Obicetrapib’s Lipid-Lowering Effect Improves Cardiovascular Event Risk

Obicetrapib, a highly selective and potent cholesteryl ester transfer protein (CETP), is associated with a greater reduction in cardiovascular event rates compared to placebo, according to a pooled analysis of the BROOKLYN and BROADWAY phase 3 clinical trials.1

In previous trials, obicetrapib has proven its efficacy in lowering levels of LDL-C, ApoB, and lipoprotein(a) (Lp[a]), as well as raising HDL-C, when given in addition to high-intensity statin therapy. This lipid-lowering effect also enables patients at risk of cardiovascular events to achieve LDL-C targets and thereby reduce their risk.1

“The impact of obicetrapib on cardiovascular events remains to be established,” wrote Stephen Nicholls, PhD, program director of Monash Heart, Victorian Heart Institute, Monash University, and colleagues. “The objective of the present pooled analysis…was to investigate the rate of cardiovascular events in patients treated with obicetrapib compared with placebo.”1

The BROOKLYN trial evaluated patients with heterozygous familial hypercholesterolemia (HeFH), conducted to determine the degree of LDL-C reduction caused by obicetrapib. The study involved 354 adult patients ≥18 of age with HeFH diagnosed by genetic confirmation. Eligible patients were treated with maximally tolerated lipid-lowering therapy and exhibited evidence of suboptimal lipid control, which was defined by LDL-C ≥70 mg/dL. Patients were excluded if they experienced a cardiovascular event in the prior 3 months, had homozygous familial hypercholesterolemia, uncontrolled hypertension or diabetes, active liver disease, or a history of malignancy.2

The BROADWAY trial investigated obicetrapib in patients at high risk of cardiovascular events. A total of 2530 patients were included. High cardiovascular risk was determined by the presence of either HeFH or atherosclerotic cardiovascular disease (ASCVD). For inclusion, patients were required to have received treatment with maximally tolerated lipid-lowering therapy and exhibited suboptimal lipid control. This was defined as LDL-C ≥100 mg/dL or non-HDL-C ≥130 mg/dL. Patients were excluded for the same conditions as BROOKLYN.3

In both BROOKLYN and BROADWAY, patients were randomly assigned in a 2:1 ratio to treatment with either 10 mg obicetrapib or matching placebo, both of which were administered orally daily for 1 year. The primary endpoint was percent change in LDL-C from baseline to day 84; secondary endpoints included change in LDL-C from baseline to day 365, changes in other lipid and lipoprotein parameters, and the percent of patients achieving specific LDL-C goals.2,3

This post hoc analysis, combining results from both trials, had a total of 2884 patients with a mean age of 66 years. Medical history included ASCVD in 82% of patients, HeFH in 27%, and diabetes in 35%. Concomitant use of lipid-lowering therapies at baseline included statins in 91%, high-intensity statins in 69.3%, ezetimibe in 29.8%, and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors in 5.3%.1

Compared to baseline, investigators saw that patients treated with obicetrapib demonstrated greater absolute and percentage reductions in LDL-C (-34 versus -4 mg/dL, -37.8% vs -4.6%; P <.0001), ApoB (-19 versus -3 mg/dL, -21.7% versus -3.6%; P <.0001), non-HDL-C (-36 versus -4 mg/dL, -32.4% versus -3.7%; P <.0001), and Lp(a) (-9.8 versus 0 nmol/L, -32.5% versus 0%; P <.0001), and a greater increase in HDL-C (68 versus 1 mg/dL, 140% versus 1.5%; P <.0001).1

Additionally, the incidence of cardiovascular outcomes was lower across the board among obicetrapib recipients versus placebo. A total of 123 participants experienced ≥1 cardiovascular event during the 12-month period. A composite of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, and coronary neovascularization occurred in 5% of placebo patients and 3.9% of obicetrapib patients (hazard ratio [HR], 0.77; 95% CI, 0.54 to 1.11; P = .16). This translated to an HR of 0.72 (95% CI, 0.45 to 1.14) per 1 mmol/L difference in LDL-C.1

“This pooled analysis of 2 phase 3 clinical trials demonstrated a reduction in cardiovascular event rates with obicetrapib,” Nicholls and colleagues wrote. “If a reduction in cardiovascular risk is confirmed in larger and adequately powered trials, obicetrapib has the potential to play an important role in the prevention of cardiovascular disease.”1

References

1. Nicholls SJ, Nelson AJ, Ray KK, et al. Impact of Obicetrapib on Major Adverse Cardiovascular Events in High-Risk Patients: A Pooled Analysis. J Am Coll Cardiol. 2025;86(14):1046-1056. doi:10.1016/j.jacc.2025.07.056

2. NewAmsterdam Pharma. Evaluate the Effect of Obicetrapib in Patients with HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies (BROOKLYN). ClinicalTrials.gov identifier: NCT05425745. Updated June 11, 2025. Accessed October 10, 2025. https://clinicaltrials.gov/study/NCT05425745

3. NewAmsterdam Pharma. Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies (BROADWAY). ClinicalTrials.gov identifier: NCT05142722. Updated September 19, 2025. Accessed October 10, 2025. https://clinicaltrials.gov/study/NCT05142722