Long-term safety and efficacy of iptacopan in patients with paroxysmal nocturnal hemoglobinuria: 4- and 5-year follow-up of patients from Phase 2 studies who entered the roll-over extension program

Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and consequent anemia. Despite treatment with anti-C5 therapy, many patients with PNH remain anemic and may continue to experience symptoms of PNH and extravascular hemolysis. Iptacopan is an oral proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement system. In Phase 2 and Phase 3 studies of patients with PNH, iptacopan has shown rapid and sustained hemolysis control, with improvements in hemolytic markers, and a well-tolerated safety profile, regardless of prior complement inhibitor treatment. Here, we report 4- and 5-year follow-up data on the long-term safety and efficacy of iptacopan in patients who entered the roll-over extension program (REP) from Phase 2 studies. Methods PNH-REP (NCT04747613) is an ongoing, open-label, single-arm, multicenter, Phase 3 study of patients with PNH who completed the treatment extension periods (without tapering down) of Phase 2 or Phase 3 studies. This analysis reports long-term data from 26 patients who entered the PNH-REP study from two Phase 2 iptacopan studies (NCT03439839 and NCT03896152). Phase 2 studies included different treatment sequences and iptacopan dosing (25 mg, 50 mg, 100 mg, and 200 mg twice daily BID). Baseline for this analysis is first dose of iptacopan 200 mg BID. Efficacy assessments reported at 4 and 5 years of follow-up include mean hemoglobin (Hb) levels, Hb ≥12.0 g/dL (irrespective of red blood cell RBC transfusion), transfusion avoidance, mean lactate dehydrogenase (LDH) levels, LDH 1.5×upper limit of normal (ULN), absolute reticulocyte count (ARC), and ARC normalization. Safety assessments include frequency and occurrence rate (OccR, exposure-adjusted OccR expressed as total number of episodes per 100 patient-years) of breakthrough hemolysis (BTH) and major adverse vascular events (MAVEs), and frequency of adverse events (AEs) and serious AEs (SAEs). Results Of 26 patients included in the Phase 2 studies, 22entered the PNH-REP study. Among the 26 patients, sixteen (61.5%) were exposed to iptacopan treatment for ≥4 years, while 8 (30.8%) were exposed for ≥5 years. Mean (standard deviation SD) Hb levels were 12.1 g/dL (2.0) and 12.9 g/dL (2.0) at 4 and 5 years, respectively; 63.6% and 66.7% of patients achieved a Hb level of ≥12.0 g/dL irrespective of RBC transfusion, respectively. Nearly all patients (96.2%) achieved transfusion independence during the 5-year follow-up. Mean (SD) LDH levels were 315.8 U/L (123.7) and 292.2 U/L (71.9) at 4 and 5 years, respectively; the proportion of patients achieving LDH 1.5×ULN levels were 81.8% and 83.3%, respectively. Mean (SD) ARC levels were 81.4×10⁹/L (31.3) and 84.6×10⁹/L (15.7) at 4 and 5 years, respectively; all patients achieved normalization of ARC. Four BTH events occurred in 3 patients (11.5%), with an OccR (95% confidence interval) of 3.7 (1.2, 11.6). MAVE (unstable angina) occurred in 1 patient, with an OccR of 0.9 (0.1, 6.6). Twenty-two patients (84.6%) reported ≥1 AE; the most frequently reported AEs were COVID-19 and pyrexia (30.8% each), and headache (15.4%). Ten patients (38.5%) reported SAEs. No SAE occurred in more than 1 patient. Treatment-emergent infection SAEs occurred in 3 patients (11.5%) and included pneumonia (considered related to study drug by investigator), bacterial pneumonia, pneumococcal pneumonia, sepsis, and urinary tract infection. Three deaths (11.5%) occurred; none of which were considered related to study drug by investigator. Conclusions: These long-term data show that initial improvement in Hb levels with iptacopan is retained over time, with most patients keeping normal Hb levels at their latest follow-up. This hematologic improvement was associated with transfusion independence, as well as with LDH 1.5×ULN, and ARC normalization in most patients, confirming the comprehensive, long-term control of intravascular and extravascular hemolysis with iptacopan. Despite the increased proportion of PNH erythrocytes, BTH and MAVEs remain rare. Iptacopan was well tolerated, with no new safety findings. These results support oral iptacopan as a potentially practice-changing treatment for patients with PNH.