PI-057 - DOSE–RESPONSE MODEL PREDICTIONS OF THE PHARMACODYNAMIC EFFECT OF BEMPEDOIC ACID, A COMPETITIVE INHIBITOR OF ATP CITRATE LYASE, IN COMBINATION WITH EZETIMIBE AND STATINS.

D. Epling¹, R. Crass¹, B. Smith¹, S. Chapel¹, M. Kerschnitzki², W. Sasiela³, M. Louie³, M. Emery³, B. Amore³; ¹Ann Arbor Pharmacometrics Group, Inc., Ann Arbor, MI, USA, ²Daiichi Sankyo Europe GmbH, Munich, Germany, ³Esperion Therapeutics, Inc., Ann Arbor, MI, USA.

Background: Many patients at high risk for atherosclerotic cardiovascular disease (ASCVD) have low-density lipoprotein cholesterol (LDL-C) exceeding guideline-recommended thresholds, despite the use of maximally tolerated lipid-lowering therapies. Bempedoic acid (BA) significantly lowers LDL-C in combination with statins, including with or without nonstatin therapy, in patients with hypercholesterolemia and ASCVD.

Methods: An indirect effect dose–response model was developed to predict serum LDL-C for background statins combined with BA (BA + statin), ezetimibe (EZE + statin), or BA plus EZE (BA + EZE + statin). Model parameters were estimated from pooled data of 14 clinical studies involving 3,909 patients, using a first-order conditional estimation with interaction method in NONMEM® (Version 7.4). Model-based predictions were generated for the combinations.

Results: Model-predicted median LDL-C extrapolated to untreated baseline among low-, medium-, and high-intensity statin groups were 160 (n=66), 171 (n=718), and 201 (n=781) mg/dL, respectively. LDL-C reduction was greater when statins were combined with BA + EZE (three drugs) than with either BA or EZE (two drugs). With stable high-intensity statins, LDL-C reduction as a percent change (90% prediction interval [PI]) from untreated baseline was −59.5% (−68.4, −55.4) for BA and −59.4% (−66.2, −59.4) for EZE. BA plus EZE added to a background of low-, medium-, or high-intensity statins resulted in LDL-C reductions (90% PI) of −59.6% (−69.3, −52.3), −65.0% (−79.2, −58.1), and −69.5% (−77.9, −65.8), respectively.

Conclusion: Dose–response model predictions indicated that the BA + EZE + statin combination may be a therapeutic option for some patients at high risk of ASCVD.