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 (AUC0-72 ) 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 AUC0-72 and maximum plasma concentration (Cmax ) 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.