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Meta-Analysis
19 March 2026

Indirect treatment comparison of iptacopan versus pegcetacoplan for patients with paroxysmal nocturnal hemoglobinuria and residual anemia despite C5 inhibitor treatment

Authors: Austin Kulasekararaj https://orcid.org/0000-0003-3180-3570 [email protected], Phillip Scheinberg https://orcid.org/0000-0002-9047-4538, Maria-Magdalena Balp https://orcid.org/0000-0002-8612-7680, Olivier Somenzi https://orcid.org/0009-0007-4087-8802, Anggie Wiyani https://orcid.org/0000-0002-5203-9797, Josefin Snellman https://orcid.org/0009-0003-6634-3823, Sarah Walsh https://orcid.org/0000-0003-2988-6506, Katharina Pannagl https://orcid.org/0009-0002-2505-1405, Jason Steenkamp https://orcid.org/0009-0006-0685-069X, and Régis Peffault de Latour https://orcid.org/0000-0001-6222-4753Author Info & Affiliations
Volume 15, Number 4
https://doi.org/10.57264/cer-2025-0167
PDFFormats

Abstract

This study conducted an indirect treatment comparison (ITC) of iptacopan, the first oral monotherapy targeting factor B, versus pegcetacoplan, a subcutaneous infusion targeting complement component 3, in patients with paroxysmal nocturnal hemoglobinuria (PNH) and residual anemia despite complement component 5 inhibitors (C5i). An unanchored matching adjusted ITC was performed, using phase III APPLY-PNH and PEGASUS studies, identified by a systematic literature review. The outcomes were: change from baseline (CfB) in hemoglobin (Hb), with and without post-transfusion data, CfB in lactate dehydrogenase (LDH), CfB in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and serious adverse events. Two adjustment scenarios were analyzed: (A) baseline Hb, sex, transfusion history ≤12 months, and (B) scenario A plus reticulocyte count, baseline LDH and age. After matching and adjusting, baseline characteristics were similar across trials. Iptacopan showed greater Hb improvements than pegcetacoplan with post-transfusion data (mean difference – scenario A: 1.05 g/dl; p < 0.001, scenario B: 0.76 g/dl; p = 0.018) and without (A: 1.31 g/dl; p < 0.001, B: 1.01 g/dl; p = 0.014). Odds of transfusion avoidance were higher with iptacopan (A: odds ratio [OR] = 9.17, p = 0.013; B: OR = 12.71, p = 0.009). No significant difference was noted in CfB in LDH and FACIT-Fatigue score. These findings suggest that iptacopan may improve Hb levels and reduce transfusion dependency compared with pegcetacoplan in PNH patients with residual anemia despite C5i and must be interpreted in the context of ITCs.

Plain language summary

What is this article about?

This study compared two newer medications for paroxysmal nocturnal hemoglobinuria (PNH), iptacopan and pegcetacoplan, to see which works better for patients who are still experiencing anemia despite standard treatment. Because no clinical trial has compared these drugs directly, a statistical method was used to match patient data from two separate studies, ensuring the groups were as similar as possible in areas like starting hemoglobin levels and previous transfusion history.

What were the results?

The results showed that patients taking iptacopan had significantly greater improvements in their hemoglobin levels and were much more likely to avoid the need for blood transfusions compared with those on pegcetacoplan. However, there were no significant differences between the two drugs in reducing fatigue or hemolysis.

What do the results mean?

While these findings suggest iptacopan may be more effective at raising hemoglobin levels and reducing transfusion dependency, they are associated with limitations because they are based on a small number of patients and should be confirmed with future direct comparisons.

Supplementary Material

File (supplementary materials.docx)

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