Gaya Anna, Munir Talha, Urbano-Ispizua Alvaro, Griffin Morag, Taubel Jorg, Bush Jim, Bhan Ishir, Borodovsky Anna, Wang Yue, Badri Prajakta, Garg Pushkal
Hospital Clinic of Barcelona Barcelona Spain.
Leeds Teaching Hospitals St. James' University Hospital Leeds UK.
EJHaem. 2023 Jun 26;4(3):612-624. doi: 10.1002/jha2.748. eCollection 2023 Aug.
Complement dysregulation underpins the physiopathology of paroxysmal nocturnal hemoglobinuria (PNH). Cemdisiran, an RNA interference investigational treatment, silences complement component 5 (C5) expression in the liver. Previously reported results showed sustained reduction in C5 levels following cemdisiran monotherapy, with >90% reduction in patients with PNH. This phase 1/2 study evaluated single (Part A, = 32; 50-900 mg) or multiple (Part B, = 24; 100-600 mg) ascending doses of cemdisiran or placebo (double-blind, randomized 3:1) in healthy adults, or cemdisiran in patients with PNH who were naive to, or receiving, eculizumab (Part C, = 6; 200 or 400 mg weekly; open-label). The primary objective was to assess the safety and tolerability of cemdisiran. Other assessments included change in complement activity, lactate dehydrogenase levels, and inhibition of hemolysis following cemdisiran treatment. Cemdisiran was generally well tolerated in this study. Overall, 75%, 89%, and 100% of subjects in Parts A, B, and C, respectively, experienced ≥1 non-serious adverse event (AE). Most events were Grade 1 or 2 in severity and the most common AEs included nasopharyngitis and headache. Cemdisiran elicited robust, sustained reductions in the complement activity in healthy adults and patients with PNH. In Part C, exploratory analyses showed that cemdisiran monotherapy was insufficient to prevent hemolysis in patients with PNH as measured by serum lactate dehydrogenase levels. Cemdisiran and eculizumab combination therapy reduced the dose of eculizumab required to provide adequate control of intravascular hemolysis. These results demonstrate a potential benefit of cemdisiran coadministration in patients who are inadequate responders to eculizumab alone.
补体调节异常是阵发性夜间血红蛋白尿（PNH）病理生理学的基础。Cemdisiran是一种RNA干扰研究性治疗药物，可使肝脏中的补体成分5（C5）表达沉默。先前报道的结果显示，Cemdisiran单药治疗后C5水平持续降低，PNH患者降低幅度>90%。这项1/2期研究评估了健康成年人中单次（A部分，n = 32；50 - 900 mg）或多次（B部分，n = 24；100 - 600 mg）递增剂量的Cemdisiran或安慰剂（双盲，随机3:1），或评估了初治或正在接受依库珠单抗治疗的PNH患者中Cemdisiran的疗效（C部分，n = 6；每周200或400 mg；开放标签）。主要目的是评估Cemdisiran的安全性和耐受性。其他评估包括Cemdisiran治疗后补体活性、乳酸脱氢酶水平的变化以及溶血抑制情况。在本研究中，Cemdisiran总体耐受性良好。总体而言，A、B和C部分分别有75%、89%和100%的受试者经历了≥1次非严重不良事件（AE）。大多数事件严重程度为1级或2级，最常见的AE包括鼻咽炎和头痛。Cemdisiran在健康成年人和PNH患者中引起补体活性的强劲、持续降低。在C部分，探索性分析表明，以血清乳酸脱氢酶水平衡量，Cemdisiran单药治疗不足以预防PNH患者的溶血。Cemdisiran与依库珠单抗联合治疗降低了充分控制血管内溶血所需的依库珠单抗剂量。这些结果表明，Cemdisiran联合给药对单独使用依库珠单抗反应不足的患者具有潜在益处。
