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

Abstract

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.

Clinical Pharmacokinetics and Pharmacodynamics of CSL112

“…In the previously mentioned Phase 1 study performed by Zheng et al [40], the authors performed a cross-study comparison to compare PK parameters of apoA-I across five completed CSL112 clinical trials, including healthy volunteers, stable CAD, and post-MI patients [20,21,29,30,41]. Overall, CSL112 exposure and CEC enhancement were similar in Japanese and non-Japanese subjects, which further confirmed the consistent PK/PD profiles of CSL112.…”

“…The early CSL112 Phase 1 trials were performed mostly in White males (97.2%), with a different incidence of CAD, post-MI AEs, and lipoprotein metabolisms compared to other ethnic groups. Therefore, a CSL112 Phase 1 study was conducted on 34 Japanese volunteers to evaluate the PK/PD profiles and safety of different CSL112 doses (2, 4, and 6 g single dose) compared to placebo in oriental races (Table 1) [40]. Furthermore, they randomized White subjects to either 6 g or placebo (one administration only) to compare the two populations (6 g in Japanese vs 6 g in White).…”

“…Data from the Phase 1 and 2 trials have been combined in 3 different pooled data analyses to increase the study's sample size and assess the PK/PD profiles among different subgroups [20,40,46].…”

“…RCT SAD of CSL112/placebo(5,15,40, 70, 105, and 135 mg/kg) Immediate increase in apoA-I, with T max at 2 h, and biphasic decline Dose-proportional, robust increases in apoA-I concentration Sustained apoA-I levels above baseline for ~ 3 days ApoA-I t ½ ranged from 39.8 to 99.5 NA Gille et al [30] Healthy volunteers (n = 36) Double-blind, placebo-controlled RCT MAD of CS112/placebo administered once (3.4 or 6.8 g) or twiceweekly (3.4 g) Immediate increase in apoA-I and PC, with T max at 2 h, and biphasic decline Sustained apoA-I levels above baseline for ~ 3 days No accumulation of apoA-I in 1-week infusion, and small accumulation in 2-week Dose-proportional elevations in apoA-I Wide variability of t ½ of apoA-I Vd of apoA-I, 5.6-9.7 L PC AUC 0-T (mg/h/dL) 3270 ± 2280 (first dose, similar to last dose) 3.4 g once a week, 6779 ± 2897(first dose, similar to last dose) 6.8 g once a week, 2178 ± 948 (first dose) and 4730 ± 1838(last dose) for the 3.4 g twice a week PC C max (mg/dL) 113.7 ± 13.4 and 123.7 ± 27.1, 254.7 ± 48.3 and 268.3 ± 48.5, 125.6 ± 26.5 and 168.7 ±39.9, respectively, first and last dose of 3.4 g per week, 6.8 g per week and 3.4 g per 2 weeks PC t ½ ranged: 3.4 g 1-week last infusion: 2.8 h 6.8 g 1-week 1st infusion: 81.5 h area under the effect time curve from 0 to 72 h, AUEC area under the effect time curve, AUEC 0-24 area under the effect time curve from 0 to 24 h, AUEC 0-last area under the plasma concentration-time curve from time point zero (before dosing) to the last time point above baseline, CAD coronary artery disease, CE cholesterol efflux, CEC cholesterol efflux capacity, CKD chronic kidney disease, C max maximum plasma concentration, HDL-C high-density lipoprotein cholesterol, HDL-VS very small HDL (i.e., pre-β1-HDL), h hours, MAD multiple ascending dose study, NA not available, PC phosphatidylcholine, PD pharmacodynamics, PK pharmacokinetics, RCT randomized controlled trial, RI renal impairment, SAD single ascending dose study, t 1/2 terminal elimination half-life, TC total cholesterol, T max time to reach maximum concentration in plasma, Vd apparent volume of distribution a Moderate renal impairment defined as an eGFR ≥ 30 and < 60 mL/min/1.73 m 2 . Normal renal function is defined as an eGFR ≥ 90 mL/min/1.73 m 2 .…”