From Failure to Promise: Obicetrapib and the Renaissance of Cholesteryl Ester Transfer Protein Inhibition in Atherosclerotic Cardiovascular Disease

Figures

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  Figure 1. Mechanism of action of obicetrapib (TA‐8995), a selective CETP inhibitor. Obicetrapib inhibits CETP‐mediated transfer of cholesteryl esters from HDL to apolipoprotein B–containing lipoproteins, resulting in reductions in LDL‐C and apolipoprotein B, with concomitant increases in HDL‐C. It enhances reverse cholesterol transport, decreases atherogenic lipoproteins, and upregulates hepatic LDL receptors, leading to reduced atherosclerotic cardiovascular disease risk. Based on data from prior mechanistic and clinical studies. 4 , 5 , 6 Apo A1 indicates apolipoprotein A1; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; HDL, high‐density lipoprotein; HDL‐C, high‐density lipoprotein cholesterol; LDL, low‐density lipoprotein; LDL‐C, low‐density lipoprotein cholesterol; Lp(a), lipoprotein(a); TG, triglycerides; and VLDL, very‐low‐density lipoprotein.

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  Figure 2. Lipid effects of lipid‐lowering monotherapies. Bars represent approximate percentage changes from untreated baseline in LDL‐C, apolipoprotein B, lipoprotein(a), and HDL‐C. LDL‐C, apolipoprotein B, and lipoprotein(a) reflect effects on atherogenic lipoprotein burden, whereas HDL‐C changes are shown for descriptive purposes only. Values are derived from placebo‐controlled randomized trials and contemporary guideline summaries. 4 , 16 , 17 , 18 , 19 , 20 , 21 Apo B indicates apolipoprotein B; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; and Lp(a), lipoprotein(a).

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  Figure 3. Expected lipid effects of combination lipid‐lowering therapy on a background of high‐intensity statin treatment. Bars depict approximate and schematic percent changes relative to untreated baseline in LDL‐C, apolipoprotein B, lipoprotein(a), and HDL‐C with commonly used combination regimens added to high‐intensity statin therapy. Values reflect typical effects inferred from placebo‐corrected randomized trials, guideline summaries, and established biological relationships, rather than direct measurements from factorial trials for every combination. 1 , 15 , 16 , 17 , 18 , 19 , 22 LDL‐C and Apo B represent atherogenic lipoprotein burden, whereas HDL‐C changes are shown for descriptive purposes only. Apo B indicates apolipoprotein B; HDL‐C, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; and Lp(a), lipoprotein(a).

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  Figure 4. Clinical development timeline of obicetrapib (TA‐8995), a selective CETP inhibitor. Timeline summarizes the phase 1 to 3 clinical development of obicetrapib (TA‐8995). Lipid changes are shown for the 10‐mg obicetrapib dose. LDL‐C values are based on Friedewald‐calculated estimates for consistency across trials. Early studies demonstrated favorable safety and significant lipid lowering, with LDL cholesterol (LDL‐C) reductions up to 53% and HDL cholesterol (HDL‐C) increase up to 140%. The phase 2 TULIP trial demonstrated LDL‐C reductions of approximately 45% and HDL‐C increase upto 179% with obicetrapib 10 mg. Subsequent Phase 2b trials (ROSE, ROSE2) confirmed dose‐dependent LDL‐C lowering and additive efficacy with ezetimibe. Phase 3 trials include BROOKLYN, conducted in patients with heterozygous familial hypercholesterolemia (HeFH); BROADWAY and TANDEM, conducted in patients with atherosclerotic cardiovascular disease (ASCVD) and HeFH (with TANDEM evaluating a fixed‐dose combination [FDC] of obicetrapib and ezetimibe); PREVAIL, an ongoing cardiovascular outcomes trial in patients with ASCVD; and REMBRANDT, assessing the effect of the obicetrapib/ezetimibe FDC on coronary plaque…

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  Figure 5. PREVAIL trial overview (obicetrapib phase 3). The PREVAIL trial is a randomized, double‐blind, placebo‐controlled, parallel‐group phase 3 study evaluating the efficacy and safety of obicetrapib 10 mg daily vs placebo in patients with established ASCVD whose lipid levels remain inadequately controlled despite maximally tolerated lipid‐lowering therapy. All participants continue background lipid‐lowering therapy. The primary end point is a composite of cardiovascular death, myocardial infarction, stroke, or nonelective coronary revascularization. The event‐driven trial began in 2022 and is ongoing. 28 ASCVD indicates atherosclerotic cardiovascular disease; CV, cardiovascular; LLT, lipid‐lowering therapy; and MI, myocardial infarction.