Kavanagh David, Greenbaum Larry A, Bagga Arvind, Karki Rajeshri G, Chen Chien-Wei, Vasudevan Sajita, Charney Alan, Dahlke Marion, Fakhouri Fadi
National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK, and Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Division of Pediatric Nephrology, Emory School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Kidney Int Rep. 2023 Apr 29;8(7):1332-1341. doi: 10.1016/j.ekir.2023.04.029. eCollection 2023 Jul.
Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, and life-threatening form of thrombotic microangiopathy (TMA) which is caused by dysregulation of the alternative complement pathway (AP). Complement inhibition is an effective therapeutic strategy in aHUS, though current therapies require intravenous administration and increase the risk of infection by encapsulated organisms, including meningococcal infection. Further studies are required to define the optimal duration of existing therapies, and to identify new agents that are convenient for long-term administration. Iptacopan (LNP023) is an oral, first-in-class, highly potent, proximal AP inhibitor that specifically binds factor B (FB). In phase 2 studies of IgA nephropathy, paroxysmal nocturnal hemoglobinuria, and C3 glomerulopathy, iptacopan inhibited the AP, showed clinically relevant benefits, and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with the convenience of oral administration.
Alternative Pathway Phase III to Evaluate LNP023 in aHUS (APPELHUS; NCT04889430) is a multicenter, single-arm, open-label, phase 3 study to evaluate the efficacy and safety of iptacopan in patients ( = 50) with primary complement-mediated aHUS naïve to complement inhibitor therapy (including anti-C5). Eligible patients must have evidence of TMA (platelet count <150 × 10/l, lactate dehydrogenase ≥1.5 × upper limit of normal, hemoglobin ≤ lower limit of normal, serum creatinine ≥ upper limit of normal) and will receive iptacopan 200 mg twice daily. The primary objective is to assess the proportion of patients achieving complete TMA response without the use of plasma exchange or infusion or anti-C5 antibody during 26 weeks of iptacopan treatment.
APPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS.
非典型溶血尿毒综合征（aHUS）是一种罕见的、进行性的、危及生命的血栓性微血管病（TMA），由替代补体途径（AP）失调引起。补体抑制是aHUS的一种有效治疗策略，尽管目前的疗法需要静脉给药，并增加了被包膜菌感染的风险，包括脑膜炎球菌感染。需要进一步研究来确定现有疗法的最佳持续时间，并识别便于长期给药的新药物。Iptacopan（LNP023）是一种口服的、同类首创的、高效的近端AP抑制剂，可特异性结合B因子（FB）。在IgA肾病、阵发性夜间血红蛋白尿和C3肾小球病的2期研究中，iptacopan抑制了AP，显示出临床相关益处，且耐受性良好。因此，iptacopan有潜力成为一种有效且安全的aHUS治疗方法，具有口服给药的便利性。
评估LNP023治疗aHUS的替代途径3期研究（APPELHUS；NCT04889430）是一项多中心、单臂、开放标签的3期研究，旨在评估iptacopan对50例初治补体抑制剂治疗（包括抗C5）的原发性补体介导的aHUS患者的疗效和安全性。符合条件的患者必须有TMA证据（血小板计数<150×10⁹/l，乳酸脱氢酶≥正常上限的1.5倍，血红蛋白≤正常下限，血清肌酐≥正常上限），并将接受每日两次200mg的iptacopan治疗。主要目标是评估在iptacopan治疗26周期间，无需进行血浆置换、输注或抗C5抗体即可实现完全TMA缓解的患者比例。
APPELHUS将确定iptacopan对aHUS患者是否安全有效。
