Iptacopan Promotes Anemia Resolution in Paroxysmal Nocturnal Hemoglobinuria


Iptacopan monotherapy improved hematologic outcomes in both anti-C5–treated patients with persistent anemia and those not treated with complement inhibitors across two phase 3 trials.

Regis Peffault de Latour, MD, PhD | Image Credit: Hôpital Saint-Louis

Regis Peffault de Latour, MD, PhD

Credit: Hôpital Saint-Louis

Oral iptacopan monotherapy led to clinically meaningful improvement in hemoglobin levels in patients with paroxysmal nocturnal hemoglobinuria (PNH) with persistent anemia treated with anti-C5 and those without previous complement inhibitor treatment.1

Iptacopan, a first-in-class oral factor B inhibitor, was assessed in two phase 3 trials, APPLY-PNH and APPOINT-PNH, over a 24-week core treatment period and a 24-week extension period. Across both trials, nearly two-thirds of patients reached normal or near-normal hemoglobin levels, suggesting proximal complement inhibition may benefit the resolution of anemia in PNH.

“Enhancing the efficiency of anticomplement agents is likely to shift the focus of PNH treatment toward the resolution of anemia,” wrote the investigative team, led by Regis Peffault de Latour, MD, PhD, French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Université de Paris.

A rare disease, PNH is characterized by hemolysis, thrombosis, and bone marrow failure. Intravenous anti-C5 monoclonal antibodies became the standard of care for hemolytic PNH, but many patients continue to experience anemia, with up to 40% of patients undergoing red-cell transfusions. These treatment challenges led to the development of proximal complement inhibitors, including iptacopan.

In phase 2 research, iptacopan maintained intravascular hemolysis control in patients with PNH and persistent anemia and those without complement inhibitors. In this report, de Latour and colleagues described the primary efficacy and safety data from the 24-week core treatment period of the randomized, phase 3 APPLY-PNH and APPOINT-PNH trials.

Both trials enrolled individuals aged ≥18 with mean hemoglobin levels of ≤10 g per deciliter and no laboratory evidence of bone marrow failure.

In APPLY-PNH, patients treated with anti-C5 therapy were randomly assigned (8:5) to switch to iptacopan or continue anti-C5 therapy. In APPOINT-PNH, a single group of patients who had not received complement inhibitors, and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range, underwent iptacopan treatment.

Upon analysis of the APPLY-PNH trial, iptacopan was superior to anti-C5 therapy according to the study’s two primary end points. Among the 60 patients who received iptacopan in APPLY-PNH, 51 had an increase in the hemoglobin level of ≥2 g per deciliter from baseline, and 42 reached a hemoglobin level of ≥12 g per deciliter. None of the 35 patients who received anti-C5 therapy met the primary end point levels.

Moreover, in the APPOINT-PNH trial, 31 of 33 evaluable patients demonstrated an increase in the hemoglobin level of ≥2 g per deciliter from baseline without red-cell transfusion, meeting the study’s primary end point.

Between days 14 and 168, 59 of 62 patients who received iptacopan, and 14 of 35 who received anti-C5, met the criteria for red-cell transfusion avoidance in the APPLY-PNH trial. No patients in the APPOINT-PNH trial received a red-cell transfusion or met the criteria for receiving a transfusion in the same period.

Other efficacy end points revealed treatment with iptacopan increased hemoglobin levels, reduced FACIT-Fatigue scores, reticulocyte counts, and bilirubin levels, and led to improved mean LDH levels, with 95% of patients exhibiting levels that were less than 1.5 times the upper limit of the normal range.

According to the safety data, there were no reported deaths or adverse events leading to iptacopan discontinuation, in either trial. Mild-to-moderate headaches were the most frequently reported non-serious adverse events linked to iptacopan treatment.

Only two patients treated with iptacopan in the APPLY-PNH trial, and no patients in the APPOINT-PNH trial, experienced clinical breakthrough hemolysis. de Latour and colleagues noted breakthrough hemolysis appeared to occur less frequently, and less severely, than with the anti-C3 agent pegcetacoplan, suggesting iptacopan’s more favorable pharmacokinetic profile.

“Because anti-complement treatment is lifelong in PNH and complement-amplifying events can occur at any time, follow-up beyond 24 weeks is necessary to better characterize the overall risk of breakthrough hemolysis with iptacopan,” investigators wrote.


  1. Peffault de Latour R, Röth A, Kulasekararaj AG, et al. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med. 2024;390(11):994-1008. doi:10.1056/NEJMoa2308695
  2. Luzzatto L, De Franceschi L. Hemo- lytic anemias. In: Loscalzo J, Fauci AS, Kasper DL, Hauser SL, Longo DL, James- on JL, eds. Harrison’s principles of internal medicine. 21st ed. New York: McGraw Hill, 2022:776-90
  3. Risitano AM, Röth A, Soret J, et al. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, sin- gle-arm, phase 2, proof-of-concept trial. Lancet Haematol 2021;8(5):e344-e354
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