3月 07, 2023

今日,诺华在阵发性睡眠性血红蛋白尿症(PNH)适应症临床研发阶段的创新药物Iptacopan(LNP023)胶囊,获得国家药品监督管理局药品审评中心(CDE)“突破性治疗药物”认定。

阵发性睡眠性血红蛋白尿症(PNH)是一种补体介导的慢性罕见血液疾病1-4。PNH患者的造血干细胞PIG-A基因发生突变,导致其产生易于被补体系统过早破坏的红细胞1-4,5-8。从而引发血管内溶血(红细胞在血管内被破坏)和血管外溶血(红细胞在脾脏和肝脏中被破坏),临床主要表现为贫血、阵发性血红蛋白尿、骨髓造血功能衰竭和血栓形成等5-9。PNH是一种严重影响患者生活质量的罕见病。据统计,发病率约百万分之一到二,亚洲人群发病率高于欧美5,10。PNH可在任何年龄发生,常见于30-40岁人群11

抗补体C5疗法(依库珠单抗或Ravulizumab)是既往国际公认的PNH标准治疗,但在抗C5治疗后,仍有大部分患者有残留贫血、疲乏和输血依赖,严重影响生活质量1,5-9,12,13

Iptacopan作为特异性补体B因子抑制剂,作用于补体系统C5末端通路的上游,同时控制血管内溶血和血管外溶血,弥补了抗C5抗体的不足,同时为患者提供了口服单药的治疗选择1,2,14。APPLY-PNH III期研究达到了两个主要终点,证明Iptacopan治疗经抗C5治疗后仍有残存贫血的PNH成人患者,显著优于继续使用抗C5疗法。APPOINT-PNH III期研究也进一步证实了在未接受过补体抑制剂治疗的PNH患者中使用Iptacopan的疗效和安全性。

除PNH之外,Iptacopan目前也处于其他许多补体介导疾病(CMD)的关键研究阶段,包括C3肾小球病(C3G)、IgA肾病(IgAN)、非典型溶血性尿毒症综合征(aHUS)、狼疮性肾炎(LN)和冷凝集素病(CAD)等17-19

声明
1.  Iptacopan目前尚未在全球获批。
2.  本资料目的在于提供疾病领域的相关知识、提高疾病认知的水平、非广告用途。
3.  本资料中涉及的信息仅供参考,请遵从医生或其他医疗卫生专业人士的意见或指导。

参考资料

[1] Jang JH, et al. Iptacopan Effectively Controls Intra- And Extravascular Hemolysis And Leads To Durable Hemoglobin Increase In Patients With Treatment-Naïve PNH. Abstract presented at the 26th Annual Congress of the European Hematology Association (EHA) 2021. 

[2] Schubart A, Anderson K, Mainolfi N, et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci USA. 2019;116(16):7926-7931. doi:10.1073/pnas.1820892116.

[3] Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement System Part II: Role in Immunity. Front Immunol. 2015;6:257. Published 2015 May 26. doi:10.3389/fimmu.2015.00257.

[4] Risitano AM, et al. Addition of Iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021;8(5):e344-e354. doi: 10.1016/S2352-3026(21)00028-4.

[5] Hill A, et al. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 2017;3:17028.

[6] Risitano AM. Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies. Adv Exp Med Biol. 2013;735:155–72.

[7] Risitano AM and Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents. Biologics 2008;2(2):205–222.

[8] Hill A, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 2010;95(4):567–573.

[9] Schrezenmeier H, et al. Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica 2014;99(5):922–929.

[10] Cançado RD, Araújo A da S, Sandes AF, et al. Consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria. Hematol Transfus Cell Ther. 2021;43(3):341-348. doi:10.1016/j.htct.2020.06.006.

[11] Shah N, Bhatt H. Paroxysmal Nocturnal Hemoglobinuria. [Updated 2021 Aug 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK562292/.

[12] Risitano AM. Anti-Complement Treatment in Paroxysmal Nocturnal Hemoglobinuria: Where we Stand and Where we are Going. Transl Med UniSa. 2014;8:43–52.

[13]  Debureaux P, et al. Hematological Response to Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify Unmet Clinical Needs and Future Clinical Goals. Blood. 2019;134(Suppl 1):3517.

[14] Novartis. Data on file.

[15] Regis Peffault De Latour, et al. Oral Monotherapy with Iptacopan, a Proximal Complement Inhibitor of Factor B, Has Superior Efficacy to Intravenous Terminal Complement Inhibition with Standard of Care Eculizumab or Ravulizumab and Favorable Safety in Patients with Paroxysmal Nocturnal Hemoglobinuria and Residual Anemia: Results from the Randomized, Active-Comparator-Controlled, Open-Label, Multicenter, Phase III Apply-PNH Study. Abstract presented at the 26th Annual Congress of the American Society of Hematology(ASH) 2022.

[16] Clinicaltrials.gov. Study of Efficacy and Safety of Twice Daily Oral Iptacopan (LNP023) in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy (APPOINT-PNH). Available at https://clinicaltrials.gov/ct2/show/NCT04820530. Accessed September 2022.

[17] Clinicaltrials.gov. Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy. (APPEAR-C3G). Available at https://clinicaltrials.gov/ct2/show/NCT04817618. Accessed September 2022.

[18] Clinicaltrials.gov. Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN). Available at https://clinicaltrials.gov/ct2/show/NCT04578834. Accessed September 2022.

[19]  Clinicaltrials.gov. Efficacy and Safety of Iptacopan (LNP023) in Adult Patients With Atypical Hemolytic Uremic Syndrome Naive to Complement Inhibitor Therapy (APPELHUS). Available at https://clinicaltrials.gov/ct2/show/NCT04889430. Accessed September 2022.