A Study to Assess the Pharmacokinetics and Safety of CSL312 in Healthy Japanese and Caucasian Adults

Study Overview
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Brief Summary
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This will be a 2- part, phase 1, open-label, single center, single ascending dose study to investigate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of subcutaneous (SC) and intravenous (IV) administration of CSL312 in healthy adult Japanese and Caucasian subjects.

Official Title
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A 2-Part, Phase 1, Single Center, Open-label, Single Ascending Dose Study to Investigate the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Subcutaneous and Intravenous CSL312 in Healthy Adult Japanese and Caucasian Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Biological: CSL312


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Caucasian and Japanese male or female subjects 18 to 55 years old (inclusive) that meet the following criteria at Screening: Japanese subjects defined as being born in Japan, having not lived outside of Japan for more than 10 years, and having both parents and four grandparents who are of Japanese ancestry. Caucasian subjects, defined as having both parents and four grandparents descended from and of the peoples of Europe, the Middle East, or North Africa, who are body weight-matched (± 15%) 1:1 with Japanese subjects. Body weight in the range of ≥ 50 kg and ≤ 100 kg Body mass index of ≥ 18 kg/m2 and ≤ 30 kg/m2 Exclusion Criteria: Positive serology test for human immunodeficiency virus (HIV)-1 / 2 antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or hepatitis C virus (HCV) antibody. Received any live viral or bacterial vaccinations within 8 weeks of Screening or is expected to receive any live virus or bacterial vaccinations during the study. Evidence of current active infection. Known malignancy or a history of malignancy in the past 5 years . Blood pressure or pulse rate measurements outside the normal range for the subject's age. Female subject of childbearing potential or fertile male subject either not using or not willing to use an acceptable method of contraception Pregnant, breastfeeding, or not willing to cease breastfeeding. Donation or loss of more than 500 mL of blood within 3 months, or donated plasma within 7 days History of clinically significant arterial or venous thrombosis, bleeding disorder, or any abnormal coagulation test result

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL312 (Cohort 1a, low dose)<br>Factor XIIa antagonist monoclonal antibody administered subcutaneously | Biological: CSL312<br>* Fully human immunoglobulin G4/lambda recombinant monoclonal antibody against Factor XIIa<br>* Other names: garadacimab;|
| Experimental: CSL312 (Cohort 1b, low dose)<br>Factor XIIa antagonist monoclonal antibody administered subcutaneously | Biological: CSL312<br>* Fully human immunoglobulin G4/lambda recombinant monoclonal antibody against Factor XIIa<br>* Other names: garadacimab;|
| Experimental: CSL312 (Cohort 2, high dose)<br>Factor XIIa antagonist monoclonal antibody administered subcutaneously | Biological: CSL312<br>* Fully human immunoglobulin G4/lambda recombinant monoclonal antibody against Factor XIIa<br>* Other names: garadacimab;|
| Experimental: CSL312 (Cohort 3, low dose)<br>Factor XIIa antagonist monoclonal antibody administered intravenously | Biological: CSL312<br>* Fully human immunoglobulin G4/lambda recombinant monoclonal antibody against Factor XIIa<br>* Other names: garadacimab;|
| Experimental: CSL312 (Cohort 4, high dose)<br>Factor XIIa antagonist monoclonal antibody administered intravenously | Biological: CSL312<br>* Fully human immunoglobulin G4/lambda recombinant monoclonal antibody against Factor XIIa<br>* Other names: garadacimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of CSL312 after subcutaneous dosing |  | Up to 85 days postdose | 
| Area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf) of CSL312 after subcutaneous dosing |  | Up to 85 days postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to maximum concentration (Tmax) of CSL312 after subcutaneous dosing |  | Up to 85 days postdose | 
| Area under the concentration-time curve from time 0 to the last measurable concentration (AUC0-last) of CSL312 after subcutaneous dosing |  | Up to 85 days postdose | 
| Half-life (t1/2) of CSL312 after subcutaneous dosing |  | Up to 85 days postdose | 
| Apparent clearance (CL/F) of CSL312 after subcutaneous dosing |  | Up to 85 days postdose | 
| Apparent volume of distribution (Vz/F) of CSL312 after subcutaneous dosing |  | Up to 85 days postdose | 
| Cmax of CSL312 after intravenous dosing |  | Up to 85 days postdose | 
| Tmax of CSL312 after intravenous dosing |  | Up to 85 days postdose | 
| AUC0-last of CSL312 after intravenous dosing |  | Up to 85 days postdose | 
| AUC0-inf of CSL312 after intravenous dosing |  | Up to 85 days postdose | 
| t1/2 of CSL312 after intravenous dosing |  | Up to 85 days postdose | 
| Clearance (CL) of CSL312 after intravenous dosing |  | Up to 85 days postdose | 
| Volume of distribution (Vd) of CSL312 after intravenous dosing |  | Up to 85 days postdose | 
| Mean FXIIa-mediated kallikrein activity |  | Up to 85 days postdose | 
| Number of subjects experiencing adverse events (AEs) |  | Up to 85 days postdose | 
| Percentage of subjects experiencing AEs |  | Up to 85 days postdose | 
| Number of subjects experiencing serious adverse events (SAEs) |  | Up to 85 days postdose | 
| Percentage of subjects experiencing SAEs |  | Up to 85 days postdose | 
| Number of subjects experiencing adverse events of special interest (AESIs) |  | Up to 85 days postdose | 
| Percentage of subjects experiencing AESIs |  | Up to 85 days postdose | 
| Number of subjects experiencing Anti-CSL312 antibodies |  | Up to 85 days postdose | 
| Percentage of subjects experiencing Anti-CSL312 antibodies |  | Up to 85 days postdose | 
| Number of subjects with injection / infusion site reaction by severity |  | Up to 48 hours after start of infusion or injection | 
| Percentage of subjects with injection / infusion site reaction by severity |  | Up to 48 hours after start of infusion or injection |