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

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 10 mg/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 (t_max) occurred at 7 days post-dose, and garadacimab exposure, based on maximum plasma concentration (C_max) 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 C_max and AUC close to 100%. Following IV administration, t_max 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.