Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous and Intravenous Garadacimab Following Single-Dose Administration in Healthy Japanese and White Adults.

Abstract

Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long-term prophylaxis of hereditary angioedema. Here, we report the results from a two-part, phase 1, open-label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight-matched White and Japanese participants, and 600 mg dose in Japanese participants. Part 2 assessed 3 and 10mg/kg IV doses in Japanese participants. Follow-up for safety was over 84 days post-dose. Overall, 37 participants received garadacimab dosing and 36 completed the study, with one participant lost to follow-up. Following SC administration, time to maximum plasma concentration (tmax) occurred at 7 days post-dose, and garadacimab exposure, based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC), increased less than 3-fold when tripling the dose. PK was comparable between Japanese and White participants, with geometric mean ratios for Cmax and AUC close to 100%. Following IV administration, tmax occurred at the end of infusion, and garadacimab exposure increased in a dose-proportional manner. Inhibition of FXIIa-mediated kallikrein activity versus baseline was observed in all participants receiving the SC and IV doses. No anti-drug antibodies against garadacimab were reported. Consistent with pivotal phase 3 (VANGUARD) outcomes, no safety concerns and no difference in the safety profile of garadacimab were observed between healthy Japanese and White participants.