de Latour Regis Peffault, Kulasekararaj Austin, Dingli David, Wilson Koo, Wojciechowski Piotr, Hakimi Zalmai, Nazir Jameel, Czech Barbara, Hillmen Peter, Szer Jeff
French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Paris, France.
Department of Haematological Medicine, King's College Hospital, National Institute of Health Research/Wellcome King's Clinical Research Facility, London, UK.
Eur J Haematol. 2025 Aug;115(2):125-133. doi: 10.1111/ejh.14422. Epub 2025 Apr 25.
Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare, acquired non-malignant haematological disorder characterised by thrombosis risk, serious complications and debilitating symptoms in untreated patients.
This anchored indirect treatment comparison (ITC) evaluated efficacy data between proximal complement 3 inhibitor (C3i) pegcetacoplan and factor B inhibitor, iptacopan, in patients with PNH previously treated with complement 5 inhibitors (C5i; eculizumab, ravulizumab).
Respective pivotal studies provided patient-level trial data for pegcetacoplan (16-week PEGASUS [NCT03500549]) and published data for iptacopan (24-week APPLY PNH [NCT04558918]). Differences in study design, duration and statistical methods between PEGASUS and APPLY PNH necessitated the comparative analyses to be conducted on secondary measures based on haemoglobin (Hb) levels, absolute reticulocyte count (ARC), lactate dehydrogenase (LDH) levels, and patient-reported outcomes on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale scores. The availability of a common reference C5i treatment group in both PEGASUS and APPLY PNH studies allowed anchored ITC (Bucher method). Simulated treatment comparison (STC) assessed the robustness of the main analysis.
Overall, baseline characteristics of the populations in the PEGASUS and APPLY PNH studies were broadly comparable. Anchored ITC showed comparable outcomes (mean difference, [95% CI]) on change-from-baseline to end of study for pegcetacoplan versus C5i, and iptacopan versus C5i, respectively, across endpoints: Hb level (-0.49 g/dL [-1.78, 0.80]); ARC (-34.41 × 10/L [-90.02, 21.21]); LDH level (-115.16 U/L [-244.40, 14.01]); FACIT-Fatigue score (3.57 [-5.60, 12.73]). Finally, the STC produced results consistent with the main Bucher analyses across all clinical endpoints and patient-reported fatigue, providing similar point estimates and confidence intervals.
This anchored ITC, based on data from pivotal trials, did not indicate significant differences in clinical or patient-reported outcomes between pegcetacoplan and iptacopan in PNH treatment. The findings suggest that PNH treatment decisions should also consider individualised disease- and patient-related factors.
ClinicalTrials.gov identifier: NCT03500549.
阵发性睡眠性血红蛋白尿（PNH）是一种极其罕见的获得性非恶性血液系统疾病，其特征为血栓形成风险、严重并发症以及未经治疗患者的衰弱症状。
本锚定间接治疗比较（ITC）评估了在先前接受补体5抑制剂（C5i；依库珠单抗、ravulizumab）治疗的PNH患者中，近端补体3抑制剂（C3i）培克西普坦与因子B抑制剂依他可泮之间的疗效数据。
各自的关键研究提供了培克西普坦的患者水平试验数据（16周的PEGASUS [NCT03500549]）以及依他可泮已发表的数据（24周的APPLY PNH [NCT04558918]）。PEGASUS和APPLY PNH在研究设计、持续时间和统计方法上的差异使得需要基于血红蛋白（Hb）水平、绝对网织红细胞计数（ARC）、乳酸脱氢酶（LDH）水平以及慢性疾病治疗功能评估 - 疲劳（FACIT - 疲劳）量表评分的患者报告结局等次要指标进行比较分析。PEGASUS和APPLY PNH研究中共同参考C5i治疗组的可用性允许进行锚定ITC（布彻方法）。模拟治疗比较（STC）评估了主要分析的稳健性。
总体而言，PEGASUS和APPLY PNH研究中人群的基线特征大致可比。锚定ITC显示，在各个终点上，培克西普坦与C5i、依他可泮与C5i从基线到研究结束的变化方面具有可比的结果（平均差异，[95%置信区间]）：Hb水平（-0.49 g/dL [-1.78, 0.80]）；ARC（-34.41×10⁹/L [-90.02, 21.21]）；LDH水平（-115.16 U/L [-244.40, 14.01]）；FACIT - 疲劳评分（3.5 [-5.60, 12.73]）。最后，STC在所有临床终点和患者报告的疲劳方面产生了与主要布彻分析一致的结果，提供了相似的点估计和置信区间。
基于关键试验数据的本锚定ITC表明，在PNH治疗中，培克西普坦和依他可泮在临床或患者报告的结局方面没有显著差异。研究结果表明，PNH治疗决策还应考虑个体化的疾病和患者相关因素。
ClinicalTrials.gov标识符：NCT03500549。
