A Randomized, Parallel, Open-Label, Single-Dose and Multiple-Dose Clinical Trial to Investigate the Pharmacokinetic, Pharmacodynamic, and Safety Profiles of Obicetrapib in Healthy Participants in China.

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open-label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals. The maximum concentration and area under the drug concentration-time curve of obicetrapib from 0 h to infinity increased with dose after all single doses of obicetrapib. After 7 consecutive days of dosing, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively. Primary PK and PD parameters after single- and multiple-dose administration of obicetrapib were similar to those in healthy white participants in previous studies. One participant in the 5 mg dose group experienced a treatment-emergent adverse event of decreased white blood cell and neutrophil counts, which resolved without intervention. In conclusion, these findings support the inclusion of Chinese individuals in the ongoing phase 3 clinical development program of obicetrapib.

Guiding Dyslipidemia Treatment: A Population Pharmacokinetic-Pharmacodynamic Framework for Obicetrapib.

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3-compartment model with 4-compartment transit absorption and first-order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) concentrations. The maximum stimulatory effect of obicetrapib on LDL-C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL-C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL-C and HDL-C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision-making throughout the development lifecycle.

Obicetrapib on top of maximally tolerated lipid-modifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Obicetrapib as an Adjunct to Stable Statin Therapy in Japanese Subjects: Results from a Randomized Phase 2 Trial.

AIMS: Obicetrapib is a highly selective cholesteryl ester transfer protein (CETP) inhibitor shown to reduce low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), when taken as monotherapy and in combination with ezetimibe on a background of statins, in clinical trials predominantly conducted in Northern European/Caucasian participants. We characterized the efficacy, safety, and tolerability of obicetrapib within an Asian-Pacific region population. METHODS: This double-blind, randomized, phase 2 trial examined obicetrapib 2.5, 5, and 10 mg/d, compared with placebo, for 8 weeks as an adjunct to stable statin therapy (atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d) in Japanese men and women who had not achieved 2022 Japan Atherosclerosis Society Guidelines and had LDL-C ＞70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ＞100 mg/dL and triglycerides (TG) ＜400 mg/dL. Endpoints included LDL-C, non-HDL-C, HDL-C, very low-density lipoprotein cholesterol, apolipoproteins, TG, steady state pharmacokinetics (PK) in obicetrapib arms, safety, and tolerability. RESULTS: In the 102 randomized subjects (mean age 64.8 y, 71.6% male), obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C at all doses; responses in the obicetrapib 10 mg group were -45.8%, -29.7%, -37.0%, and +159%, respectively (all p＜0.0001 vs. placebo). The PK profile demonstrated near complete elimination of drug by 4 weeks. Obicetrapib was well tolerated and there were no adverse safety signals. CONCLUSIONS: All doses of obicetrapib taken as an adjunct to stable statin therapy significantly lowered atherogenic lipoprotein lipid parameters, showed near complete elimination of drug by 4 weeks, and were safe and well tolerated in a Japanese population, similar to previous studies of obicetrapib conducted in predominantly Caucasian participants.

Obicetrapib plus ezetimibe as an adjunct to high-intensity statin therapy: A randomized phase 2 trial.

BACKGROUND: Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein particles, and apolipoproteins, when added to high-intensity statin in patients with dyslipidemia. OBJECTIVE: To evaluate the safety and lipid-altering efficacy of obicetrapib plus ezetimibe combination therapy as an adjunct to high-intensity statin therapy. METHODS: This double-blind, randomized, phase 2 trial administered 10 mg obicetrapib plus 10 mg ezetimibe (n = 40), 10 mg obicetrapib (n = 39), or placebo (n = 40) for 12 weeks to patients with LDL-C >70 mg/dL and triglycerides (TG) <400 mg/dL, on stable high-intensity statin. Endpoints included concentrations of lipids, apolipoproteins, lipoprotein particles, and proprotein convertase subtilisin kexin type 9 (PCSK9), safety, and tolerability. RESULTS: Ninety-seven patients were included in the primary analysis (mean age 62.6 years, 63.9% male, 84.5% white, average body mass index of 30.9 kg/m2). LDL-C decreased from baseline to week 12 by 63.4%, 43.5%, and 6.35% in combination, monotherapy, and placebo groups, respectively (p<0.0001 vs. placebo). LDL-C levels of <100, <70, and <55 mg/dL were achieved by 100%, 93.5%, and 87.1%, respectively, of patients taking the combination. Both active treatments also significantly reduced concentrations of non-HDL-C, apolipoprotein B, and total and small LDL particles. Obicetrapib was well tolerated and no safety issues were identified. CONCLUSION: The combination of obicetrapib plus ezetimibe significantly lowered atherogenic lipid and lipoprotein parameters, and was safe and well tolerated when administered on top of high-intensity statin to patients with elevated LDL-C.

Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial.

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.

IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Novo Nordisk.

A Phase 1 Randomized Dose-Escalation Study of a Human Monoclonal Antibody to IL-6 in CKD.

Background: Chronic systemic inflammation is highly prevalent in patients with CKD (measured as an elevated high-sensitivity C-reactive protein, hsCRP) and independently associated with cardiovascular events and all-cause mortality. An IL-6 blocker to suppress inflammation represents a potential novel paradigm to reduce cardiovascular risk in CKD. Methods: A phase 1 trial of ziltivekimab, a fully human mAb against IL-6, was conducted in patients with moderate-to-severe nondialysis-dependent CKD (eGFR of 20-60 ml/min per 1.73 m2) and evidence of chronic inflammation (hsCRP level >2 mg/L over two consecutive measurements). Three cohorts of n=4 (3:1 active:placebo) were blindly randomized to a single dose of ziltivekimab (5 mg, 15 mg, and 50 mg subcutaneous injection), and followed for 12 weeks for safety and pharmacokinetic/pharmacodynamic assessments, with an additional 20 weeks for safety and antidrug antibody assessments. Results: Participants were 67±11 years old; baseline eGFR: 40±13 ml/min per 1.73 m2; baseline hsCRP: 5.0±2.5 mg/L. Dose escalation was approved, and all adverse events were within the expected range for a CKD population with chronic inflammation. No serious adverse events were reported in any active cohort. hsCRP levels were substantially reduced with ziltivekimab. Of participants, 100% achieved suppression of hsCRP to <2 mg/L with the 15 mg and 50 mg dose, and several patients had undetectable levels of hsCRP with the 50 mg dose. The mean t1/2 ranged from of 45 to 65 days. Conclusions: In adults with moderate-to-severe CKD and evidence of chronic inflammation, a single-injection of the IL-6 inhibitor ziltivekimab was safe and highly effective at suppressing hsCRP over 12 weeks.

Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: a randomized, controlled, double-blind trial.

BACKGROUND: This study examined the effects of a mixture of highly bioavailable omega-3 carboxylic acids (OM3-CA) on nuclear magnetic resonance spectroscopy-assessed lipoprotein particle concentrations and sizes and other cardiovascular risk markers in statin-treated patients with fasting triglycerides (TG) ≥ 2.3 mmol/L (200 mg/dL) and <5.6 mmol/L (500 mg/dL) and at high cardiovascular risk. METHODS: After a diet lead-in and statin-stabilization period, 647 patients were randomly assigned to receive capsules of control (olive oil, OO) 4 g/d, OM3-CA 2 g/d (plus OO 2 g/d), or OM3-CA 4 g/d for 6 weeks. RESULTS: Compared with OO, low-density lipoprotein (LDL) particle size was increased with OM3-CA 2 g/d (p < 0.01) and 4 g/d (p < 0.001), and very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) particle sizes were decreased with both OM3-CA dosages vs. OO (p < 0.001 and p < 0.05 for VLDL and HDL, respectively). Total VLDL/chylomicron remnant particle concentration was reduced by 8.5 and 16.0 % with OM3-CA 2 and 4 g/d, respectively, vs. a 6.9 % reduction with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Total HDL particle concentration was also reduced by 1.5 and 3.2 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.6 % increase with OO (at least p < 0.05 for both comparisons). Changes in total LDL particle concentration were not significantly different for OO vs. OM3-CA at either dosage. Apolipoprotein (Apo) CIII levels decreased by 7.6 and 13.1 % with OM3-CA 2 and 4 g/d, respectively, vs. 3.2 % with OO (p < 0.001 for OM3-CA 4 g/d vs. OO). Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass was reduced by 6.2 and 10.7 % with OM3-CA 2 and 4 g/d, respectively, vs. a 0.1 % increase with OO (p < 0.001 for both vs. OO). There were no significant differences between treatments in high-sensitivity C-reactive protein responses. CONCLUSION: OM3-CA were associated with shifts in lipoprotein particle sizes and concentrations, and reductions in Apo CIII and Lp-PLA2, in patients with hypertriglyceridemia while taking a statin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01408303.

Addition of omega-3 carboxylic acids to statin therapy in patients with persistent hypertriglyceridemia.

The incidence of hypertriglyceridemia has grown alongside that of obesity. Statin therapy has been widely recommended for the treatment of dyslipidemias. Omega-3 (OM3) fatty acid concentrates are commonly prescribed concurrently with statins in patients with persistent hypertriglyceridemia for additional lowering of triglyceride and non-HDL cholesterol. The bioavailability of currently available OM3 ethyl ester drugs is limited by their need for hydrolysis by pancreatic lipases, largely stimulated by dietary fat, prior to intestinal absorption. This review will discuss the chemistry, pharmacokinetics and clinical efficacy of a novel OM3 carboxylic acid drug that provides polyunsaturated docosahexaenoic and eicosapentaenoic acids in the free fatty acid form, which is readily absorbed by the intestine. This drug was approved in May 2014 as an adjunct to diet to reduce triglyceride levels in adults with severe (≥500 mg/dl) hypertriglyceridemia.