EMATOLOGIA

PNH — Giugno 2026

LONG-TERM SAFETY WITH IPTACOPAN TREATMENT IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH): POOLED ANALYSIS OF DATA FROM PHASE 2 AND 3 STUDIES AND THE ROLL-OVER EXTENSION PROGRAM

Alexander Röth et al
West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany
Background
  • Iptacopan demonstrated sustained hematologic control and a favorable safety profile in patients with paroxysmal nocturnal hemoglobinuria (PNH) in phase 2 and 3 studies and the roll-over extension program (PNH-REP); long-term safety data are limited.
  • The aim of the study is to assess long-term safety of iptacopan in patients with PNH using pooled data from phase 2 and 3 studies and the PNH-REP.
Methods
  • Safety data were pooled from 3 phase 3 studies (APPOINT-PNH [NCT04820530]; APPLY-PNH [NCT04558918] and APPULSE-PNH [NCT05630001]), 2 phase 2 studies (X2201 [NCT03439839] and X2204 [NCT03896152]) and the PNH-REP (NCT04747613).
  • Baseline was defined as day 1 of receiving iptacopan 200 mg twice daily in the parent study. Safety assessments included incidence and exposure-adjusted occurrence rates (OccR, expressed as number of events/100 patient-years [py]) of breakthrough hemolysis (BTH), major adverse vascular events (MAVEs), treatment-emergent adverse events (TEAEs) and serious TEAEs.
  • Total cholesterol was calculated in the whole population; high- (HDL) and low-density lipoprotein (LDL) cholesterol endpoints were calculated in the pooled phase 3 populations only.
Results
  • The analysis population comprised 223 patients. Total iptacopan exposure was 676.1 py; 126 (56.5%) patients were exposed to iptacopan for ≥3 years and 34 (15.2%) for ≥4 years. At data cut-off, 95 (42.6%) patients had completed study, 106 (47.5%) were on study and 22 (9.9%) had discontinued treatment, including 3 (1.3%) due to adverse events (AEs), 2 (0.9%) due to pregnancy and 8 (3.6%) due to death. BTH occurred in 29 (13.0%) patients (OccR 6.7 events/100 py) and serious BTH events in 6 (2.7%; OccR 0.9 events/100 py).
  • Eight MAVEs were reported in 7 (3.1%) patients (OccR 1.2 events/100 py). These included transient ischemic attack (3 patients); lacunar infarction, unstable angina, thrombophlebitis/deep vein thrombosis (1 patient each); intestinal infarction and portal vein thrombosis (in the same patient). Overall, 210 (94.2%) patients experienced ≥1 TEAE (OccR 329.4 events/100 py). Most frequently reported TEAEs were COVID-19 in 79 (35.4%) patients (OccR 13.8 events/100 py), nasopharyngitis in 50 (22.4%; OccR 11.4 events/100 py) and headache in 47 (21.1%; OccR 11.5 events/100 py). Sixty-seven (30.0%) patients experienced ≥1 serious TEAE (OccR 19.4 events/100 py), of which infections were the most frequent, in 29 (13.0%) patients (OccR 7.0 events/100 py).
  • To evaluate potential lipid alterations, cholesterol levels were assessed. Mean (SD) total cholesterol was 4.9 (1.2) mmol/L at year 3 (n=129) and 5.0 (1.0) mmol/L at year 4 (n=32), with respective mean (SD) elevations of 0.9 (0.9) and 1.1 (0.7) mmol/L from baseline. HDL cholesterol remained stable with mean (SD) change from baseline of 0.0 (0.3) and 0.1 (0.3) mmol/L at years 3 and 4, respectively; LDL cholesterol showed a mean (SD) increase from baseline of 0.8 (0.8) mmol/L at both timepoints. Of 9 reported pregnancies, 4 resulted in elective abortions, 2 in spontaneous abortions, 1 in ectopic pregnancy and 2 in healthy live births.
Conclusion
  • The safety profile of iptacopan in this pooled analysis of long-term safety data is consistent with that previously reported, with no new safety findings. MAVEs and serious BTH events were infrequent; there were minimal changes in LDL cholesterol levels.
  • Rates of treatment discontinuation for AEs were low. These findings demonstrate that iptacopan is well tolerated in the long-term treatment of PNH.