Randomised, phase 1 evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of iptacopan in healthy volunteers

Abstract Background and Purpose Overactivation of the alternative pathway (AP) underlies several diseases. Iptacopan is an oral, first‐in‐class, highly potent specific inhibitor of factor B, a key AP protease. Experimental Approach The analysis included data from two phase 1 randomised, volunteer‐blinded, placebo‐controlled studies: Study 1, a single ascending dose (SAD; 5–400 mg), multiple ascending dose (MAD; 25–200 mg twice daily), and food effect study of iptacopan in healthy volunteers; Study 2, a SAD (25–400 mg) study of iptacopan in healthy Japanese males. The objectives were to evaluate the safety and tolerability of iptacopan, and the pharmacokinetics/pharmacodynamics of SAD and MAD doses. Key Results In Study 1 (n = 100) and Study 2 (n = 30), iptacopan was rapidly absorbed; pharmacokinetic variability was low, with a half‐life between 18.4 and 25.0 h across steady‐state MAD doses, and iptacopan exhibited target‐mediated drug disposition behaviour. Japanese and non‐Japanese healthy volunteers had similar pharmacokinetics/pharmacodynamics. Food intake did not affect pharmacokinetics. Iptacopan 200 mg twice daily showed the highest and most persistent AP inhibition; ~67% AP inhibition remained 24 h after the last dose, while ex vivo classical complement pathway activation was not impaired. This dose also provided the highest proportion of volunteers achieving EC90 values for the complement biomarkers Wieslab® assay in serum, plasma Bb and sC5b‐9. Iptacopan was well tolerated across doses. Conclusions and Implications These results characterise the pharmacokinetics/pharmacodynamics of iptacopan in healthy volunteers; the data helped build semi‐mechanistic population pharmacokinetic/pharmacodynamic models, which guided the accelerated clinical development of iptacopan.