Effect of CSL112 (apolipoprotein A‐I [human]) on cholesterol efflux capacity in Japanese subjects: Findings from a phase I study and a cross‐study comparison

CSL112 (apolipoprotein A‐I [apoA‐I, human]) is a novel drug in development to reduce the risk of recurrent cardiovascular events following acute myocardial infarction by increasing cholesterol efflux capacity (CEC). This phase I study aimed to compare the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of CSL112 in Japanese and White subjects. A total of 34 Japanese subjects were randomized to receive a single infusion of CSL112 (2, 4, or 6 g) or placebo and 18 White subjects were randomized to receive a single dose of 6 g CSL112 or placebo, followed by PK/PD assessment and adverse events monitoring. In addition, PK/PD parameters were compared across the CSL112 clinical development program. Plasma exposure of apoA‐I increased in a dose‐dependent but nonlinear manner in Japanese subjects receiving a single dose of CSL112. Mean baseline‐corrected area under the curve from 0 to 72 h (AUC_0–72) increased from 840 to 6490 mg h/dl, in the 2 and 6 g cohorts, respectively, followed by dose‐dependent increase of CEC. The plasma PK profile of apoA‐I and increases in total and ATP binding cassette transporter A1 dependent CEC were comparable in Japanese and White subjects. The geometric mean ratio (Japanese:White) for plasma apoA‐I AUC_0–72 and maximum plasma concentration (C_max) was 1.08 and 0.945, respectively. Cross‐study comparison analysis demonstrated similar CSL112 exposure and CEC enhancement in Japanese and non‐Japanese subjects (including patients with cardiovascular disease) and further confirmed consistent PKs/PDs of CSL112. This study suggests CSL112 acutely enhances CEC and is well‐tolerated with no differences between Japanese and White subjects.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC? Cholesterol efflux, mediated by apolipoprotein A‐I (apoA‐I), removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion; impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates. CSL112 (apoA‐I, human) has been shown to enhance cholesterol efflux capacity and is being investigated as a novel therapy to reduce the risk of early recurrent CV events. Japanese ethnicity is known to confer differences in lipoprotein metabolism. WHAT QUESTION DID THIS STUDY ADDRESS? This ethno‐bridging study characterized the pharmacokinetics (PKs), pharmacodynamics, safety and tolerability of CSL112 in healthy Japanese subjects compared with healthy White subjects to identify any ethnicity‐based differences in cholesterol efflux capacity (CEC) and safety issues and determine the appropriate dose in Japanese subjects prior to inclusion in future or ongoing studies. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Japanese ethnicity confers no clinically relevant difference in CSL112 exposure and CEC compared to White populations and safety profiles were comparable between populations. This study supports the inclusion of Japanese subjects in an ongoing phase III study, investigating the impact of CSL112 on CV risk reduction post‐myocardial infarction, with no dose adjustment needed. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study contributes to the discussion around PK differences between ethnic groups. It confirms similarity of apoA‐I exposure and CEC responses in Japanese and White populations, which warrants further investigation of this novel treatment approach to reduce the risk of early recurrent CV events.