Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments

• Published in: Current atherosclerosis reports Vol. 26; no. 2; pp. 35 - 44
• Main Authors: Kastelein, John J. P., Hsieh, Andrew, Dicklin, Mary R., Ditmarsch, Marc, Davidson, Michael H.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2024
• Subjects: Angiology; Atherosclerosis - drug therapy; Cardiology; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials and Their Interpretations; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Lipoproteins; Medicine; Medicine & Public Health; Review; Topical Collection on Evidence-Based Medicine; High-density lipoprotein cholesterol (HDL-C); Atherosclerotic cardiovascular disease (ASCVD); Obicetrapib; Cardiovascular outcomes trial; Cholesteryl ester transfer protein (CETP) inhibitor; Low-density lipoprotein cholesterol (LDL-C)
• ISSN: 1523-3804; 1534-6242
• DOI: 10.1007/s11883-023-01184-1

Purpose of Review To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral, once-daily, low-dose CETP inhibitor in late-stage development for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). Recent Findings Phase 1 and 2 trials have evaluated the safety and lipid/lipoprotein effects of obicetrapib as monotherapy, in conjunction with statins, on top of high-intensity statins (HIS), and with ezetimibe on top of HIS. In ROSE2, 10 mg obicetrapib monotherapy and combined with 10 mg ezetimibe, each on top of HIS, significantly reduced low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total LDL particles, small LDL particles, small, dense LDL-C, and lipoprotein (a), and increased HDL-C. Phase 3 pivotal registration trials including a cardiovascular outcomes trial are underway. Summary Obicetrapib has an excellent safety and tolerability profile and robustly lowers atherogenic lipoproteins and raises HDL-C. As such, obicetrapib may be a promising agent for the treatment of ASCVD.