Wong Raymond S M
Sir Y.K. Pao Centre for Cancer and Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong.
Ther Adv Hematol. 2022 Jul 28;13:20406207221114673. doi: 10.1177/20406207221114673. eCollection 2022.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by complement-mediated hemolysis, thrombosis, and various degrees of bone marrow dysfunction. Until recently, C5 inhibition with eculizumab or ravulizumab represented the only therapies approved for patients with PNH by the United States Food and Drug Administration (US FDA). Although C5-inhibitors reduce PNH-related signs and symptoms, many patients continue to exhibit persistent anemia and require frequent blood transfusions. In May 2021, pegcetacoplan became the third US FDA-approved treatment for adults with PNH, and the first to target C3, a complement component upstream of C5. The novel strategy of inhibiting proximal complement activity with pegcetacoplan controls C5-mediated intravascular hemolysis and prevents C3-mediated extravascular hemolysis. Here, we review the results from multiple pegcetacoplan clinical studies on the efficacy and safety of pegcetacoplan treatment in adults with PNH. This review summarizes findings from three studies in complement-inhibitor-naïve patients with PNH (PADDOCK [phase Ib], PALOMINO [phase IIa], PRINCE [phase III; pegcetacoplan versus standard treatment excluding complement-inhibitors]), and one phase III study (PEGASUS) that compared eculizumab to pegcetacoplan in patients who remained anemic (hemoglobin levels < 10.5 g/dL) despite stable eculizumab treatment (⩾3 months). These studies found that pegcetacoplan contributed to superior improvements in primary and secondary endpoints related to hemoglobin levels and other hematologic parameters and provided effective management of anemia and anemia-related complications (i.e. transfusion burden, reticulocyte production, and fatigue). Furthermore, we summarize results from the 32-week open-label period from the PEGASUS trial, which confirmed the long-term safety and durable efficacy of pegcetacoplan as demonstrated by sustained improvements in clinical and hematologic outcomes in pegcetacoplan-treated patients. Pegcetacoplan is approved for the treatment of adults with PNH in the United States (Empaveli™) and for adult patients who remain anemic after at least 3 months of stable C5-inhibitor therapy in the European Union (Aspaveli) and Australia (Empaveli; also approved for patients intolerant to C5-inhibitors).
阵发性睡眠性血红蛋白尿（PNH）是一种罕见的获得性血液疾病，其特征为补体介导的溶血、血栓形成以及不同程度的骨髓功能障碍。直到最近，依库珠单抗或ravulizumab抑制C5仍是美国食品药品监督管理局（US FDA）批准用于PNH患者的唯一疗法。尽管C5抑制剂可减轻PNH相关的体征和症状，但许多患者仍持续存在贫血，需要频繁输血。2021年5月，培克妥昔单抗成为美国食品药品监督管理局批准的用于成人PNH的第三种疗法，也是首个靶向C3（C5上游的一种补体成分）的疗法。用培克妥昔单抗抑制近端补体活性的新策略可控制C5介导的血管内溶血，并预防C3介导的血管外溶血。在此，我们回顾了多项关于培克妥昔单抗治疗成人PNH疗效和安全性的临床研究结果。本综述总结了三项针对未接受过补体抑制剂治疗的PNH患者的研究（PADDOCK [Ib期]、PALOMINO [IIa期]、PRINCE [III期；培克妥昔单抗与不包括补体抑制剂的标准治疗对比]），以及一项III期研究（PEGASUS）的结果，该研究在接受依库珠单抗稳定治疗（≥3个月）但仍贫血（血红蛋白水平<10.5 g/dL）的患者中比较了依库珠单抗和培克妥昔单抗。这些研究发现，培克妥昔单抗在与血红蛋白水平及其他血液学参数相关的主要和次要终点方面有更显著的改善，并有效管理了贫血及与贫血相关的并发症（即输血负担、网织红细胞生成和疲劳）。此外，我们总结了PEGASUS试验32周开放标签期的结果，该结果证实了培克妥昔单抗的长期安全性和持久疗效，培克妥昔单抗治疗的患者在临床和血液学结果方面持续改善。培克妥昔单抗在美国被批准用于治疗成人PNH（Empaveli™），在欧盟（Aspaveli）和澳大利亚（Empaveli；也被批准用于对C5抑制剂不耐受的患者）被批准用于至少3个月稳定C5抑制剂治疗后仍贫血的成人患者。
