IMPACT OF THE CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITOR, OBICETRAPIB, ON LIPOPROTEIN(A) LEVELS: POOLED DATA FROM PHASE 3 CLINICAL TRIALS

Abstract

Therapeutic Area

Pharmacologic Therapy

Background

Increasing evidence implicates lipoprotein(a) [Lp(a)] in atherosclerotic cardiovascular disease (ASCVD) causality, stimulating efforts to develop Lp(a) lowering therapies. While all ASCVD patients require low-density lipoprotein cholesterol (LDL-C) lowering, 50% have Lp(a) levels greater than 50 nmol/L, likely to promote residual risk. Therapies lowering LDL-C and Lp(a) have cardiovascular benefit potential since both are 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. Obicetrapib’s impact on Lp(a) levels remains to be fully elucidated.

Methods

To investigate obicetrapib’s Lp(a) changes in patients greater than 50 nmol/L at baseline, a pooled analysis was conducted within (1) BROADWAY (obicetrapib and placebo in heterozygous familial hypercholesterolemia (HeFH) or ASCVD patients), (2) BROOKLYN (obicetrapib and placebo in HeFH patients) and (3) TANDEM (fixed dose combination of obicetrapib, ezetimibe, obicetrapib/ezetimibe and placebo in patients with or at high risk of ASCVD) clinical trials. Median differences in placebo-adjusted percentage and absolute LDL-C and Lp(a) changes from baseline to day 84 were determined by Hodges-Lehman analyses.

Results

Patients (n=2538) had median LDL-C baseline levels of 92 mg/dL and Lp(a) of 42.7 nmol/L. Obicetrapib produced LDL-C placebo-adjusted reductions by 37.4% and 35.0 mg/dL. Correlation between absolute changes in apoB and LDL-C was r=0.88, however, correlation between absolute change in apoB and Lp(a) was r=0.18. In patients with baseline Lp(a) levels ³50 but below 150 nmol/L, obicetrapib produced 44.8% Lp(a) placebo-adjusted percent reductions and 37.4 nmol/L absolute reductions in Lp(a). While patients with baseline Lp(a) ³150 nmol/L demonstrated lower percentage reduction in Lp(a) with obicetrapib than those with baseline levels between 50 and 150 nmol/L, absolute reduction in Lp(a) was similar in both groups (-33.1 vs. -37.4 nmol/L). (Table).

Conclusions

Obicetrapib reduced both LDL-C and Lp(a). 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. Combined effects of obicetrapib on both LDL-C and Lp(a) have potential to be an effective approach to lowering cardiovascular risk and is undergoing evaluation in a large cardiovascular outcomes trial.