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Review
. 2024 Feb;26(2):35-44.
doi: 10.1007/s11883-023-01184-1. Epub 2023 Dec 22.

Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments

John J P Kastelein  1 , Andrew Hsieh  2 , Mary R Dicklin  3 , Marc Ditmarsch  1 , Michael H Davidson  1
Affiliations
Review

Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments

John J P Kastelein et al. Curr Atheroscler Rep. 2024 Feb.

Abstract

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. 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.

Keywords: Atherosclerotic cardiovascular disease (ASCVD); Cardiovascular outcomes trial; Cholesteryl ester transfer protein (CETP) inhibitor; High-density lipoprotein cholesterol (HDL-C); Low-density lipoprotein cholesterol (LDL-C); Obicetrapib.

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Conflict of interest statement

J.J.P.K, A.H., M.D., and M.H.D. are employees of NewAmsterdam Pharma and they also report that they receive stock or stock options. J.J.P.K is the Chief Scientific Officer of NewAmsterdam Pharma. A.H. is the Executive Director, R&D, NewAmsterdam Pharma. M.D. is the Chief Development Officer of NewAmsterdam Pharma. M.H.D. is the Chief Executive Officer of NewAmsterdam Pharma. M.R.D., as an employee of Midwest Biomedical Research, is a consultant for NewAmsterdam Pharma. In addition, M.R.D., as an employee of Midwest Biomedical Research, reports the following companies contracted consulting and/or research with their institution and it received the consulting fees and grant funding from Acasti Pharma, Beren Therapeutics, Eli Lilly and Company, Indiana University and Foundation, Matinas BioPharma, NewAmsterdam Pharma, and 89Bio.

Figures

Fig. 1
Fig. 1
Proposed mechanisms of action for low-density lipoprotein cholesterol lowering with the combination of obicetrapib with ezetimibe on top of statins. Abbreviations: ABCG5/G8, ATP-binding cassette sub-family G member 5/member 8; CE, cholesteryl ester; CoA, coenzyme A; HDL, high-density lipoprotein; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; NPC1L1, Niemann Pick C-1 Like-1; TG, triglyceride; SRB1, scavenger receptor class B, type 1; TICE, transintestinal cholesterol excretion (used with permission from Elsevier from: Ballantyne CM, et al. J Clin Lipidol. 2023. 10.1016/j.jacl.2023.05.098, permission conveyed through Copyright Clearance Center, Inc.) [•]
See this image and copyright information in PMC

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