Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death globally.1 Low-density lipoprotein cholesterol (LDL-C), a clinically measured surrogate of circulating atherogenic apolipoprotein (Apo) B-containing particles, is a primary cause of ASCVD and the target of many interventions aimed at reducing ASCVD events.2, 3, 4, 5, 6, 7, 8 Meta-analyses of randomized controlled trials have shown that each 1 mmol/L reduction in LDL-C is associated with ∼22% lower risk of major vascular events, with no lower threshold to this observed benefit, supporting the concept of “the lower, the better” for LDL-C.2,3, 9, 10, 11 Thus, treatment guidelines from the American Heart Association/American College of Cardiology and the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) for high risk and very high risk patients have recommended reducing LDL-C by ≥50% from baseline to achieve an LDL-C <70 mg/dL or <55 mg/dL (EAS/ESC) for patients at very high-risk (∼50% of patients with ASCVD).3,5

Currently available strategies for LDL-C-lowering include lifestyle interventions and drug therapies such as statins, ezetimibe, bempedoic acid (and their fixed dose combination), and proprotein convertase subtilisin kexin type 9 (PCSK9) modulating therapies. Statins are the first-line drug therapy for reducing LDL-C. The most potent statins may reduce LDL-C by >50%; however, this may be inadequate for persons with severely elevated LDL-C levels such as those with presumed or confirmed familial hypercholesterolemia (FH) or those with prevalent ASCVD in whom the lowest LDL-C levels are recommended.3, 12, 13, 14, 15, 16 In clinical practice, fewer than 1 in 4 patients with established ASCVD on a high-intensity statin has an LDL-C level <55 mg/dL.17 Multiple studies have now shown that even when statins are uptitrated, the incremental benefit of doubling the statin dose is limited (just 6%).18 Furthermore, at higher statin doses, the frequency of statin-associated muscle symptoms and other side effects also increases. These may limit the use of high-intensity statins.19, 20, 21 While non-statin therapies may be added, the available oral non-statin therapies, including ezetimibe and bempedoic acid, are limited by their relatively modest effects on LDL-C; both ezetimibe and bempedoic acid monotherapies only lower LDL-C by ∼20%.22, 23, 24, 25 While PCSK9 inhibitor therapies have higher degrees of LDL-C lowering, they are only available in injectable forms, and their uptake has been limited in part due to access barriers.23,26 In the United States, among over 700,000 patients with ASCVD, fewer than 2% were taking a PCSK9 inhibitor in 2021.27

Despite use of high-intensity statin monotherapy and multiple new therapies for LDL-C lowering in the past decade, attainment of LDL-C control at a population level remains inadequate. In the DA VINCI study, a European-wide cross-sectional observational study from 2017-2018, only 17% and 22% of very high-risk primary and secondary prevention patients, respectively, achieved the current ESC/EAS therapeutic objective for LDL-C, with an even lower ratio among patients from Central and Eastern European countries.15,28 Baseline data from the multinational observational SANTORINI study also showed that 80% of high- and very high-risk patients in Europe between 2020 and 2021 failed to achieve the 2019 ESC/EAS LDL-C goals.29 A prospective observational registry study in the United States from 2016-2018 of 5006 patients with ASCVD and receiving lipid-lowering therapy demonstrated that only 1 in 3 achieved an LDL-C level <70 mg/dL, and 1 in 10 achieved an LDL-C level <55 mg/dL.14 A simulation based on the DA VINCI study designed to evaluate treatment optimization scenarios, indicated that most patients at high cardiovascular risk are unlikely to achieve LDL-C goals even with statin optimization and ezetimibe, and would require a monoclonal antibody PCSK9 inhibitor.30 Given that a majority of individuals in clinical practice experience residual risk from an inability to achieve recommended levels of LDL-C, there remains a significant unmet need for therapies that substantially reduce LDL-C and consequent ASCVD risk, particularly in a convenient oral dosage form and with favorable tolerability.3,13,16

Obicetrapib is an oral selective cholesteryl ester transfer protein (CETP) inhibitor that was developed as a tetrahydroquinoline derivative with a pyrimidine and an ethoxycarbonyl structure with two chiral centers. In Phase II studies, obicetrapib potently lowered LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), Apo B, LDL particle (LDL-P) concentration, particularly small LDL-P, and lipoprotein(a) [Lp(a)], as well as to significantly increase HDL-C and Apo A1, with a safety and tolerability profile comparable to placebo.31, 32, 33, 34, 35 Phase II trials of obicetrapib in participants with dyslipidemia include: the TA-8995: Its Use in Patients with Mild Dyslipidaemia (TULIP) trial, which administered obicetrapib 1, 2.5, 5, or 10 mg monotherapy, and 10 mg in combination with 20 mg atorvastatin or 10 mg rosuvastatin for 12 weeks (after a washout of all previous lipid-modifying therapies); the Randomized Study of Obicetrapib as an Adjunct to Statin Therapy (ROSE), which administered obicetrapib 5 or 10 mg on top of high-intensity statin for 8 weeks; and the Study to Evaluate the Effect of Obicetrapib in Combination with Ezetimibe as an Adjunct to High-Intensity Statin Therapy (ROSE2), which administered obicetrapib 10 mg on top of high-intensity statin in combination with ezetimibe for 12 weeks.32, 33, 34 High-intensity statin was defined as atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg.5 Lipid results from ROSE are shown in Table 1.33 Based on the results from investigations demonstrating near maximal effects on CETP activity and lipoprotein lipid levels without safety concerns at the 10 mg dose, the 10 mg dose was selected for Phase III trials.31, 32, 33, 34 Obicetrapib also appears to have no clinically meaningful food effect and, unlike anacetrapib, a previous CETP inhibitor whose development was discontinued, it does not accumulate in adipose or other tissues, likely due to its physiochemical properties including lower lipophilicity and higher polar surface area.31, 32, 33, 34,36,37

The reduction in LDL-C that occurs with CETP inhibition is based on an upregulation of LDL receptors and a consequent increased fractional catabolic rate of Apo B-containing lipoproteins.38, 39, 40 CETP inhibition impairs the transfer of cholesteryl esters from HDL to Apo B-containing particles and may also increase biliary as well as transintestinal cholesterol excretion.41, 42, 43 The effects of CETP inhibition on Lp(a) levels are reportedly due to a decrease in the production of apo(a).44,45CETP gene polymorphisms associated with decreased CETP activity were found to be associated with increased HDL-C and reduced risk of ASCVD; Mendelian randomization analyses have also confirmed the relationship between reduced CETP and LDL-C levels and decreased risk of ASCVD.46, 47, 48, 49 The Randomized Evaluation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial demonstrated a significant reduction in major coronary events with anacetrapib.50,51 While anacetrapib had relatively modest LDL-C-lowering (-17% by beta-quantification; 11 mg/dL difference from placebo) and non-HDL-C lowering effects (-18%), the associated ASCVD risk reduction of 9% over a median follow-up of 4.1 years was consistent with what would be expected based on this degree of LDL-C (non-HDL-C) lowering.9,50 To examine this relationship for obicetrapib, the Phase III Cardiovascular Outcome Study to Evaluate the Effect of Obicetrapib in Patients with Cardiovascular Disease (PREVAIL; NCT05202509) is underway and expected to complete enrollment in early 2024.

Two important ongoing Phase III trials are the focus of this article: the Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies (BROADWAY) and to Evaluate the Effect of Obicetrapib in Patients with HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies (BROOKLYN). Both trials are examining the efficacy of obicetrapib for lowering atherogenic lipoprotein lipid levels when added to maximally tolerated lipid-modifying therapies. BROADWAY is enrolling participants with a history of ASCVD and/or underlying heterozygous familial hypercholesterolemia (HeFH) and BROOKLYN is a dedicated trial of participants with HeFH, a condition with particularly elevated risk of ASCVD.3, 5, 6, 7,12,22,23

The purpose of this article is to present the rationale, trial designs, statistical analysis plans, and baseline participant characteristics for BROADWAY and BROOKLYN. Results from these trials will provide additional information regarding the effects of adding obicetrapib to other lipid-modifying therapies in patients at elevated risk of ASCVD due to their prior history of ASCVD and/or underlying HeFH.