OBICETRAPIB TARGETS ALL ATHEROGENIC LIPOPROTEINS BEYOND LDL-C

Abstract

Therapeutic Area: Kidney Disease Background: Despite reductions in low-density lipoprotein cholesterol (LDL-C) with statin and non-statin lipid-lowering therapies, a large proportion of cardiovascular disease (CVD) risk remains. An investigation of 8 large CV outcome trials with statins demonstrated, on average, a relative risk reduction of 25%, leaving the majority of risk unaddressed. Residual risk is due in part to lipid components beyond LDL-C, such as LDL particle (-P) concentration, small dense (sd)LDL-C, and lipoprotein(a) [Lp(a)]. Obicetrapib is a cholesteryl ester transfer protein inhibitor under investigation for reducing atherogenic lipoproteins and CVD events. Methods: ROSE1 (n=120) and ROSE2 (n=119) were phase II trials of obicetrapib on top of high-intensity statins for 8 or 12 weeks and TA-8995-203 (n=102) was a phase II trial of obicetrapib on top of atorvastatin 10/20 mg or rosuvastatin 5/10 mg for 8 weeks in Japanese participants. All trials enrolled men and women without CVD who had LDL-C >70 mg/dL; all included a treatment arm of obicetrapib 10 mg monotherapy. Additionally, ROSE2 combined obicetrapib 10 mg with ezetimibe 10 mg. A complete lipid profile and apolipoprotein (Apo) B were measured in all trials. Additionally, Lp(a) was measured in ROSE1 and ROSE2, and sdLDL-C and nuclear magnetic resonance-assessed lipoprotein subfractions were analyzed in ROSE2. Results: In addition to significantly lowering LDL-C by up to 50.8%, Apo B by up to 29.8%, and non-HDL-C by up to 44.4%, in ROSE2 obicetrapib 10 mg monotherapy compared to placebo significantly decreased total LDL-P, small LDL-P, and sdLDL-C by 54.8%, 92.7%, and 30.9%, respectively. A pooled analysis of Lp(a) demonstrated a placebo-corrected reduction of 57.1%. Obicetrapib plus ezetimibe also significantly reduced total LDL-P (-72.1%), small LDL-P (-95.4%), and sdLDL-C (-44.4%), beyond its significant effects on LDL-C (-63.4%), non-HDL-C (-55.6%), and Apo B (-34.4%). Obicetrapib had an adverse event profile similar to placebo, and it was nearly completely eliminated from circulation within 4 weeks after dosing. Conclusions: By reducing atherogenic lipoproteins beyond LDL-C, obicetrapib monotherapy on top of statins and in combination with ezetimibe represents a promising therapy to address residual lipoprotein-related risk for CVD on top of currently available LDL-C-lowering therapies.