Oral iptacopan monotherapy demonstrates clinically meaningful hemoglobin increases in patients with paroxysmal nocturnal hemoglobinuria with baseline hemoglobin levels 10 to <12 g/dl on anti-C5 therapy: Subgroup analysis of the appulse-pnh Phase 3b trial
Year: 2025
Type: conference-abstract
Abstract: Introduction: Despite achieving a ‘good response’ with anti-C5 therapy (defined as hemoglobin [Hb] levels 10 to <12 g/dL), some patients with paroxysmal nocturnal hemoglobinuria (PNH) remain anemic and continue to experience symptoms due to extravascular hemolysis. Iptacopan, the first oral selective factor B inhibitor, demonstrated superior efficacy vs anti-C5 therapy (eculizumab/ravulizumab) in patients with PNH and Hb <10 g/dL on anti-C5 in APPLY-PNH (NCT04558918). APPULSE-PNH (NCT05630001) was a Phase 3b trial evaluating iptacopan in patients with Hb ≥10 g/dL who had received anti-C5 therapy. The study met its primary and key secondary objectives: noninferiority and superiority in Hb change from baseline (BL) after switching to iptacopan. Here, we present subgroup analyses in patients with BL Hb 10 to <12 g/dL. Methods: In APPULSE-PNH,adult patients with PNH and mean Hb ≥10 g/dL on stable anti-C5 therapy for ≥6 months, who had not received red blood cell (RBC) transfusions for 6 months, were switched to oral iptacopan monotherapy 200 mg twice daily for 24 weeks. The primary endpoint was change from BL in Hb, tested hierarchically for noninferiority (primary objective) and superiority (key secondary objective) compared with anti-C5 therapy using predefined thresholds (lower bound of 95% confidence interval [CI] greater than –1 and 0 g/dL, respectively). All endpoints reported as adjusted mean change from BL, or ratio vs BL, used the mean of four visits between Days 126 and 168, except Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) and Treatment Satisfaction Questionnaire for Medication – 9 items (TSQM-9), which used Day 168 only. Exploratory subgroup analyses of BL Hb levels 10 to <12 g/dL were performed for the primary and key secondary endpoints. Results: Of the52 patients enrolled in APPULSE-PNH, 32 (61.5%) had BL Hb 10 to <12 g/dL. In this subgroup of patients, mean age was 47.0 years; 43.8% were female and mean (standard deviation [SD]) time since diagnosis was 9.4 (6.8) years; 93.8% switched from ravulizumab and 6.3% from eculizumab. The mean (SD) duration of anti-C5 treatment was 3.0 (2.2) years. Mean (SD) BL Hb and lactate dehydrogenase (LDH) were 11.1 (0.5) g/dL and 236.6 (75.5) U/L, respectively. Overall adjusted mean (95% CI) change from BL in Hb was +2.0 g/dL (1.7, 2.3; P<0.0001 for both noninferiority and superiority). In patients with BL Hb 10 to <12 g/dL, adjusted mean (95% CI) change from BL in Hb was +2.4 (2.0, 2.7) g/dL. The lower bound of the 95% CI exceeded thresholds for noninferiority and superiority. No patients required RBC transfusions between Days 1 and 168. Adjusted mean (95% CI) change from BL in absolute reticulocyte count (ARC) was −101.9 109/L (−107.9, −95.9) in these patients. Geometric adjusted mean ratio (95% CI) of LDH vs BL was 1.0 (0.9, 1.1) in patients with Hb 10 to <12 g/dL. FACIT-Fatigue improved by +6.4 (95% CI: 3.2, 9.5). TSQM-9 scores for effectiveness, convenience, and global satisfaction improved by +11.1 (95% CI: 0.7, 21.6), +25.1 (16.4, 33.9), and +20.6 (12.3, 28.8) in patients with 10 to <12 g/dL, respectively. In the overall population of APPULSE-PNH (N=52), the most frequently occurring treatment-emergent adverse events were headache (17.3% of patients), diarrhea, nausea, and nasopharyngitis (11.5% each). No patients experienced clinical breakthrough hemolysis, major adverse vascular events, treatment-related serious adverse events, or died.Conclusions: In APPULSE-PNH, switching from anti-C5 to oral iptacopan monotherapy led to clinically meaningful increases in Hb in patients with PNH and Hb ≥10 g/dL. Results in patients with BL Hb 10 to <12 g/dL were consistent with the overall study findings. Iptacopan was well tolerated. These results support iptacopan as a potentially practice-changing, outpatient treatment option for patients with PNH with BL Hb 10 to <12 g/dL.
Source: Blood
Authors: Austin Kulasekararaj, Flore Sicre-de-Fontbrune, Anna Gaya, Ilene Weitz, David Kuter, David Araten, Bhumika Patel, Abhay Singh, Richard Kelly, Eros Di Bona, Michael Loschi, Vinod Pullarkat, Jörg Schubert, Alessandro Maria Vannucchi, Mustafa Yenerel, Regis Peffault De Latour, Navin Mahajan, Luca Monaco, Tao Ding, Tomasz Lawniczek, Philippe Ferber, Marion Dahlke, Antonio Risitano
Institutions: National Institute for Health and Care Research, European Society for Blood and Marrow Transplantation, King's College Hospital, European Society for Blood and Marrow Transplantation, Hospital Clínic de Barcelona, University of Southern California, Keck Hospital of USC, USC Norris Comprehensive Cancer Center, Harvard University, Massachusetts General Hospital, NYU Langone Health, New York University, Prisma Health, Cleveland Clinic, St James's University Hospital, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, City Of Hope National Medical Center, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Istanbul University, Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Novartis (Switzerland), Azienda Ospedaliera S.Giuseppe Moscati, University of Naples Federico II
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4417018376
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