†Pharmacokinetics, Pharmacodynamics, and Safety of Bempedoic Acid in a Phase 1 Clinical Trial in Healthy Japanese, Chinese, and White subjects

Lead Author's Financial Disclosures

Benny M. Amore is a current employee of Esperion Therapeutics, Inc., and may own Esperion stock and/or stock options.

Study Funding

Esperion Therapeutics, Inc.

Background/Synopsis

Bempedoic acid (BA) is an inhibitor of ATP-citrate lyase that significantly lowers LDL-C levels, after single and multiple oral dose administration.

Objective/Purpose

To investigate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of BA, in White and first-, second-, or third-generation Japanese and Chinese subjects living in the US.

Methods

This double-blind, placebo-controlled study was conducted at a single US site in a total of 40 healthy subjects randomized (3:1) to receive BA or placebo. The PK, PD, and safety of BA were assessed in Japanese subjects after a single dose of BA 60, 120, or 180mg; and in Japanese, Chinese, and White subjects (baseline LDL-C 70−190 mg/dL; not receiving a statin) after daily BA 180mg dosing for 14 days.

Results

Enrolled subjects (28% female) ranged 23 - 59 years of age. In Japanese subjects, single dose maximum BA plasma concentrations increased proportionally, and AUC increased slightly greater than proportional to dose. After 14 days of BA 180mg, mean estimates of BA elimination half-life were 25.2, 20.0 and 23.9 hours in Japanese, Chinese, and White subjects, respectively. Active metabolite ESP15228 AUC exposures were approximately 20% of BA across subjects. Mean oral clearance (CL/F) in Japanese (0.494 L/h) and Chinese (0.592 L/h) subjects was 29% and 15% less and volume of distribution (Vz/F) in Japanese (18.0 L) and Chinese (19.2 L) subjects was 32% and 27% less than in White subjects, respectively. Differences in CL/F and Vz/F were decreased after body weight (BW) normalization, with higher mean BW for White subjects (80.6 kg) observed relative to Japanese (67.4 kg) and Chinese (74.1 kg) subjects. A reduction in fasting LDL-C, non-HDL-C, and hsCRP was observed with BA. The mean (SD) percent change from baseline in LDL-C among subjects (n=6 each) receiving BA 180 mg was −29% (14) for Japanese subjects, −39% (8) for Chinese subjects, and −17% (28) for White subjects compared with +17% (21) for subjects receiving placebo.

Conclusions

Results from this study suggest that administration of BA 180mg once daily over 14 days markedly reduced LDL-C and was well tolerated in all subjects. PK differences, largely explained after normalizing CL/F and Vz/F by subject BW, are not expected to result in clinically meaningful differences in the efficacy or safety profiles of BA.