治疗相关的严重不良事件。3 例非相关严重不良事件中，2 例发生在同一名患者（1 例在入组前和接触伊普可潘之前）。
每天两次 200mg 的伊普可潘慢性剂量耐受性良好，无任何主要与药物相关的安全性发现，在大多数阵发性夜间血红蛋白尿症患者中，在第 13 周及以后，伊普可潘可降低乳酸脱氢酶并使血红蛋白正常化，即使在单药治疗中也是如此。基于这些数据，伊普可潘将作为单药在关键性试验中进行测试，以研究其在更广泛的阵发性夜间血红蛋白尿症患者中的血液学益处。
诺华生物医学研究所。
