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

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.