Impact of cholesteryl ester transfer protein inhibitor, obicetrapib, on lipoprotein(a) levels: pooled data from phase iii clinical trials.

Abstract

Background: Increasing evidence implicates lipoprotein(a) [Lp(a)] in the causality of atherosclerotic cardiovascular disease (ASCVD). This has stimulated efforts to develop therapies that lower Lp(a) levels. While all patients with ASCVD require low-density lipoprotein cholesterol (LDL-C) lowering, 50% have Lp(a) levels greater than 50 nmol/L that are likely to promote residual risk. Therapies that lower both LDL-C and Lp(a) in this setting have the potential to produce cardiovascular benefit, since they are both independent risk factors. The highly selective cholesteryl ester transfer protein (CETP) inhibitor, obicetrapib, reduced LDL-C by up to 51% and raised high-density lipoprotein cholesterol (HDL-C) up to 165% in early trials. Purpose(s): Given that the impact of obicetrapib on Lp(a) levels remains to be fully elucidated, a pooled analysis of obicetrapib's Phase III studies was conducted to investigate the impact of obicetrapib on changes in Lp(a) levels in patients with baseline levels greater than 50 nmol/L. Method(s): A pooled analysis was performed of Phase III clinical trials evaluating the impact of obicetrapib on lipid levels including (1) BROADWAY (NCT05142722) evaluating obicetrapib and placebo in patients with heterozygous familial hypercholesterolemia (HeFH) or ASCVD, (2) BROOKLYN (NCT05425745) evaluating obicetrapib and placebo in patients with HeFH and (3) TANDEM (NCT06005597) evaluating the fixed dose combination of obicetrapib, ezetimibe, obicetrapib/ezetimibe and placebo in patients with or at high risk of ASCVD. Median differences in placebo-adjusted percentage and absolute changes in LDL-C and Lp(a) from baseline to day 84 were determined by Hodges- Lehman analyses. Result(s): Patients (n=2538) had median baseline levels of LDL-C of 92 mg/dL and Lp(a) of 42.7nmol/L. Obicetrapib produced placebo-adjusted reductions in LDL-C by 37.4% and 35.0 mg/dL. The correlation between absolute changes in apoB and LDL-C was r=0.88, however the correlation between absolute change in apoB and Lp(a) was r=0.18. In patients with baseline Lp(a) levels >50 but below 150 nmol/L, obicetrapib produced placebo- adjusted percent reductions in Lp(a) by 44.8% and absolute reductions in Lp(a) by 37.4 nmol/L. While patients with baseline Lp(a) > 150 nmol/L demonstrated a lower percentage reduction in Lp(a) with obicetrapib than those with baseline levels between 50 and 150 nmol/L, the absolute reduction in Lp(a) was similar in both groups (-33.1 vs. -37.4 nmol/L). Conclusion(s): Obicetrapib administration results in reductions in levels of both LDL-C and Lp(a). The absolute reduction in Lp(a) was similar in patients with mildly elevated Lp(a) levels, who are unlikely to qualify for administration of RNA targeted Lp(a) lowering agents. These combined effects of obicetrapib on both LDL-C and Lp(a) have the potential to be an effective approach to lowering cardiovascular risk. This is undergoing evaluation in a large cardiovascular outcomes trial.