Subgroup analysis shows durable efficacy, safety of iptacopan for PNH treatment

In a subgroup analysis of patients with paroxysmal nocturnal haemoglobinuria (PNH) with a history of aplastic anaemia and concomitant immunosuppressive therapy (AA + IST), long-term treatment with iptacopan yields clinically meaningful improvements in haemoglobin levels, transfusion needs, and haemolysis control, with safety outcomes comparable to those in individuals without AA.

This analysis included participants who completed the APPLY-PNH (n=96) and APPOINT-PNH (n=40) trials and enrolled in the ongoing phase III rollover extension PNH-REP trial (n=136). Of these, 11 had AA + IST, while the remaining participants did not. [ASH 2025, abstract 4978]

At 2 years, the mean haemoglobin levels in participants with and without AA + IST were similar at 13.32 and 12.63 g/dL, respectively.

All patients with AA + IST were able to avoid red blood cell transfusion through 2 years. Among those without AA + IST, the corresponding transfusion avoidance rate was 89.6 percent.

Fewer participants with AA + IST achieved lactate dehydrogenase (LDH) levels <1.5 × ULN at 2 years than those without AA + IST (63.6 percent vs 91.2 percent). The mean LDH levels were 375.55 and 293.05 U/L, respectively.

In patients with AA + IST, the mean absolute reticulocyte count level was 77.78 × 10⁹/L, the mean neutrophil count was 2.37 × 10⁹/L, and the mean platelet count was 145.18 × 10⁹/L. The corresponding mean levels among those without AA + IST were not significantly different (78.90 × 10⁹/L, 2.71× 10⁹/L, and 135.47 × 10⁹/L, respectively).

Among those with AA + IST, one patient experienced breakthrough haemolysis (4.5 episodes per 100 patient-years [PY]), and none had major adverse vascular events. Among those without, the corresponding proportions were 13 (8.7 episodes per 100 PY) and three (1.7 episodes per 100 PY).

Serious infection-related treatment-emergent adverse events were reported in two patients with and 18 of those without AA + IST.

Cyclosporine exposure

“Although concomitant use of iptacopan and cyclosporine has not been studied clinically, the European public assessment report does not recommend concomitant use of iptacopan with cyclosporine due to the potential for reduced efficacy,” noted Dr Regis Peffault de Latour from the French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglubinuria, Paris, France, at ASH 2025.

In this analysis, the mean exposure to cyclosporine was 1,853.36 days, and only four patients discontinued cyclosporine during the study, he noted. “However, this was not due to toxicity or interactions with iptacopan. This is reassuring for physicians regarding the possible association between iptacopan and cyclosporine in these patients.”

Unique mechanism of action

PNH is a rare, life-threatening haematologic disorder characterized by complement-mediated haemolysis, thrombosis, and potential concurrent bone marrow failure. [Blood 2014;124:2802-2811; Mayo Clin Proc 2025;100:2206-2227]

“A strong clinical relationship exists between PNH and AA, with approximately 40–60 percent of patients having overlapping PNH and AA,” noted de Latour.

IST, although effective for the treatment of AA, typically results in incomplete recovery of blood cell count. “For patients with overlapping disease, in which haemolysis is more dominant than bone marrow failure, treatment with complement inhibitors is required,” de Latour noted.

Iptacopan, an oral proximal complement inhibitor, has been approved for the treatment of PNH, targeting factor B to inhibit the alternative complement pathway and provide comprehensive control of haemolysis. [N Engl J Med 2024;390:994-1008; Lancet Haematol 2025;12:e414-e430] Its oral administration, unique mechanism of action, and safety profile present potential advantages over other complement inhibitors, supporting its long-term evaluation in patients with overlapping AA and PNH.

“These findings support the durable efficacy and safety of iptacopan in this population. These are very reassuring data,” de Latour said, who called for larger studies to validate the results.