{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T14:59:13Z","timestamp":1788274753248,"version":"build-2803163510"},"reference-count":92,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,31]],"date-time":"2024-08-31T00:00:00Z","timestamp":1725062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Apellis Pharmaceuticals, Inc."},{"name":"Swedish Orphan Biovitrum AB"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, including the complement regulatory proteins CD55 and CD59. With decreased or a lack of CD55 and CD59 expression on their membranes, PNH red blood cells become susceptible to complement-mediated hemolysis (symptoms of which include anemia, dysphagia, abdominal pain, and fatigue), leading to thrombosis. State-of-the-art PNH treatments act by inhibiting the dysregulated complement at distinct points in the activation pathway: late at the C5 level (C5 inhibitors, eculizumab, ravulizumab, and crovalimab), centrally at the C3 level (C3\/C3b inhibitors and pegcetacoplan), and early at the initiation and amplification of the alternative pathway (factor B inhibitor, iptacopan; factor D inhibitor, danicopan). Through their differing mechanisms of action, these treatments elicit varying profiles of disease control and offer valuable insights into the molecular underpinnings of PNH. This narrative review provides an overview of the mechanisms of action of the six complement inhibitors currently approved for PNH, with a focus on the C3\/C3b-targeted therapy, pegcetacoplan.<\/jats:p>","DOI":"10.3390\/ijms25179477","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T09:56:42Z","timestamp":1725357402000},"page":"9477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors"],"prefix":"10.3390","volume":"25","author":[{"given":"Peter","family":"Hillmen","sequence":"first","affiliation":[{"name":"Apellis Pharmaceuticals, Inc., Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Horneff","sequence":"additional","affiliation":[{"name":"Swedish Orphan Biovitrum AB, 171 65 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Yeh","sequence":"additional","affiliation":[{"name":"Apellis Pharmaceuticals, Inc., Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7208-3875","authenticated-orcid":false,"given":"Martin","family":"Kolev","sequence":"additional","affiliation":[{"name":"Apellis Pharmaceuticals, Inc., Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Deschatelets","sequence":"additional","affiliation":[{"name":"Apellis Pharmaceuticals, Inc., Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17028","DOI":"10.1038\/nrdp.2017.28","article-title":"Paroxysmal nocturnal haemoglobinuria","volume":"3","author":"Hill","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1182\/blood-2019-125867","article-title":"Epidemiology of PNH and real-world treatment patterns following an incident PNH diagnosis in the US","volume":"134","author":"Jalbert","year":"2019","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1182\/blood.2019003812","article-title":"How I treat paroxysmal nocturnal hemoglobinuria","volume":"137","author":"Brodsky","year":"2021","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/ejh.13640","article-title":"The incidence and prevalence of patients with paroxysmal nocturnal haemoglobinuria and aplastic anaemia PNH syndrome: A retrospective analysis of the UK\u2019s population-based haematological malignancy research network 2004\u20132018","volume":"107","author":"Richards","year":"2021","journal-title":"Eur. J. Haematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/ijlh.14281","article-title":"Complement inhibition in paroxysmal nocturnal hemoglobinuria: From biology to therapy","volume":"46","author":"Versino","year":"2024","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1182\/blood.V79.6.1400.1400","article-title":"Defective glycosylphosphatidylinositol anchor synthesis in paroxysmal nocturnal hemoglobinuria granulocytes","volume":"79","author":"Mahoney","year":"1992","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3699","DOI":"10.1182\/blood-2005-04-1717","article-title":"Diagnosis and management of paroxysmal nocturnal hemoglobinuria","volume":"106","author":"Parker","year":"2005","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1056\/NEJM199511093331904","article-title":"Natural history of paroxysmal nocturnal hemoglobinuria","volume":"333","author":"Hillmen","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1007\/s00277-020-04052-z","article-title":"Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): Updated analysis from the International PNH Registry","volume":"99","author":"Schrezenmeier","year":"2020","journal-title":"Ann. Hematol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1182\/asheducation-2016.1.208","article-title":"Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria","volume":"2016","author":"Parker","year":"2016","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1182\/hematology.2021000245","article-title":"When does a PNH clone have clinical significance?","volume":"2021","author":"Babushok","year":"2021","journal-title":"Hematology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/j.1460-2075.1994.tb06240.x","article-title":"Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene","volume":"13","author":"Bessler","year":"1994","journal-title":"EMBO J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1111\/bjh.14862","article-title":"The evolution of paroxysmal nocturnal haemoglobinuria depends on intensity of immunosuppressive therapy","volume":"182","author":"Bat","year":"2018","journal-title":"Br. J. Haematol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Risitano, A.M., Marotta, S., Ricci, P., Marano, L., Frieri, C., Cacace, F., Sica, M., Kulasekararaj, A., Calado, R.T., and Scheinberg, P. (2019). Anti-complement treatment for paroxysmal nocturnal hemoglobinuria: Time for proximal complement inhibition? A position paper from the SAAWP of the EBMT. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01157"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e628","DOI":"10.1097\/HS9.0000000000000628","article-title":"High prevalence of PNH-phenotype cells in patients who received CD19-targeted CAR T-cell therapy","volume":"5","author":"Yoshihara","year":"2021","journal-title":"Hemasphere"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1056\/NEJM200104053441406","article-title":"Complement. First of two parts","volume":"344","author":"Walport","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1146\/annurev-immunol-032713-120154","article-title":"Complement and its receptors: New insights into human disease","volume":"32","author":"Holers","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/imr.13138","article-title":"With complements: C3 inhibition in the clinic","volume":"313","author":"Kolev","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0140-6736(23)01524-6","article-title":"Complement in human disease: Approved and up-and-coming therapeutics","volume":"403","author":"West","year":"2024","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.molimm.2017.05.012","article-title":"Intracellular complement\u2014The complosome\u2014In immune cell regulation","volume":"89","author":"Arbore","year":"2017","journal-title":"Mol. Immunol."},{"key":"ref_21","unstructured":"Goldberg, R.A., Kitchens, J.W., Lad, E., and Zarbin, M.A. (2024, August 28). The evolving treatment paradigm in geographic atrophy. A panel of experts translates clinical trial data to real-world practice. Retin. Today, Available online: https:\/\/retinatoday.com\/articles\/2024-may-june-supplement2\/the-evolving-treatment-paradigm-in-geographic-atrophy."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s00281-021-00892-7","article-title":"Tipping the balance: Intricate roles of the complement system in disease and therapy","volume":"43","author":"Pouw","year":"2021","journal-title":"Semin. Immunopathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1182\/blood.2023021762","article-title":"Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria","volume":"143","author":"Kelly","year":"2024","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1056\/NEJMoa1502950","article-title":"Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria","volume":"373","author":"Kelly","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102435","DOI":"10.1016\/j.rpth.2024.102435","article-title":"A case report of pegcetacoplan use for a pregnant woman with paroxysmal nocturnal hemoglobinuria","volume":"8","author":"Du","year":"2024","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/ejh.13176","article-title":"How we treat paroxysmal nocturnal hemoglobinuria: A consensus statement of the Canadian PNH Network and review of the national registry","volume":"102","author":"Patriquin","year":"2019","journal-title":"Eur. J. Haematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1111\/ejh.14080","article-title":"Long-term effectiveness of eculizumab: Data from the International PNH Registry","volume":"111","author":"Terriou","year":"2023","journal-title":"Eur. J. Haematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101041","DOI":"10.1016\/j.blre.2023.101041","article-title":"Biomarkers and laboratory assessments for monitoring the treatment of patients with paroxysmal nocturnal hemoglobinuria: Differences between terminal and proximal complement inhibition","volume":"59","author":"Kulasekararaj","year":"2023","journal-title":"Blood Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"922","DOI":"10.3324\/haematol.2013.093161","article-title":"Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry","volume":"99","author":"Schrezenmeier","year":"2014","journal-title":"Haematologica"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"567","DOI":"10.3324\/haematol.2009.007229","article-title":"Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization","volume":"95","author":"Hill","year":"2010","journal-title":"Haematologica"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/S0140-6736(23)01520-9","article-title":"Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): Two multicentre, randomised, double-masked, sham-controlled, phase 3 trials","volume":"402","author":"Heier","year":"2023","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1016\/j.ekir.2023.08.033","article-title":"Clinical safety and efficacy of pegcetacoplan in a phase 2 study of patients with C3 glomerulopathy and other complement-mediated glomerular diseases","volume":"8","author":"Dixon","year":"2023","journal-title":"Kidney Int. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1093\/ndt\/gfab281","article-title":"Membranoproliferative glomerulonephritis: No longer the same disease and may need very different treatment","volume":"38","author":"Noris","year":"2023","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_34","unstructured":"Soliris (Eculizumab) US Prescribing Information (2024, August 26). Available online: https:\/\/alexion.com\/Documents\/Soliris_USPI.pdf."},{"key":"ref_35","unstructured":"European Medicines Agency (2024, August 26). Soliris (Eculizumab). Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/soliris#authorisation-details."},{"key":"ref_36","unstructured":"Ultomiris (Ravulizumab) (2024, August 26). US Prescribing Information. Available online: https:\/\/alexion.com\/Documents\/ultomiris_uspi."},{"key":"ref_37","unstructured":"European Medicines Agency (2024, August 26). Ultomiris (Ravulizumab). Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/ultomiris#product-details."},{"key":"ref_38","unstructured":"Piasky (Crovalimab-Akkz) (2024, August 26). US Prescribing Information. Available online: https:\/\/www.gene.com\/download\/pdf\/piasky_prescribing.pdf."},{"key":"ref_39","unstructured":"Empaveli (Pegcetacoplan) US Prescribing Information (2024, August 26). Available online: https:\/\/pi.apellis.com\/files\/PI_Empaveli.pdf."},{"key":"ref_40","unstructured":"European Medicines Agency (2024, August 26). Aspaveli (Pegcetacoplan). Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/aspaveli#authorisation-details."},{"key":"ref_41","unstructured":"Fabhalta (Iptacopan) (2024, August 26). US Prescribing Information. Available online: https:\/\/www.novartis.com\/us-en\/sites\/novartis_us\/files\/fabhalta.pdf."},{"key":"ref_42","unstructured":"European Medicines Agency (2024, August 26). Fabhalta (Iptacopan). Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/fabhalta#product-details."},{"key":"ref_43","unstructured":"Voydeya (Danicopan) (2024, August 26). US Prescribing Information. Available online: https:\/\/alexion.com\/Documents\/voydeya_uspi."},{"key":"ref_44","unstructured":"European Medicines Agency (2024, August 26). Voydeya (Danicopan). Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/voydeya#product-details."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1056\/NEJMoa061648","article-title":"The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria","volume":"355","author":"Hillmen","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1111\/bjh.17753","article-title":"How we(\u2018ll) treat paroxysmal nocturnal haemoglobinuria: Diving into the future","volume":"196","author":"Risitano","year":"2022","journal-title":"Br. J. Haematol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1056\/NEJMoa031688","article-title":"Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria","volume":"350","author":"Hillmen","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1182\/blood-2018-09-876805","article-title":"Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: The 302 study","volume":"133","author":"Kulasekararaj","year":"2019","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1182\/blood-2018-09-876136","article-title":"Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: The 301 study","volume":"133","author":"Lee","year":"2019","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1002\/ajh.27412","article-title":"Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition","volume":"99","author":"He","year":"2024","journal-title":"Am. J. Hematol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1002\/ajh.27413","article-title":"Phase 3 randomized COMMODORE 1 trial: Crovalimab versus eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria","volume":"99","author":"Scheinberg","year":"2024","journal-title":"Am. J. Hematol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1182\/blood-2007-06-094136","article-title":"Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria","volume":"111","author":"Brodsky","year":"2008","journal-title":"Blood"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/bjh.12347","article-title":"Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria","volume":"162","author":"Hillmen","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1182\/blood-2008-11-189944","article-title":"Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab","volume":"113","author":"Risitano","year":"2009","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1182\/blood-2015-02-625871","article-title":"Complement C3dg-mediated erythrophagocytosis: Implications for paroxysmal nocturnal hemoglobinuria","volume":"126","author":"Lin","year":"2015","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1182\/blood-2016-08-732800","article-title":"Incomplete inhibition by eculizumab: Mechanistic evidence for residual C5 activity during strong complement activation","volume":"129","author":"Harder","year":"2017","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1182\/blood.2021014868","article-title":"Pegcetacoplan for paroxysmal nocturnal hemoglobinuria","volume":"139","author":"Gerber","year":"2022","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1248\/bpb.b15-00703","article-title":"Eculizumab dosing intervals longer than 17 days may be associated with greater risk of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria","volume":"39","author":"Nakayama","year":"2016","journal-title":"Biol. Pharm. Bull."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1056\/NEJMra2201664","article-title":"Breakthrough hemolysis in PNH with proximal or terminal complement inhibition","volume":"387","author":"Notaro","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3324\/haematol.2019.236877","article-title":"Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria","volume":"106","author":"Brodsky","year":"2021","journal-title":"Haematologica"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1182\/blood-2014-03-560540","article-title":"Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab","volume":"125","author":"Porcher","year":"2015","journal-title":"Blood"},{"key":"ref_62","first-page":"1445","article-title":"Breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria treated with complement inhibitors: A multicenter international study","volume":"8","author":"Fattizzo","year":"2024","journal-title":"HemaSphere"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1182\/blood-2013-11-536573","article-title":"Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria","volume":"123","author":"Risitano","year":"2014","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"884","DOI":"10.4049\/jimmunol.157.2.884","article-title":"Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library","volume":"157","author":"Sahu","year":"1996","journal-title":"J. Immunol."},{"key":"ref_65","first-page":"273","article-title":"Compstatin: A complement inhibitor on its way to clinical application","volume":"632","author":"Ricklin","year":"2008","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1002\/ajh.25960","article-title":"C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab","volume":"95","author":"Grossi","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5519","DOI":"10.1038\/s41467-022-33003-7","article-title":"Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors","volume":"13","author":"Lamers","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/eci.12419","article-title":"Compstatin: A C3-targeted complement inhibitor reaching its prime for bedside intervention","volume":"45","author":"Mastellos","year":"2015","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_69","first-page":"42","article-title":"Forty-eight week efficacy and safety of pegcetacoplan in adult patients with paroxysmal nocturnal hemoglobinuria and suboptimal response to prior eculizumab treatment","volume":"5","author":"Szer","year":"2021","journal-title":"HemaSphere"},{"key":"ref_70","first-page":"i727","article-title":"Pegcetacoplan maintains early improvements seen in post-transplant recurrent C3G and IC-MPGN: 1-year results from the phase II NOBLE trial","volume":"39","author":"Fakhouri","year":"2024","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1007\/s00277-022-04903-x","article-title":"Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria","volume":"101","author":"Wong","year":"2022","journal-title":"Ann. Hematol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1056\/NEJMoa2029073","article-title":"Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria","volume":"384","author":"Hillmen","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e648","DOI":"10.1016\/S2352-3026(22)00210-1","article-title":"Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial","volume":"9","author":"Szer","year":"2022","journal-title":"Lancet Haematol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1182\/bloodadvances.2022009129","article-title":"Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria","volume":"7","author":"Wong","year":"2023","journal-title":"Blood Adv."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/BF02918259","article-title":"Complement deficiency states and meningococcal disease","volume":"12","author":"Figueroa","year":"1993","journal-title":"Immunol. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/bjh.15790","article-title":"Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis","volume":"185","author":"Marantz","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.4049\/jimmunol.160.6.2619","article-title":"Local synthesis of C3 within the splenic lymphoid compartment can reconstitute the impaired immune response in C3-deficient mice","volume":"160","author":"Fischer","year":"1998","journal-title":"J. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5363","DOI":"10.4049\/jimmunol.171.10.5363","article-title":"Myeloid C3 determines induction of humoral responses to peripheral herpes simplex virus infection","volume":"171","author":"Verschoor","year":"2003","journal-title":"J. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.it.2012.06.001","article-title":"The complotype: Dictating risk for inflammation and infection","volume":"33","author":"Harris","year":"2012","journal-title":"Trends Immunol."},{"key":"ref_80","first-page":"1471","article-title":"Thrombosis and meningococcal infection rates in pegcetacoplan patients with paroxysmal nocturnal hemoglobinuria in the post-marketing setting","volume":"8","author":"Panse","year":"2024","journal-title":"HemaSphere"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1182\/bloodadvances.2023011691","article-title":"Management of acute breakthrough hemolysis with intensive pegcetacoplan dosing in patients with PNH","volume":"8","author":"Griffin","year":"2024","journal-title":"Blood Adv."},{"key":"ref_82","first-page":"1433","article-title":"Characterization of clinically significant breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria treated with pegcetacoplan","volume":"8","author":"Mulherin","year":"2024","journal-title":"HemaSphere"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1182\/blood-2012-09-311381","article-title":"Thrombosis in paroxysmal nocturnal hemoglobinuria","volume":"121","author":"Hill","year":"2013","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"102416","DOI":"10.1016\/j.rpth.2024.102416","article-title":"Thrombosis and meningococcal infection rates in pegcetacoplan-treated patients with paroxysmal nocturnal hemoglobinuria in the clinical trial and postmarketing settings","volume":"8","author":"Kelly","year":"2024","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1159\/000507254","article-title":"Update on C3 glomerulopathy: A complement-mediated disease","volume":"144","author":"Lucientes","year":"2020","journal-title":"Nephron"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7926","DOI":"10.1073\/pnas.1820892116","article-title":"Small-molecule factor B inhibitor for the treatment of complement-mediated diseases","volume":"116","author":"Schubart","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1056\/NEJMoa2308695","article-title":"Oral iptacopan monotherapy in paroxysmal nocturnal hemoglobinuria","volume":"390","author":"Kulasekararaj","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1365-2249.2004.02627.x","article-title":"The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation","volume":"138","author":"Harboe","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.molimm.2009.09.005","article-title":"The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification","volume":"47","author":"Harboe","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_90","first-page":"S268","article-title":"Alternative complement pathway pharmacodynamics of iptacopan","volume":"8","author":"Schmouder","year":"2023","journal-title":"Kidney Int. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.3324\/haematol.2020.261826","article-title":"Danicopan: An oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria","volume":"106","author":"Risitano","year":"2021","journal-title":"Haematologica"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e955","DOI":"10.1016\/S2352-3026(23)00315-0","article-title":"Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): A double-blind, randomised, phase 3 trial","volume":"10","author":"Lee","year":"2023","journal-title":"Lancet Haematol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9477\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:46:11Z","timestamp":1760111171000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9477"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,31]]},"references-count":92,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25179477"],"URL":"https:\/\/doi.org\/10.3390\/ijms25179477","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,31]]}}}