Impact of obicetrapib on major adverse cardiovascular events: a pooled analysis of phase 3 clinical trials.

Abstract

Background: The highly selective cholesteryl ester transfer protein inhibitor, obicetrapib, decreases levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] and raises high-density lipoprotein cholesterol (HDL-C) in patients treated with maximally tolerated statin therapy as evident within the Phase III BROOKLYN (NCT05425745) trial assessing the effects of daily administration of obicetrapib 10 mg compared with matching placebo (2:1) for 365 days on changes in lipid and lipoprotein parameters in 364 patients with heterozygous familial hypercholesterolemia (HeFH)) and in the Phase III BROADWAY (NCT05142722) trial involving 2530 patients with atherosclerotic cardiovascular disease (ASCVD) with or without HeFH. Purpose(s): Since the effect of obicetrapib on cardiovascular events is unknown, a pooled analysis of both BROOKLYN and BROADWAY trials was conducted. Method(s): The time to first occurrence of major adverse cardiovascular events was compared between the treatment groups in a pooled analysis of both trials in an analysis that included stratification by the presence of HeFH, statin intensity at baseline and study. Result(s): The pooled cohort had a median age of 66 years, 36% were female with a history of ASCVD in 82%, HeFH in 27% and diabetes in 35%. Baseline medication use included statins in 91%, high-intensity statins in 69%, ezetimibe in 30% and PCSK9 inhibitors in 5%. Median baseline lipid levels included LDL-C of 92 mg/dL, HDL-C of 48 mg/dL, apoB of 87 mg/dL and Lp(a) of 40.5 nmol/L. Treatment with obicetrapib produced greater reductions in LDL-C (-37.8% vs -4.6%), apoB (-21.7% vs -3.6%) and Lp(a) (-32.5% vs 0%) and greater increases in HDL-C (+140.0% vs +1.5%) compared with placebo. The incidence of the composite of coronary heart disease death, myocardial infarction, ischemic stroke or coronary revascularization was lower in the obicetrapib group (3.9% vs 5.0%, HR (95% CI) 0.77 (0.54, 1.11), P=0.16). A time-based analysis revealed no effect of obicetrapib in the first 6 months (HR (95% CI) 1.03 (0.59, 1.78), P=0.92) and a reduction in risk in the second 6 months (HR (95% CI) 0.60 (0.37, 0.99), P=0.04). The incidence of the composite of coronary heart disease death, myocardial infarction or coronary revascularization was lower in the obicetrapib group (3.2% vs 4.7%, HR (95% CI) 0.68 (0.46, 1.00), P=0.048). A time-based analysis revealed no effect of obicetrapib in the first 6 months (HR (95% CI) 1.06 (0.60, 1.90), P=0.83) and a reduction in risk in the second 6 months (HR (95% CI) 0.45 (0.26, 0.77), P=0.003). Mediation analysis will investigate whether changes in LDL-C, apoB, Lp(a) and HDL-C contribute to the reduction in cardiovascular events. Conclusion(s): Treatment of high cardiovascular risk patients with obicetrapib resulted in a decrease in LDLC, apoB and Lp(a), increase in HDL-C and a reduction in coronary events, which became evident beyond 6 months of treatment. This highlights the potential for obicetrapib to be a useful adjunctive therapy to lower cardiovascular risk.