{"title":"Obicetrapib 除 LDL-C 外,还能靶向所有致动脉粥样硬化脂蛋白","authors":"","doi":"10.1016/j.ajpc.2024.100752","DOIUrl":null,"url":null,"abstract":"<div><h3>Therapeutic Area</h3><div>Kidney Disease</div></div><div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":72173,"journal":{"name":"American journal of preventive cardiology","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"OBICETRAPIB TARGETS ALL ATHEROGENIC LIPOPROTEINS BEYOND LDL-C\",\"authors\":\"\",\"doi\":\"10.1016/j.ajpc.2024.100752\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Therapeutic Area</h3><div>Kidney Disease</div></div><div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>\",\"PeriodicalId\":72173,\"journal\":{\"name\":\"American journal of preventive cardiology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.3000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of preventive cardiology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S266666772400120X\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of preventive cardiology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S266666772400120X","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
OBICETRAPIB TARGETS ALL ATHEROGENIC LIPOPROTEINS BEYOND LDL-C
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.