{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:06:29Z","timestamp":1788404789509,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Novartis Pharma AG"},{"id":[{"id":"https:\/\/ror.org\/01a80cj23","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by complement-mediated hemolytic anemia and thrombosis. The first treatments approved were complement 5 inhibitors (C5is), eculizumab and ravulizumab. Recently approved treatments include pegcetacoplan, iptacopan, danicopan (as an add-on to a C5i), and crovalimab. Methods: A systematic literature review (SLR) was conducted to identify clinical evidence on all available treatments. Outcomes evaluated were hemoglobin and lactate dehydrogenase (LDH) levels, transfusion avoidance, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and safety. Results: In total, 133 records met the inclusion criteria. Of these, 54 records reporting on 11 Phase 3 trials and 2 extension studies are summarized. Eight trials and one extension study evaluated complement inhibitor (CI)-na\u00efve patients, three trials evaluated CI-experienced patients with residual anemia, and one extension study evaluated both groups. In both patient groups, all treatments led to improved outcomes. Conclusions: This SLR is the first to provide an overview of clinical trials assessing the efficacy and safety of all currently approved PNH treatments, which could help inform clinical decisions. Although some head-to-head trials are available, direct comparative evidence remains limited for several comparators, necessitating an indirect treatment comparison (ITC) to assess the efficacy and safety across the treatment landscape.<\/jats:p>","DOI":"10.3390\/jcm15114217","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:36:18Z","timestamp":1780076178000},"page":"4217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy and Safety of Treatments for Paroxysmal Nocturnal Hemoglobinuria: A Systematic Literature Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3532-231X","authenticated-orcid":false,"given":"Shreyans","family":"Gandhi","sequence":"first","affiliation":[{"name":"Department of Haematological Medicine, King\u2019s College Hospital NHS Foundation Trust, London SE5 9RS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isobel","family":"Munro","sequence":"additional","affiliation":[{"name":"Source Health Economics, London WC1V 7AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8323-0734","authenticated-orcid":false,"given":"Victoria","family":"Shodimu","sequence":"additional","affiliation":[{"name":"Source Health Economics, London WC1V 7AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8390-0837","authenticated-orcid":false,"given":"Neil","family":"Webb","sequence":"additional","affiliation":[{"name":"Source Health Economics, London WC1V 7AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2505-1405","authenticated-orcid":false,"given":"Katharina","family":"Pannagl","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals UK Ltd., London W12 7FQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5203-9797","authenticated-orcid":false,"given":"Anggie","family":"Wiyani","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals UK Ltd., London W12 7FQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8612-7680","authenticated-orcid":false,"given":"Maria-Magdalena","family":"Balp","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, 4056 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/0092-8674(93)90250-T","article-title":"Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria","volume":"73","author":"Takeda","year":"1993","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.7680492","article-title":"The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis","volume":"259","author":"Miyata","year":"1993","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1056\/NEJM199401273300404","article-title":"Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria","volume":"330","author":"Miyata","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1182\/blood-2014-02-522128","article-title":"Paroxysmal nocturnal hemoglobinuria","volume":"124","author":"Brodsky","year":"2014","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"214","DOI":"10.3346\/jkms.2016.31.2.214","article-title":"Predictive Factors of Mortality in Population of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Results from a Korean PNH Registry","volume":"31","author":"Jang","year":"2016","journal-title":"J. Korean Med. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e23008","DOI":"10.1002\/jcla.23008","article-title":"Analysis of clinical characteristics of 92 patients with paroxysmal nocturnal hemoglobinuria: A single institution experience in China","volume":"34","author":"Fu","year":"2020","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0140-6736(95)12360-1","article-title":"Paroxysmal nocturnal haemoglobinuria: Long-term follow-up and prognostic factors","volume":"348","author":"Socie","year":"1996","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.3389\/fimmu.2019.01157","article-title":"Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper from the SAAWP of the EBMT","volume":"10","author":"Risitano","year":"2019","journal-title":"Front Immunol."},{"key":"ref_10","unstructured":"Food and Drug Administration (FDA) (2023, April 24). Soliris (Eculizumab) Package Insert, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/125166s434lbl.pdf."},{"key":"ref_11","unstructured":"European Medicines Agency (EMA) (2023, September 18). Eculizumab (Soliris) Summary of Product Characteristics. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/soliris-epar-product-information_en.pdf."},{"key":"ref_12","unstructured":"Food and Drug Administration (FDA) (2023, April 24). Ultomiris (Ravulizumab) Package Insert, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/761108s020lbl.pdf."},{"key":"ref_13","unstructured":"European Medicines Agency (EMA) (2023, September 18). Ravulizumab (Ultomiris) Assesment Report (EPAR). Available online: https:\/\/www.ema.europa.eu\/en\/documents\/assessment-report\/ultomiris-epar-public-assessment-report_en.pdf."},{"key":"ref_14","unstructured":"Food and Drug Administration (FDA) (2023, April 24). Empaveli (Pegcetacoplan) Package Insert, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/215014s000lbl.pdf."},{"key":"ref_15","unstructured":"European Medicines Agency (EMA) (2023, September 18). Pegcetacoplan (ASPAVELI) Summary of Product Characteristics. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/aspaveli-epar-product-information_en.pdf."},{"key":"ref_16","unstructured":"Food and Drug Administration (FDA) (2025, September 18). Fabhalta (Iptacopan) Package Insert, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/218276s001lbl.pdf."},{"key":"ref_17","unstructured":"European Medicines Agency (EMA) (2024, March 08). Iptacopan (Fabhalta) Overview. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/fabhalta."},{"key":"ref_18","unstructured":"Food and Drug Administration (FDA) (2025, September 18). Voydeya (Danicopan) Package Insert, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/218037s000lbl.pdf."},{"key":"ref_19","unstructured":"European Medicines Agency (EMA) (2025, September 18). Danicopan (Voydeya) Overview. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/voydeya."},{"key":"ref_20","unstructured":"Food and Drug Administration (FDA) (2025, September 18). Piasky (crovalimab) Package Insert, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/761388s000lbl.pdf."},{"key":"ref_21","unstructured":"European Medicines Agency (EMA) (2025, September 18). Crovalimab (Piasky) Overview. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/piasky#overview."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"613","DOI":"10.2147\/JBM.S431493","article-title":"Paroxysmal Nocturnal Hemoglobinuria: Current Management, Unmet Needs, and Recommendations","volume":"14","author":"Oliver","year":"2023","journal-title":"J. Blood Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00277-021-04715-5","article-title":"The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: Results from a US patient survey","volume":"101","author":"Dingli","year":"2022","journal-title":"Ann. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"266","DOI":"10.3390\/hematolrep15020027","article-title":"Changes in Hematologic Lab Measures Observed in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with C5 Inhibitors, Ravulizumab and Eculizumab: Real-World Evidence from a US Based EMR Network","volume":"15","author":"Fishman","year":"2023","journal-title":"Hematol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6786","DOI":"10.1182\/blood-2011-02-333997","article-title":"Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: Sustained efficacy and improved survival","volume":"117","author":"Kelly","year":"2011","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/ajh.24278","article-title":"Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: A treatment versus no-treatment study","volume":"91","author":"Loschi","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"20406207231216080","DOI":"10.1177\/20406207231216080","article-title":"Efficacy of complement inhibitors for patients with paroxysmal nocturnal hemoglobinuria: A systematic review and meta-analysis","volume":"14","author":"Lee","year":"2023","journal-title":"Ther. Adv. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.clicom.2022.11.002","article-title":"Efficacy and safety of current treatments for paroxysmal nocturnal hemoglobinuria: A systematic review","volume":"3","author":"Ciecilinsky","year":"2023","journal-title":"Clin. Immunol. Commun."},{"key":"ref_29","unstructured":"Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V. (2024). Cochrane Handbook for Systematic Reviews of Interventions Version 6.5 (Updated August 2024), Cochrane. Available online: https:\/\/onlinelibrary.wiley.com\/doi\/book\/10.1002\/9781119536604?msockid=3e011267770662d30c07054776e2636c."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_32","unstructured":"(2023, December 07). Critical Appraisal Skills Programme. CASP (Cohort Study) Checklist. Available online: https:\/\/casp-uk.net\/casp-tools-checklists\/cohort-study-checklist\/."},{"key":"ref_33","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_34","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_35","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_36","doi-asserted-by":"crossref","first-page":"4123","DOI":"10.1182\/blood-2007-06-095646","article-title":"Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria","volume":"110","author":"Hillmen","year":"2007","journal-title":"Blood"},{"key":"ref_37","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_38","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_39","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1007\/s12325-024-02827-8","article-title":"Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48 Weeks: 307 Open-Label Extension Study","volume":"41","author":"Patriquin","year":"2024","journal-title":"Adv. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1056\/NEJMoa2308695","article-title":"Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria","volume":"390","author":"Roth","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_41","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":"Roth","year":"2024","journal-title":"Am. J. Hematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1002\/ajh.26998","article-title":"Efficacy and safety of the C5 inhibitor crovalimab in complement inhibitor-naive patients with PNH (COMMODORE 3): A multicenter, phase 3, single-arm study","volume":"98","author":"Liu","year":"2023","journal-title":"Am. J. Hematol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/jha2.632","article-title":"A phase III, randomised, double-blind, multi-national clinical trial comparing SB12 (proposed eculizumab biosimilar) and reference eculizumab in patients with paroxysmal nocturnal haemoglobinuria","volume":"4","author":"Jang","year":"2023","journal-title":"eJHaem"},{"key":"ref_44","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_45","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."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s41687-023-00609-4","article-title":"Clinically important change for the FACIT-Fatigue scale in paroxysmal nocturnal hemoglobinuria: A derivation from international PNH registry patient data","volume":"7","author":"Cella","year":"2023","journal-title":"J. Patient-Rep. Outcomes"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1038\/s41409-021-01372-0","article-title":"Categorizing hematological response to eculizumab in paroxysmal nocturnal hemoglobinuria: A multicenter real-life study","volume":"56","author":"Debureaux","year":"2021","journal-title":"Bone Marrow Transplant."},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"2329030","DOI":"10.1080\/16078454.2024.2329030","article-title":"Expert consensus on the management of pharmacodynamic breakthrough-hemolysis in treated paroxysmal nocturnal hemoglobinuria","volume":"29","author":"Dingli","year":"2024","journal-title":"Hematology"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/11\/4217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:55:47Z","timestamp":1780077347000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/11\/4217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["jcm15114217"],"URL":"https:\/\/doi.org\/10.3390\/jcm15114217","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]}}}