LONG-TERM HEMATOLOGIC CONTROL AND SAFETY IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA TREATED WITH IPTACOPAN: 6-YEAR FOLLOW-UP FROM PHASE 2 STUDIES AND ROLL-OVER EXTENSION PROGRAM
Antonio M. Risitano et al
University of Naples Federico II, Naples, Italy
Background
- Iptacopan has shown sustained hematologic control and a favorable safety profile in patients with paroxysmal nocturnal hemoglobinuria (PNH).
- The aim of the study is to report long-term safety and efficacy outcomes with up to 6 years of follow-up from patients with PNH who received iptacopan 200 mg twice daily (BID) in two phase 2 studies (NCT03439839 and NCT03896152) and an ongoing roll-over extension program (PNH-REP; NCT04747613).
Methods
- Long-term data were reported for patients from the phase 2 studies and PNH-REP. Baseline was defined as the first day of receiving iptacopan 200 mg BID. Efficacy outcomes included mean hemoglobin (Hb) levels and Hb ≥12.0 g/dL, mean lactate dehydrogenase (LDH) levels and LDH <1.5×upper limit of normal (ULN), mean absolute reticulocyte count (ARC) and ARC normalization, transfusion independence, hematologic parameters, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, breakthrough hemolysis (BTH) rates, and prevention of major adverse vascular events (MAVEs).
- Safety assessments included frequency and number of events per 100 patient years (py) of treatment-emergent adverse events (TEAEs) and serious TEAEs.
Results
- Of the 26 patients treated with iptacopan 200 mg BID in the phase 2 studies, 22 entered the PNH‑REP; at data cut-off, 21/26 (80.8%) patients were ongoing, 1 (3.8%) had completed the study, and 4 (15.4%) had discontinued. Sixteen of 26 (61.5%) patients had ≥5 years and 8/26 (30.8%) had ≥6 years of exposure; median duration of exposure was 66.1 months. Hematologic response was sustained from 6 months to 6 years (Figure).
- At 5 and 6 years, Hb ≥12.0 g/dL irrespective of red blood cell (RBC) transfusion was achieved by 7/12 (58.3%) and 6/7 patients (85.7%) with available data, respectively, and LDH <1.5×ULN was achieved by 10/12 (83.3) and 6/7 patients (85.7%), respectively. ARC normalization at 5 and 6 years was achieved by 12/12 (100%) and 6/7 patients (85.7%), respectively, with mean (SD) being 73.5 (16.8) and 81.4×10⁹/L (36.1).
- Most patients (23/26 [88.5%] at 5 and 6 years) remained RBC transfusion-free. Bilirubin and haptoglobin levels, platelet and neutrophil counts, and FACIT-Fatigue scores observed at 6 months were sustained to 6 years. Overall, 6 BTH events (none serious) occurred in 5/26 patients (19.2%; 4.7/100 py): 2 mild, 3 moderate, and 1 severe event (deemed study drug-related by investigators). A MAVE (unstable angina) was reported in 1/26 patients (3.8%; 0.8/100 py) who had pre-existing hypertension, left ventricular hypertrophy, and nephropathy.
- In total, 23/26 patients (88.5%) reported ≥1 TEAE, most frequently COVID-19 and pyrexia (30.8% each). Serious TEAEs occurred in 11/26 patients (42.3%; 13.2/100 py), with serious infections in 3/26 patients (11.5%; 3.9/100 py). Three of 26 (11.5%) patients died during phase 2 studies; no events leading to deaths were deemed study drug-related.
Conclusion
- Over a 6-year follow-up, iptacopan treatment was associated with sustained hematologic control, including maintenance of Hb levels and transfusion independence. In most of the patients, LDH <1.5×ULN and ARC normalization were achieved at 6 months through to 6 years, showing control of intravascular hemolysis and absence of treatment-emergent extravascular hemolysis.
- Low rates of BTH and MAVEs were observed. A consistent safety profile was maintained, with no new safety findings compared with previous reports. These findings further characterize the long-term effects of iptacopan treatment in patients with PNH.
