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In a randomized trial involving patients at high cardiovascular risk, the cholesteryl ester transfer protein inhibitor obicetrapib reduced low-density lipoprotein cholesterol levels by 29.9% at 84 days.

A novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia. This study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non–HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease. In this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥200 mg/dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events. In the 627 subjects in the intention to treat sample, non–HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (–3.9% and –6.9%, respectively) compared with OO (–0.9%) (both, P < 0.05), as were TG levels (–14.6% and –20.6%, respectively, vs –5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) (P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d. OM3-FFA was well tolerated and lowered non–HDL-C and TG levels at both 2- and 4-g/d dosages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental improvements compared with 2 g/d. ClinicalTrials.gov identifier: NCT01408303.

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half‐life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre‐clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13‐week recovery period. In healthy humans receiving 1–25 mg of obicetrapib, the mean terminal half‐life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6‐fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post‐treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half‐life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.

IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction. RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117. Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were –66·2% for the 7·5 mg group, –77·7% for the 15 mg group, and –87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. Novo Nordisk.

Global guidelines for the management of high-cardiovascular-risk patients include aggressive goals for low-density lipoprotein cholesterol (LDL-C). Statin therapy alone is often insufficient to reach goals and nonstatin options have limitations. Here, we tested the lipid-lowering effects of the cholesteryl ester transfer protein (CETP) inhibitor drug obicetrapib in a randomized, double-blind, placebo-controlled trial in dyslipidaemic patients ( n  = 120, median LDL-C 88 mg dl −1 ) with background high-intensity statin treatment (NCT04753606). Over the course of 8 weeks, treatment with 5 mg or 10 mg obicetrapib resulted in a significant decrease as compared with placebo in median LDL-C concentration (by up to 51%; P  < 0.0001), the primary trial outcome. As compared with placebo, obicetrapib treatment also significantly ( P  < 0.0001) decreased apolipoprotein B (by up to 30%) and non-high-density lipoprotein cholesterol (non-HDL-C) concentration (by up to 44%), and significantly ( P  < 0.0001) increased HDL-C concentration (by up to 165%; the secondary trial outcomes) and had an acceptable safety profile. These results support the potential of obicetrapib to address an unmet medical need for high-cardiovascular-risk patients. In a phase 2 randomized clinical trial, an inhibitor of cholesteryl ester transfer protein (CETP), obicetrapib, lowered low-density lipoprotein cholesterol when administered in conjunction with high-intensity statins, paving the way for studies investigating the effects of obicetrapib on cardiovascular events.

Reducing LDL cholesterol prevents atherosclerotic cardiovascular disease (ASCVD) events. The aim of this study was to evaluate the LDL cholesterol-lowering efficacy of a fixed-dose combination (FDC) of obicetrapib, a CETP inhibitor, and ezetimibe. This randomised, double-blind trial across 48 US sites including hospitals, private and group practices, and independent research centres included participants at least 18 years old with pre-existing or high risk for ASVCD or heterozygous familial hypercholesterolaemia with LDL cholesterol concentrations of 1·8 mmol/L (70 mg/dL) or greater despite maximally tolerated lipid-lowering therapy excluding ezetimibe, or having statin intolerance. Participants were randomly assigned (1:1:1:1) to obicetrapib 10 mg plus ezetimibe 10 mg FDC, obicetrapib 10 mg monotherapy, ezetimibe 10 mg monotherapy, or placebo administered daily for 84 days. The co-primary endpoints in the intention-to-treat population were the percent LDL cholesterol changes in the FDC group compared with placebo, ezetimibe monotherapy, and obicetrapib monotherapy, and the placebo-adjusted change in the obicetrapib monotherapy group. The trial was prospectively registered (NCT06005597) and is completed. Between March 4 and July 3, 2024, 407 participants were randomly assigned. The median age was 68·0 years (IQR 62·0–73·0) and 177 (43%) were female. Mean baseline LDL cholesterol was 2·4 mmol/L, 2·5 mmol/L, 2·6 mmol/L, and 2·5 mmol/L in the placebo (n=102), ezetimibe monotherapy (n=101), obicetrapib monotherapy (n=102), and FDC groups (n=102), respectively. At day 84, percent differences in LDL cholesterol reduction with the FDC were –48·6% (95% CI –58·3 to –38·9) versus placebo, –27·9% (–37·5 to –18·4) versus ezetimibe, and –16·8% (–26·4 to –7·1) versus obicetrapib. Obicetrapib monotherapy decreased LDL cholesterol by 31·9% (22·1 to 41·6) versus placebo. Adverse event rates were similar in the FDC (52 [51%] of 102), obicetrapib (55 [54%] of 102), and ezetimibe (54 [53%] of 101) groups and lowest with placebo (38 [37%] of 102). Serious adverse event rates were generally similar across FDC (three [3%] of 102), obicetrapib (six [6%] of 102), ezetimibe (seven [7%] of 101), and placebo (four [4%] of 102) groups. Deaths occurred in one [1%] of 102 participants with FDC, one [1%] of 102 with obicetrapib, one [1%] of 101 with ezetimibe, and none with placebo. Combination therapy of obicetrapib and ezetimibe significantly reduced LDL cholesterol. This oral, single-pill therapy could improve LDL cholesterol management in patients with pre-existing or high risk for ASCVD. NewAmsterdam Pharma.

Background Cholesteryl ester transfer protein (CETP) regulates lipid metabolism, mediating the transfer of cholesteryl esters and triglycerides between LDL and HDL cholesterol particles. The CETP inhibitor, obicetrapib, reduces LDL‐C and increases HDL‐C. Genetic evidence and preclinical studies suggest that CETP inhibition might mitigate dementia and Alzheimer’s disease (AD) risk, particularly in individuals carrying the APOE4 allele. Dysfunctional cholesterol transport is a hallmark of AD, characterized by impaired lipidation of ApoE particles leading to neuroinflammation and neurodegeneration. Methods BROADWAY study (NCT05142722), a Phase 3, double‐blind, placebo‐controlled trial evaluated obicetrapib 10 mg daily versus placebo over 12 months in individuals with established atherosclerosis cardiovascular disease. Participants (n =1727) were randomized 2:1 to treatment with obicetrapib or placebo. Plasma lipid levels including LDL‐C and HDL‐C were measured at baseline and at 12 months. AD plasma biomarkers, p ‐tau217, p ‐tau181, GFAP, NFL, and p ‐tau217/Aβ42:Aβ40 ratio, were also assessed at both time points. APOE status was determined. Results The mean age of participants was 65 years, 33% were female. Obicetrapib significantly lowered LDL‐C by 33% and increased HDL‐C by 125% relative to placebo. Obicetrapib demonstrated significant attenuation of increase in the median plasma p ‐tau217 (1.1% obicetrapib vs. 4.8% with placebo; p =0.01) and p ‐tau217/Aβ42:Aβ40 ratio (2.7% obicetrapib vs. 6.5% placebo; p =0.006). At baseline, p ‐tau217 levels were higher in ApoE4 carriers compared with non‐carriers (0.47 pg/ml vs 0.39 pg/ml; (p <0.0001). ApoE4 carriers (n =367) showed greater benefit, with obicetrapib stabilizing p ‐tau217 levels (0% increase vs. 5.7% with placebo; p =0.03) and limiting increases in the p ‐tau217/Aβ42:Aβ40 ratio (2.1% vs. 10.2% placebo; p =0.005). Other AD biomarkers (p ‐tau181, GFAP, NFL) showed consistent favorable trends. Conclusions This very large biomarker study showed that obicetrapib significantly slowed the progression of AD biomarkers over a period of 1 year, particularly p ‐tau217 and p ‐tau217/Aβ42:Aβ40 ratio, with most pronounced effects in older individuals carrying the APOE4 allele. These findings support the dual therapeutic potential of obicetrapib in addressing both cardiovascular and neurodegenerative disorders. Given its effects on the early evolution of β‐amyloid and tau pathology, obicetrapib represents a potential advancement in the prevention of AD, particularly in ApoE4 carriers who have an increased risks for both cardiovascular and AD pathologies.

Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a), and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2,532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.

Cholesteryl ester transfer protein (CETP) regulates lipid metabolism, mediating the transfer of cholesteryl esters and triglycerides between LDL and HDL cholesterol particles. The CETP inhibitor, obicetrapib, reduces LDL-C and increases HDL-C. Genetic evidence and preclinical studies suggest that CETP inhibition might mitigate dementia and Alzheimer's disease (AD) risk, particularly in individuals carrying the APOE4 allele. Dysfunctional cholesterol transport is a hallmark of AD, characterized by impaired lipidation of ApoE particles leading to neuroinflammation and neurodegeneration. BROADWAY study (NCT05142722), a Phase 3, double-blind, placebo-controlled trial evaluated obicetrapib 10 mg daily versus placebo over 12 months in individuals with established atherosclerosis cardiovascular disease. Participants (n =1727) were randomized 2:1 to treatment with obicetrapib or placebo. Plasma lipid levels including LDL-C and HDL-C were measured at baseline and at 12 months. AD plasma biomarkers, p -tau217, p -tau181, GFAP, NFL, and p -tau217/Aβ42:Aβ40 ratio, were also assessed at both time points. APOE status was determined. The mean age of participants was 65 years, 33% were female. Obicetrapib significantly lowered LDL-C by 33% and increased HDL-C by 125% relative to placebo. Obicetrapib demonstrated significant attenuation of increase in the median plasma p -tau217 (1.1% obicetrapib vs. 4.8% with placebo; p =0.01) and p -tau217/Aβ42:Aβ40 ratio (2.7% obicetrapib vs. 6.5% placebo; p =0.006). At baseline, p -tau217 levels were higher in ApoE4 carriers compared with non-carriers (0.47 pg/ml vs 0.39 pg/ml; (p <0.0001). ApoE4 carriers (n =367) showed greater benefit, with obicetrapib stabilizing p -tau217 levels (0% increase vs. 5.7% with placebo; p =0.03) and limiting increases in the p -tau217/Aβ42:Aβ40 ratio (2.1% vs. 10.2% placebo; p =0.005). Other AD biomarkers (p -tau181, GFAP, NFL) showed consistent favorable trends. This very large biomarker study showed that obicetrapib significantly slowed the progression of AD biomarkers over a period of 1 year, particularly p -tau217 and p -tau217/Aβ42:Aβ40 ratio, with most pronounced effects in older individuals carrying the APOE4 allele. These findings support the dual therapeutic potential of obicetrapib in addressing both cardiovascular and neurodegenerative disorders. Given its effects on the early evolution of β-amyloid and tau pathology, obicetrapib represents a potential advancement in the prevention of AD, particularly in ApoE4 carriers who have an increased risks for both cardiovascular and AD pathologies.

The systemic bioavailability of free fatty acid (FFA) forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with ethyl ester (EE) forms is dependent on the presence of intestinal lipases and is highest during consumption of high-fat meals. Given that patients with cardiovascular disease are advised to reduce dietary fat intake, potentially lowering the bioavailability and therapeutic benefit, the hypothesis that FFA forms provide for higher bioavailability compared with EE forms under low-fat diet conditions was tested where the pharmacokinetics of the FFA form (Epanova™) were compared with those of an ethyl ester form (Lovaza®) following repeat dosing. Fifty-two healthy male and female subjects were equally allocated to one of two open-label, parallel-group cohorts. Following a Therapeutic Lifestyle Changes diet for a minimum of 7 days, blood samples were drawn for endogenous values for EPA and DHA over a 24-hour period. Subjects were then administered 4 × 1 g capsules of either Epanova (OM3 FFA) or Lovaza (OM3 EE) once daily for 14 days, following which serial blood samples were drawn over a 24-hour period to characterize the bioavailability of EPA and DHA from the respective formulations. In addition, changes from baseline in lipid profile were explored. Systemic bioavailability, as measured by area under the curve from time zero to 24 hours (AUC(0-τ)) and the maximum measured plasma concentrations during the 0-24 hour dosing interval (C(max,ss)) of unadjusted total plasma EPA + DHA were approximately 3-fold and 3.9-fold higher, respectively, for Epanova relative to Lovaza. Following baseline adjustment, the magnitude of difference in bioavailability was approximately 5.8-fold and 6.5-fold higher in AUC(0-τ) and C(max,ss), respectively, for Epanova relative to Lovaza. Serum triglycerides were reduced by a significantly greater extent (P = 0.013) for Epanova relative to Lovaza (21% versus 8%). The bioavailability of the FFA forms of EPA and DHA in Epanova are significantly greater than the bioavailability from the EE forms present in Lovaza under low-fat dietary conditions normally recommended for patients with cardiovascular disease. This increased bioavailability may lead to improved triglyceride-lowering in patients with hypertriglyceridemia.