Management of a real-world cohort of patients with paroxysmal nocturnal hemoglobinuria treated with iptacopan: A multi-institutional analysis

Abstract

Abstract Introduction: Iptacopan, the first oral complement inhibitor, offers an attractive alternative to parenteral complement blockers in paroxysmal nocturnal hemoglobinuria (PNH). While clinical trials have confirmed its efficacy vs terminal C5 inhibition, real-world data on breakthrough hemolysis (BTH), complement-activating conditions (CACs), and switching patients with satisfactory response to prior therapy (hemoglobin [Hgb] ≥10 g/dL) are limited. We studied a large multi-institutional PNH cohort treated with iptacopan. Methods: We performed a retrospective analysis of 62 patients with PNH who received iptacopan for ≥3 months between FDA approval in December 2023 and April 2025 (mean exposure, 1.01 years; 62 patient-years). Patients from the Cleveland Clinic network and Mayo Clinic were analyzed. Demographics, prior therapies, reasons for transition, Hgb, lactate dehydrogenase (LDH), platelet counts, thrombotic events, CACs, BTH, and adverse events were extracted. Efficacy was assessed separately for treatment-naive patients and treatment-experienced patients (sub-optimal responders [Hgb <10 g/dL] and optimal responders to prior therapy). Results: Overall, 12 of 62 patients were treatment naive and 50 switched from prior therapy (of whom 21 had sub-optimal responses and 29 had optimal responses). In the 50 patients who switched, 60% transitioned from ravulizumab, 30% from pegcetacoplan, 8% from eculizumab, and 2% from ravulizumab and danicopan. The primary reasons for switching were the convenience of oral medications (n=17), extravascular hemolysis or BTH (n=10), prior medication side effects (n=5), desire to further improve Hgb (n=6), and not documented (n=12). A total of 4 patients discontinued iptacopan (2 pregnancies, 1 insurance reversal, 1 intolerable gastrointestinal toxicity). Three patients reported headaches, and 1 reported abdominal pain; all resolved within 1 week from treatment start. Across the 62 patient-years, no thrombotic events occurred, 18 CAC episodes were managed with iptacopan 200 mg BID (10 infections, 1 heart-failure exacerbation, 2 minor surgeries, 1 traumatic brain injury, 2 pancreatitis, 2 pregnancies), and none triggered BTH. Overall, 3 clinically significant BTH events (in 3 patients; 4.8% annualized) were recorded: 2 infection-related (managed outpatient) and 1 alcoholic pancreatitis; all resolved with a 1- to 2-day increase to iptacopan 400 mg BID ± single-dose eculizumab. Two hemolytic events secondary to non-adherence were reported (4 days after stopping iptacopan). These resolved after resuming iptacopan 200 mg BID without need for hospitalization. In treatment-naive patients, mean Hgb increased significantly by 1.87 g/dL from iptacopan initiation (baseline) to 3 months (9.9±1.9 to 11.8±1.3 g/dL; P=.005), sustained until last follow-up at 12 months. LDH decreased by 369 U/L at 3 months (P=.058), sustained through 12 months. No significant change was seen in platelets, absolute neutrophil count (ANC), or white blood cell (WBC) count. In treatment-experienced sub-optimal responders, mean Hgb increased significantly by 2.16 g/dL from baseline to 3 months (8.6±.89 to 10.8±2.1; P<0.001). At 12 months, 85% of patients had increased Hgb compared with baseline (median increase: 3.31±1.62 g/dL). LDH decreased significantly from baseline to 3 months by 229 U/L (P=.03), with no significant changes noted in LDH from 3 to 12 months or in platelets, ANC, or WBC counts. In previously treated complement inhibitor responders, mean Hgb increased significantly by 0.75 g/dL from baseline to 3 months (12.0±1.3 to 12.8±1.7 g/dL; P=.004), with 79% showing improvements from baseline at 12-month follow-up (median increase: 1.16±0.82 g/dL). LDH decreased significantly by 45 U/L from baseline to 3 months (P=.03), with no further significant changes from 3 to 12 months. Conclusions: In this real-world cohort, iptacopan provided substantial and durable hemoglobin improvement across naive and previously treated patients with PNH, with meaningful reduction in hemolytic parameters, absence of thrombosis, and low BTH rate predominantly linked to infection. Patients with previous satisfactory responses also showed improved Hgb levels. The favorable safety profile and high treatment persistence underscore iptacopan's role as an effective first-line or switch therapy and support its incorporation into evidence-based sequencing algorithms in the evolving PNH treatment landscape.