†Synergistic Effect of Obicetrapib and Ezetimibe on Circulating LDL Particles

Study Funding

NewAmsterdam Pharma.

Background/Synopsis

The oral selective cholesteryl ester transfer protein (CETP) inhibitor, obicetrapib, is in development for dyslipidemia in patients unable to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering with other lipid-lowering medications. Previous Phase 1 and 2 trials evaluated obicetrapib as monotherapy, in combination with statins and on top of high-intensity statins (HIS).

Objective/Purpose

In this study we tested the efficacy and safety of obicetrapib in combination with ezetimibe on top of HIS.

Methods

ROSE2 enrolled men and women without current clinically manifest cardiovascular disease who had LDL-C >70 mg/dL and triglycerides <400 mg/dL, while taking HIS. Participants continued their HIS and were randomized to obicetrapib 10 mg + ezetimibe 10 mg (n=40), obicetrapib 10 mg (n=39), or placebo (n=40) for 12 weeks. Endpoints included the LDL-C response to combination therapy vs. placebo (primary), and non-high-density lipoprotein cholesterol (non-HDL-C), nuclear magnetic resonance-assessed lipoprotein particles (-P), apolipoprotein B (ApoB), lipoprotein (a) [Lp(a)], small dense (sd)LDL-C, other lipid biomarkers and safety.

Results

Obicetrapib monotherapy and with ezetimibe, respectively, significantly (all P<0.05) reduced LDL-C (43.5 and 63.4%), non-HDL-C (37.5 and 55.6%), ApoB (24.2 and 34.4%), total LDL-P (54.8 and 72.1%), small LDL-P (92.7 and 95.4%), sdLDL-C (30.9 and 44.4%), and Lp(a) (47.2 and 40.2%), and increased HDL-C (142 and 136%). Obicetrapib was well tolerated, with no dose-related adverse events or clinically significant changes in vital signs, electrocardiograms, hematology or biochemistry. The tremendous lowering of LDL particles with obicetrapib + ezetimibe suggests a synergistic effect perhaps due to an additional mechanism of action (MoA) for CETP inhibition; it upregulates LDL receptors (as previous studies have indicated), but also increases cholesterol removal through transintestinal cholesterol excretion (TICE). Ezetimibe meanwhile prevents reuptake of the excreted cholesterol removed via the inhibition of Niemann-Pick C1-like 1 (Figure).

Conclusions

Obicetrapib monotherapy, in combination with HIS, and with HIS plus ezetimibe is safe, well-tolerated and produces robust reductions in LDL-C, LDL particles, sdLDL-C, and Lp(a). ROSE2 obicetrapib monotherapy results concur with findings across the phase 1/2 development program, while combination therapy results support a synergistic effect of obicetrapib + ezetimibe on circulating LDL particles, consistent with the drugs’ known and hypothesized MoAs.