A Phase 1, Safety and Pharmacokinetic Study of CSL312 in Healthy Subjects

INTERVENTION: This is a single centre, randomised, double‐blind phase 1 study to assess the safety, tolerability and pharmacokinetics (PK) of single ascending doses of intravenous (IV) or subcutaneous (SC) administrations of CSL312 in healthy subjects. Subjects can participate in only 1 dose group and will be randomly assigned to receive a single dose of either CSL312 or placebo by IV infusion or SC injection (abdomen). Study drugs will be administered at the study site by study staff. CSL312 is a fully human recombinant anti‐FXIIa antibody (Factor XIIa antagonist monoclonal antibody), solution for injection. The dose and infusion volume will be based upon the subject's body weight and the allowable drug concentration. Dose escalation requires Safety Review Committee review of available blinded safety, tolerability, PK and selected Pharmacodynamic (PD) data. Eight groups of 6 subjects are planned; 5 groups for IV administration and 3 groups for SC administration. Dosing and initial dose escalation will begin with the IV groups, and upon reaching the third IV group, the study will progress to the SC groups. Dose escalation within the IV and SC groups will then progress in parallel with the SC groups staggered to start after initial dosing in their respective IV groups. For all IV groups and the first SC group, 2 sentinel subjects per group will be randomised to receive CSL312 or placebo in a 1:1 ratio, and the remaining 4 subjects per group will be randomised to receive CSL312 or placebo in a 3:1 ratio. CONDITION: Hereditary Angioedema PRIMARY OUTCOME: The percentage of subjects with adverse events (AEs) overall, and by severity and relatedness. ; AEs will be assessed through evaluation of physical examinations, vital signs, electrocardiograms, clinical laboratory parameters, and monitoring of AEs. AEs will be recorded during the study and summarised by relatedness and severity. SECONDARY OUTCOME: Area under the plasma concentration‐time curve (AUC) of CSL312 from the time of dosing extrapolated to time infinity (AUC0‐inf) Area under the plasma concentration‐time curve (AUC) of CSL312 from the time of dosing up to collection time t (AUC0‐t) Bioavailability of CSL312 ; The percentage of CSL312 available in plasma after SC dosing Maximum concentration (Cmax) of CSL312, derived from plasma CSL312 concentration‐time profiles. Percentage of subjects with anti‐CSL312 antibodies by plasma assay Terminal elimination half‐life (t1/2) of CSL312, derived from plasma CSL312 concentration‐time profiles Time of maximum concentration (tmax) of CSL312, derived from plasma CSL312 concentration‐time profiles Total systemic clearance (CLtot) of CSL312, derived from plasma CSL312 concentration‐time profiles Volume of distribution of CSL312 during the elimination phase (Vz), derived from plasma CSL312 concentration‐time profiles INCLUSION CRITERIA: ‐ Capable of providing written informed consent and willing and able to adhere to all protocol requirements. ‐ Male aged 18 to 45 years of age at the time of providing written informed consent. ‐ Judged as healthy by an investigator after completing a comprehensive clinical assessment (detailed medical history and complete physical examination). ‐ Body mass index (BMI) of 18.0 to less than 30.0 kg/m^2.