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This open-label, randomized, multicenter, phase II trial evaluated the efficacy of iptacopan (LNP023), a novel oral selective inhibitor of complement factor B, for patients with paroxysmal nocturnal hemoglobinuria (PNH) in two dosing regimens (cohort 1, 25 mg for 4 weeks followed by 100 mg for up to 2 years; cohort 2, 50 mg for 4 weeks followed by 200 mg for up to 2 years). Notably, 100% of patients achieved the primary endpoint of a reduction in lactate dehydrogenase (LDH) levels by at least 60% by week 12 from baseline, and the mean LDH levels decreased by 77% and 85% at week 2 and by 86% and 86% at week 12 in cohorts 1 and 2, respectively. Overall, 91.7% of patients were transfusion-free up to week 12, with consistent improvements in markers of hemolysis, and no thromboembolic events were observed. Iptacopan was well-tolerated with no severe adverse events.
Among patients with PNH who received iptacopan, there was a rapid and durable decline in mean LDH levels with normalization of hemolytic markers and no thromboembolic events. Most patients had transfusion-free improvement in hemoglobin levels.
Iptacopan (LNP023) is a novel, oral selective inhibitor of complement factor B under clinical development for paroxysmal nocturnal hemoglobinuria (PNH). In this ongoing open-label phase 2 study, PNH patients with active hemolysis were randomized to receive single-agent iptacopan twice-daily, at a dose of either 25 mg for 4 weeks followed by 100 mg for up to 2 years (cohort 1) or 50 mg for 4 weeks followed by 200 mg for up to 2 years (cohort 2). At the time of interim analysis, of 13 PNH patients enrolled, all 12 evaluable for efficacy achieved the primary endpoint of reduction in serum lactate dehydrogenase (LDH) levels by at least 60% by week 12 as compared to baseline; mean LDH levels dropped rapidly and durably, namely by 77% and 85% at week 2 and by 86% and 86% at week 12 in cohorts 1 and 2, respectively. Most patients achieved a clinically meaningful improvement in hemoglobin levels and all but one patient remained transfusion-free up to week 12. Other markers of hemolysis, including bilirubin, reticulocytes and haptoglobin, showed consistent improvements. No thromboembolic events were reported, and iptacopan was well tolerated, with no severe or serious adverse events reported up until the data cutoff. In addition to the previously reported beneficial effect of iptacopan add-on therapy to eculizumab, this study showed that iptacopan monotherapy in treatment-naïve PNH patients resulted in normalization of hemolytic markers and rapid transfusion-free improvement of hemoglobin levels in most patients.