Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria
Authors: Régis Peffault de Latour, Alexander Röth, Austin G Kulasekararaj, Bing Han, Phillip Scheinberg, Jaroslaw P Maciejewski, Yasutaka Ueda, Carlos M de Castro, Eros Di Bona, Rong Fu, Li Zhang, Morag Griffin, Saskia M C Langemeijer, Jens Panse, Hubert Schrezenmeier, Wilma Barcellini, Vitor A Q Mauad, Philippe Schafhausen, Suzanne Tavitian, Eloise Beggiato, Lee Ping Chew, Anna Gaya, Wei-Han Huang, Jun Ho Jang, Toshio Kitawaki, Abdullah Kutlar, Rosario Notaro, Vinod Pullarkat, Jörg Schubert, Louis Terriou, Michihiro Uchiyama, Lily Wong Lee Lee, Eng-Soo Yap, Flore Sicre de Fontbrune, Luana Marano, Ferras Alashkar, Shreyans Gandhi, Roochi Trikha, Chen Yang, Hui Liu, Richard J Kelly, Britta Höchsmann, Cécile Kerloeguen, Partha Banerjee, Rafael Levitch, Rakesh Kumar, Zhixin Wang, Christine Thorburn, Samopriyo Maitra, Shujie Li, Aurelie Verles, Marion Dahlke, Antonio M Risitano
Journal: New England Journal of Medicine (2024)

BackgroundPersistent 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.MethodsIn 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.Download a PDF of the Research Summary.ResultsIn 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.ConclusionsIptacopan 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.) Quick Take Iptacopan for Paroxysmal Nocturnal Hemoglobinuria 2m 48s