Assessment of QT Interval Prolongation Using Concentration-QT Modeling for Iptacopan, an Oral Complement Factor B...

To assess cardiac and safety parameters of iptacopan (an oral, selective, reversible, small-molecule factor B inhibitor), we conducted a phase I, single ascending dose (SAD), exposure-response study (A2107) instead of a traditional thorough QT study. Healthy participants were randomized 3:1 to receive a single, supratherapeutic, oral dose of iptacopan 400, 800, or 1200 mg, or placebo. A2107's primary objectives were to assess iptacopan's effect on Fridericia-corrected QT interval (QTcF) in a pooled analysis with the SAD phase of the first-in-human X2101 study, and the safety and tolerability of supratherapeutic iptacopan doses in participants. Secondary objectives included pharmacokinetics, changes in selected electrocardiogram (ECG) parameters, and categorical changes to the QTcF, PR, and QRS intervals and heart rate (pooled analysis). Thirty-two participants were randomized in A2107 and 56 in X2101; demographic data were similar across treatment groups. The estimated placebo-adjusted change from Day 1 baseline in QTcF at the geometric mean maximum drug concentration was 1.61 (90% confidence intervals: 0.39 to 2.82), 1.26 (-0.42 to 2.94), and 0.84 (-1.54 to 3.22) ms for 400, 800, and 1200 mg doses, respectively. These primary results are consistent with no risk of QT prolongation at single, supratherapeutic, oral iptacopan doses; secondary ECG data support this conclusion. No deaths, serious adverse events (AEs), or AEs leading to study discontinuation were reported; iptacopan was overall well tolerated. A high systemic exposure of iptacopan was confirmed, allowing us to conclude that single, supratherapeutic, oral doses of iptacopan had no QTcF prolongation or proarrhythmic potential in healthy individuals.