Oral iptacopan monotherapy may significantly increase red blood cell survival and size as well as control extravascular and intravascular hemolysis in anti-C5-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) who also have anemia.

These results are according to a study presented during The European Hematology Association (EHA) Hybrid Congress 2023, held in Frankfurt, Germany, this June.

To analyze total PNH red blood cell clone size and C3 deposition data, the researchers recruited 97 PNH patients who received standard-of-care PNH treatment with eculizumab or ravulizumab for at least 6 months and had mean hemoglobin levels lower than 10 g/dL. The participants were randomized 8:5 to take 200 mg of iptacopan monotherapy twice per day or continue their standard of care regimen for 24 weeks.

The primary endpoints included a hemoglobin concentration increase of at least 2 g/dL or more compared with baseline as well as a hemoglobin concentration of at least 12 g/dL, both in the absence of red blood cell transfusions. Exploratory endpoints, including total PNH red blood cell clone size and C3 depositions, were assessed by flow cytometry.

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According to the results, iptacopan treatment yielded superior results than standard-of-care PNH treatment for both primary endpoints. Approximately 82.3% of the patients receiving iptacopan had at least a 2 g/dL or greater hemoglobin increase from baseline compared with only 2% of those taking standard-of-care treatment. Moreover, an estimated 68.8% of iptacopan-treated patients achieved a hemoglobin concentration of at least 12 g/dL as opposed to only 1.8% of those receiving standard therapy.

Iptacopan monotherapy was superior to anti-C5 therapies in terms of reducing the need for red blood cell transfusions, adjusted mean changes from baseline in hemoglobin, absolute reticulocyte count, as well as Functional Assessment of Chronic Illness Therapy−Fatigue score and annualized clinical breakthrough hemolysis rate.

However, the difference in lactate dehydrogenase levels and annualized major adverse vascular event rates were not as prominent between groups.

The mean total PNH red blood cell clone size (64.6% at baseline) increased by week 4, reaching a maximum of 93.4% at week 16, and stabilizing through week 24 in patients receiving iptacopan. Similarly, mean C3 deposition (19.2% at baseline) started to reduce by week 4 and further decreased by weeks 16 (0.2%) through 24 (0.3%; change from baseline: −19.2%).

In patients receiving standard-of-care treatment, the mean total PNH clone size and C3 deposition through week 24 remained similar to baseline.

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Patients who received iptacopan reported having headaches and diarrhea more often than those taking standard medications. On the other hand, serious adverse events were only reported in 2 patients receiving anti-C5 therapies. No adverse events led to standard-of-care treatment discontinuation or death in either of the groups.

“Iptacopan monotherapy may become a practice-changing, oral, outpatient treatment for PNH patients with a suboptimal response to intravenous eculizumab/ravulizumab and a preferred option for patients with hemolytic PNH,” Risitano and colleagues wrote.

PNH patients treated with standard-of-care anti-C5 therapies often suffer C3-mediated extravascular hemolysis. Iptacopan is an experimental, selective complement factor B inhibitor administered orally.  


Risitano AM, Röth A, Kulasekararaj A, et al. Oral iptacopan monotherapy increases paroxysmal nocturnal hemoglobinuria (PNH) red blood cell clone size via control of intra and extravascular hemolysis in anti-C5-treated PNH patients with anemia. Presented at: European Hematology Association (EHA) Hybrid Congress 2023, Frankfurt, Germany; June 8-11, 2023.