This is a first-in-human (FIH), single-center, randomized, double-blind, placebo-controlled, single ascending and multiple dose study evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of CITY-FXI in healthy adults, adults with Factor V Leiden (FVL) or prothrombin G20210A mutation, and adults with a history of provoked venous thromboembolism (VTE).
Males and women of non-childbearing potential (WONCBP) aged 18 to 45 years (inclusive, for Part A only)
Male and female participants aged 18 to 60 (inclusive, for Part B only), and aged 18 to 65 years (inclusive, for Part C only)
Body Mass Index (BMI) between 18 and 25 kg/m2 (inclusive, for Part B only) and 18 and 35 kg/m2 (inclusive, for Part C only) and a minimum weight of 50 kg (Parts A, B, and C)
Ability and willingness to comply fully with all study procedures and lifestyle considerations
Any clinically significant systemic disease or disorder, including but not limited to cardiovascular, hepatic, or oncological conditions
History or evidence of any bleeding disorders
History of clinically significant spontaneous bleeding
Prior treatment with an investigational agent
Sequential
CITY-FXI
DrugsiRNA (subcutaneous injection)
Placebo
DrugSaline (subcutaneous injection)
6
Treatment groupsSee each treatment group below.
Incidence, severity, and relationship of treatment-emergent adverse events (TEAEs)
To evaluate the safety and tolerability of a single dose of CITY-FXI in healthy adults and adults with Factor V Leiden (FVL) or prothrombin G20210A mutation, and of a multiple dose regimen of CITY-FXI in adults with FVL or prothrombin G20210A mutation and/or a history of provoked VTE
Maximum plasma concentration (Cmax)
To characterize the pharmacokinetics (PK) of a single dose of CITY-FXI in healthy adults and adults with FVL or prothrombin G20210A mutation, and of a multiple dose regimen of CITY-FXI in adults with FVL or prothrombin G20210A mutation and/or a history of provoked VTE
Area under plasma concentration time curve (AUC) of CITY-FXI
To characterize the pharmacokinetics (PK) of a single dose of CITY-FXI in healthy adults and adults with FVL or prothrombin G20210A mutation, and of a multiple dose regimen of CITY-FXI in adults with FVL or prothrombin G20210A mutation and/or a history of provoked VTE
Amount excreted in urine (Ae) of CITY-FXI
To characterize the pharmacokinetics (PK) of a single dose of CITY-FXI in healthy adults and adults with FVL or prothrombin G20210A mutation
Change from baseline in levels of plasma Factor XI (FXI)
To characterize the pharmacodynamics (PD) of a single dose of CITY-FXI in healthy adults and adults with FVL or prothrombin G20210A mutation, and of a multiple dose regimen of CITY-FXI in adults with FVL or prothrombin G20210A mutation and/or a history of provoked VTE
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