Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria

Author(s): Régis Peffault de Latour, M.D., Alexander Röth, M.D., Austin G. Kulasekararaj, M.D., Bing Han, M.D., Phillip Scheinberg, M.D., Jaroslaw P. Maciejewski, M.D., Yasutaka Ueda, M.D., Carlos M. de Castro, M.D., Eros Di Bona, M.D., Rong Fu, M.D., Li Zhang, M.D., Morag Griffin, M.B., Ch.B., Saskia M.C. Langemeijer, M.D., Jens Panse, M.D., Hubert Schrezenmeier, M.D., Wilma Barcellini, M.D., Vitor A.Q. Mauad, M.D., Philippe Schafhausen, M.D., Suzanne Tavitian, M.D., Eloise Beggiato, M.D., Lee Ping Chew, M.D., Anna Gaya, M.D., Wei-Han Huang, M.D., Jun Ho Jang, M.D., Toshio Kitawaki, Ph.D., Abdullah Kutlar, M.D., Rosario Notaro, M.D. https://orcid.org/0000-0002-9087-9404, Vinod Pullarkat, M.D., Jörg Schubert, M.D., Louis Terriou, M.D., Michihiro Uchiyama, M.D., Lily Wong Lee Lee, M.D., Eng-Soo Yap, M.D., Flore Sicre de Fontbrune, M.D., Luana Marano, M.D., Ferras Alashkar, M.D., Shreyans Gandhi, M.D., Roochi Trikha, Ph.D., Chen Yang, M.D., Hui Liu, M.D., Richard J. Kelly, Ph.D., Britta Höchsmann, M.D., Cécile Kerloeguen, M.Sc., Partha Banerjee, Ph.D., Rafael Levitch, M.D., Rakesh Kumar, M.Sc., Zhixin Wang, M.Sc., Christine Thorburn, Ph.D., Samopriyo Maitra, Ph.D., Shujie Li, Ph.D., Aurelie Verles, M.Sc., Marion Dahlke, M.D., and Antonio M. Risitano, M.D.
Source: N Engl J Med 2024;390:994-1008
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Rare disease but nice to have an effective oral treatment option for PNH.  Iptacopan, a first-in-class oral factor B inhibitor, has shown to improve Hb by >2g in the vast majority of patients in two studies discussed here


Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients.


In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5–treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion.


In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5–treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5–treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan.


Iptacopan treatment improved hematologic and clinical outcomes in anti-C5–treated patients with persistent anemia — in whom iptacopan showed superiority to anti-C5 therapy — and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.)

Author Affiliations

From the Hematology and Transplant Unit, French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint-Louis Hospital (R.P.L., F.S.F.), and Université de Paris (R.P.L.), Paris, Centre Hospitalier Universitaire (CHU) de Toulouse, Institut Universitaire du Cancer de Toulouse–Oncopole, Toulouse (S.T.), and CHU Lille, Université de Lille, Lille (L.T.) — all in France; the Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University Duisburg–Essen, Essen (A.R., F.A.), the Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, University Hospital RWTH Aachen, and the Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Aachen (J.P.), the University of Ulm, the Institute of Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden–Württemberg–Hessen, and University Hospital Ulm, Ulm (H.S., B. Höchsmann), the Department of Oncology, Hematology, and Bone Marrow Transplantation, Section of Pneumology, University Medical Center Hamburg–Eppendorf, Hamburg (P. Schafhausen), and Elblandklinikum Riesa, Riesa (J.S.) — all in Germany; King’s College Hospital NHS Foundation Trust (A.G.K., S.G., R.T.), the National Institute for Health and Care Research and Wellcome King’s Clinical Research Facility (A.G.K.), King’s College London (A.G.K.), and Novartis Pharmaceuticals (C.T.), London, and St. James’s University Hospital, Leeds (M.G., R.J.K.) — all in the United Kingdom; Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing (B. Han, C.Y.), the Department of Hematology, Tianjin Medical University General Hospital (R.F., H.L.), and the Department of Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (L.Z.), Tianjin, and China Novartis Institutes for BioMedical Research, Shanghai (Z.W., S.L.) — all in China; the Division of Hematology, Hospital A Beneficência Portuguesa, São Paulo (P. Scheinberg), and ABC Medical School, Santo André (V.A.Q.M.) — both in Brazil; the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (J.P.M.); Osaka University Graduate School of Medicine, Suita (Y.U.), Kyoto University Hospital, Kyoto (T.K.), and Japanese Red Cross Society Suwa Hospital, Suwa (M.U.) — all in Japan; Duke University School of Medicine and Duke Cancer Institute, Durham, NC (C.M.C.); Unità Operativa Complessa Oncoematologia, AULSS7 Pedemontana, Bassano del Grappa (E.D.B.), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan (W.B.), Division of Hematology, University of Turin, Città della Salute e della Scienza, Turin (E.B.), Instituto per lo Studio, la Prevenzione e la Rete Oncologica, and Azienda Ospedaliero–Universitaria Careggi, Florence (R.N.), AORN Moscati, Avellino (L.M., A.M.R.), and University of Naples Federico II, Naples (A.M.R.) — all in Italy; Radboud University Medical Center, Nijmegen, the Netherlands (S.M.C.L.); the Hematology Unit, Department of Medicine, Hospital Umum Sarawak, Kuching (L.P.C.), and the Hematology Unit, Queen Elizabeth Hospital, Kota Kinabalu (L.W.L.L.) — both in Malaysia; Hospital Clinic of Barcelona (A.G.) and the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (R.P.L., A.G.K., M.G., W.B., S.T., L.T., F.S.F., L.M., A.M.R.) — both in Barcelona; the Department of Hematology and Oncology and the Department of Clinical Pathology, Hualien Tzu Chi Hospital, the Buddhist Tzu Chi Medical Foundation, and the Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan (W.-H.H.); the Division of Hematology–Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (J.H.J.); Medical College of Georgia, Augusta (A.K.); City of Hope Medical Center, Duarte, CA (V.P.); the Department of Laboratory Medicine, National University Hospital, Singapore (E.-S.Y.); Novartis Pharma (C.K., R.L., M.D.) and Novartis BioMedical Research (A.V.) — both in Basel, Switzerland; and Novartis Healthcare Private, Hyderabad, India (P.B., R.K., S.M.).

Leave a Comment

Your email address will not be published. Required fields are marked *

Related Articles