The 2-year efficacy and safety of iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria with a history of aplastic anemia on concomitant immunosuppressive therapy who entered the roll-over extension program Free

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis, thrombosis, and potential concurrent bone marrow failure. A strong clinical relationship exists between PNH and aplastic anemia (AA); approximately 40-60% of patients have overlapping PNH and AA. While immunosuppressive therapy (IST) is generally effective in treating AA, recovery of blood cell count is often incomplete. For patients with overlapping disease, in which hemolysis is more dominant than bone marrow failure, treatment with complement inhibitors is required. Iptacopan is an oral proximal complement inhibitor approved for the treatment of PNH that targets factor B to inhibit the alternative complement pathway and provide comprehensive hemolysis control.

The oral administration, unique mechanism of action, and safety profile of iptacopan present potential advantages over other complement inhibitors, supporting its long-term evaluation in patients with overlapping AA and PNH. Here, we present the subgroup analysis of PNH patients with history of AA and concomitant IST (AA+IST) during the Phase 3 trials of iptacopan (APPLY- and APPOINT-PNH) who entered the roll-over extension (PNH-REP) study.

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 clinical studies. This subgroup analysis of patients from APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530) who entered PNH-REP included patients with a history of AA receiving concomitant IST (cyclosporine); patients with severe AA were excluded from the studies based on laboratory parameters. Outcomes were evaluated over 2 years by subgroup and included mean hemoglobin (Hb) levels, achievement of Hb level of ≥12 g/dL (irrespective of red blood cell [RBC] transfusion), transfusion avoidance, mean lactate dehydrogenase (LDH) levels, achievement of LDH <1.5×ULN, absolute reticulocyte count (ARC), and neutrophil and platelet counts, as well as the incidence of breakthrough hemolysis (BTH), major adverse vascular events (MAVEs), and serious treatment-emergent adverse events (TEAEs), with a focus on infections.

Results: Of the 136 patients (with AA+IST, n=11; without AA+IST, n=125) who successfully completed APPLY-PNH (n=96) and APPOINT-PNH (n=40), 132 entered the PNH-REP. At 2 years follow-up, mean (SD) Hb was 13.32 g/dL (2.037) and 12.63 g/dL (2.020) in patients with and without AA+IST, respectively (mean [SD] change from baseline, 5.65 g/dL [1.829] and 3.73 g/dL [2.454]). For patients with available data, 72.7% (8/11) and 71.7% (81/113) of patients with and without AA+IST achieved Hb ≥12 g/dL, irrespective of RBC transfusion; RBC transfusion avoidance through 2 years was achieved by 100% and 89.6% (112/125) of patients. Mean (SD) LDH at 2 years follow-up was 375.55 U/L (148.902) and 293.05 U/L (199.609) in patients with and without AA+IST, respectively; LDH <1.5×ULN was achieved by 63.6% and 91.2% of patients. Mean (SD) ARC levels at 2 years follow-up were 77.78×10⁹/L (36.998) and 78.90×10⁹/L (47.525) for patients with and without AA+IST, respectively, with mean (SD) changes from baseline of −73.18×10⁹/L (50.757) and −103.36×10⁹/L (66.471). Mean (SD) neutrophil counts were 2.37×10⁹/L (0.500) and 2.71×10⁹/L (1.259) in patients with and without AA+IST, respectively, with mean (SD) changes from baseline of 0.17×10⁹/L (1.366) and 0.42×10⁹/L (1.427). Mean (SD) platelet counts were 145.18×10⁹/L (61.437) and 135.47×10⁹/L (54.383) in patients with and without AA+IST, respectively, with mean (SD) changes from baseline of 5.00×10⁹/L (87.413) and −17.84×10⁹/L (40.348). BTH occurred in 1 patient (4.5 events per 100 patient-years) with and 13 patients (8.7 events per 100 patient-years) without AA+IST; MAVEs were reported in 0 patients with and 3 patients (1.7 events per 100 patient-years) without AA+IST. Serious infection-related TEAEs were reported in 18.2% (2/11) of patients with and 14.4% (18/125) without AA+IST.

Conclusions: In this subgroup analysis of PNH patients with AA+IST, long-term treatment with iptacopan maintained clinically meaningful improvements in Hb levels, reduced transfusion needs, and sustained control of hemolysis over 2 years, with safety outcomes comparable to patients without AA. These findings support the durable efficacy and safety of iptacopan in this population.