Funding Yes — NewAmsterdam Pharma Background/Synopsis Low-density lipoprotein cholesterol (LDL-C) is the canonical target to reduce major adverse cardiovascular events (MACE); however, small/medium (S/M) sized LDL particles (LDL-P) are considered highly atherogenic. Objective/Purpose To explore to what extent people with normal LDL-C levels but discordantly high counts of S/M LDL-P are at increased risk of major adverse cardiovascular events (MACE). Methods Nightingale nuclear magnetic resonance (NMR) metabolomics were available for 274,276 United Kingdom Biobank participants. Discordancy was defined as LDL-C below 2.6/1.8 mmol/L (with/without ASCVD history) and S/M LDL-P above 500 nmol/L, stratified by apolipoprotein B (apoB) >0.9 g/L. Cox's proportional hazards regression was used to estimate hazard ratios for incident MACE. Results Positive control hazard ratios (HRs) for incident MACE included: elevated LDL-C HR 1.03 (95% CI 1.01–1.05), elevated ApoB 1.11 (95% CI 1.09–1.14), and elevated S/M LDL-P 1.10 (95% CI 1.07–1.12). The HR for S/M LDL-P discordance (7321 people) was 1.12 (95% CI 1.06–1.19). People discordant in both S/M LDL-P and ApoB (3570) were at increased risk of MACE (HR 1.19, 95% CI 1.10–1.29), further increased in people with diabetes (1.49, 95% CI 1.18–1.89). Conclusions People with normal LDL-C levels but double discordant for ApoB and S/M LDL-P are significantly more at risk for MACE, especially when diabetic.Figures/Tables: 1

Background:Obicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that lowers LDL-C and raises HDL-C. Although prior studies have demonstrated efficacy and general tolerability, a comprehensive evaluation of its safety profile across later-stage clinical trials is needed. Methods:Safety outcomes were assessed in a pooled analysis of two phase III trials comparing obicetrapib 10 mg daily with placebo in adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD). Participants received treatment for 365 days. Safety endpoints included treatment-emergent adverse events (TEAEs) and prespecified events of special interest including hepatic, muscular, glycemic, renal and ocular parameters as well as overall rates of discontinuation. Results:A total of 2,880 participants were included (mean age 64 years; 36 % female; 82 % with ASCVD; 35.8 % with diabetes). Overall TEAE rates were similar between obicetrapib and placebo (60.2 % vs 62.0 %). AEs leading to treatment discontinuation occurred in 4.1 % of obicetrapib-treated participants and 5.3 % on placebo, Risk Ratio (RR) 0.77 [0.54-1.08]. No clinically significant change in blood pressure was observed between groups and hypertension events were comparable. There was no difference between the groups in liver or muscle-related endpoints. Reduction in eGFR occurred less often with obicetrapib ( compared to placebo (6.7 % vs. 8.7 % RR 0.77 [0.59, 1.00])). Macular degeneration was reported once in the obicetrapib group (n= 1 [0.1 %]). Deaths were similar between treatment groups. No new safety signals were identified. Conclusions:Obicetrapib demonstrated a favorable safety profile over 12 months, with AE rates comparable to placebo. These findings extend our understanding of the safety and tolerability of obicetrapib.

Funding Yes — NewAmsterdam Pharma Previously Published Yes — Accepted at ACC 2026 Background/Synopsis Patients with cardiovascular disease are at increased risk for chronic kidney disease (CKD) progression. High-density lipoprotein (HDL) dysfunction has been implicated in renal decline. Cholesterol ester transfer protein (CETP) inhibition raises high-density lipoprotein cholesterol (HDL-C) and may restore beneficial HDL functions that support kidney health. Objective/Purpose To evaluate the renal effects of obicetrapib in high-risk cardiovascular patients by measuring 365-day changes in estimated glomerular filtration rate (eGFR) and albuminuria. Methods BROADWAY was a multinational, double-blind, placebo-controlled Phase III trial enrolling 2530 patients with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD). Participants were randomized to obicetrapib 10 mg daily or placebo for 365 days on maximally tolerated lipid-lowering therapy. Results Participants had baseline eGFR 84.2 ± 18.0 mL/min/1.73m² and median albumin-to-creatinine ratio (ACR) 11.0 mg/g. Annualized eGFR decline was 0.27 vs 1.19 mL/min/1.73m² (difference 0.92; 95% CI 0.13–1.71; P = 0.023). Progression to advanced CKD occurred in 0.8% vs 1.5%. Moderate eGFR decline (≥25%) in 6.8% vs 8.3%. Albuminuria progression was numerically lower (+9.0 vs +13.8 mg/g). No dialysis or kidney transplantation was required. Conclusions CETP inhibition with obicetrapib preserved kidney function over 1 year in high cardiovascular (CV) risk patients, suggesting potential renoprotective effects through restoration of HDL-related kidney-protective mechanisms.

Funding Yes — NewAmsterdam Pharma Previously Published Yes — Under consideration at ACC 2026 Background/Synopsis Obicetrapib is a potent oral, selective cholesterol ester transfer protein (CETP) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) and raises high-density lipoprotein cholesterol (HDL-C). A comprehensive understanding of its safety profile is needed. Objective/Purpose To evaluate the safety profile of obicetrapib 10 mg in a pooled analysis of 2 Phase III trials. Methods Pooled analysis of 2 Phase III trials enrolling patients with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic cardiovascular disease (ASCVD) over 365 days. Safety endpoints included treatment-emergent adverse events (TEAEs) and prespecified events of special interest (ESI). Results Among 2880 participants (mean age 64 years; 36% female; 82% ASCVD; 35% diabetes), overall TEAE frequency was similar in obicetrapib (60.2%) vs placebo (62.0%). Adverse events (AEs) leading to discontinuation were 4.1% vs 5.3%. Dizziness, headache, hypertension, and myalgia were infrequent. New-onset diabetes mellitus, worsening glycemic control, and estimated glomerular filtration rate (eGFR) decline occurred less often with obicetrapib. Macular degeneration was rare (1 patient, 0.1%). Conclusions Obicetrapib was well tolerated, supporting its potential as an adjunct therapy for ASCVD or HeFH patients needing additional lipid-lowering options.Figures/Tables: 1

Background and aims Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) is the cornerstone in the prevention of coronary artery disease (CAD) but may also increase risk of type 2 diabetes (T2D). A comprehensive examination of the genetic evidence of T2D related side-effects of all current lipid-modifying drugs, including those in development, has not yet been performed.Methods This cis-Mendelian randomization study used individual level data from the UK Biobank, Lifelines, and publicly available genome-wide association data. We identified loci that are either targeted directly with drugs, or alternatively, targeting their gene products (mRNA and/or protein). Included are, in alphabetical order, the loci ACLY, ANGPTL3, ANGPTL4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9. We used cis-genetic instruments weighted for LDL-C, HDL-C, triglycerides, and apolipoproteins as downstream proxies for the drug targets. Main outcomes were prevalent and incident T2D, with CAD as a contrast outcome.Results Lipid modification through HMGCR is predicted to reduce CAD risk and increase T2D risk. Modification through targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 is predicted to reduce CAD risk without a change in T2D risk. Modification through ANGPTL4 and CETP is predicted to reduce risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, we found evidence for neither CAD nor T2D.Conclusions This study provides genetic evidence for variation in diabetes-related side-effects of different lipid-modifying drugs, with potential relevance for future clinical trials and individual treatment decisions.

Background Patients with cardiovascular disease have increased risk of chronic kidney disease progression. Low levels of high-density lipoprotein (HDL) or HDL dysfunction have been implicated in progressive deterioration of renal function. We investigated the impact on renal function of obicetrapib, a cholesteryl ester transfer protein (CETP) inhibitor that raises apolipoprotein A1 and HDL cholesterol (HDL-C) and improves HDL function. Methods BROADWAY (N = 2530) and BROOKLYN (N = 354) were double-blind, placebo-controlled trials of patients with heterozygous familial hypercholesterolemia and/or established atherosclerotic cardiovascular disease taking maximally tolerated lipid-lowering therapy assigned to 365-day treatment with the novel CETP inhibitor, obicetrapib 10 mg/d, or placebo. In a post hoc pooled trial analysis of randomized participants with at least 1 post-baseline renal assessment (estimated glomerular filtration rate [eGFR] n = 2832; urine albumin-to-creatinine ratio [UACR] n = 1897), renal function and its association with HDL-C were evaluated. Results Participants in BROADWAY and BROOKLYN had mean (±SD) baseline eGFR 84.4 ± 17.9 and 91.8 ± 17.8 mL/min/1.73 m² and median albumin-to-creatinine ratio 11.0 and 8.0 mg/g, respectively. Obicetrapib attenuated kidney function decline vs placebo (mean difference = 0.67 mL/min/1.73 m², nominal P = 0.02); on-treatment analysis strengthened this signal (0.82; nominal P = 0.0139). Obicetrapib-treated patients had nominally fewer cases of eGFR <15 mL/min/1.73 m2 (0 vs 0.2 %),≥40 % eGFR declines (1.3 vs 1.9 %), and a renal events composite (1.9 vs 3.0 %; hazard ratio 0.64, nominal P = 0.08). Higher achieved HDL-C was associated with lower renal composite event risk (spline nominal P < 0.0001), independent of baseline HDL-C and eGFR. Annualized percent change in UACR was not significantly different between groups. Conclusion In patients at high cardiovascular risk, CETP inhibition with obicetrapib may attenuate kidney function decline, potentially through its HDL-raising effects.

Funding Yes — NewAmsterdam Pharma Previously Published Yes — Submitted to ACC 2026 Background/Synopsis In Phase 3 studies, obicetrapib (OBI) significantly reduced low)-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] and was associated with a reduction in major adverse cardiovascular event (MACE). The extent to which these lipoprotein reductions contribute to obicetrapib's effect on MACE remains unknown. Objective/Purpose To determine the degree to which LDL-C and Lp(a) reductions mediate obicetrapib's effect on MACE. Methods Mediation analysis using pooled BROADWAY and BROOKLYN data (2884 participants with atherosclerotic cardiovascular disease [ASCVD] or heterozygous familial hypercholesterolemia [HeFH]). Time-weighted achieved concentrations in LDL-C and log-transformed Lp(a) were related to MACE risk in proportional hazard models. Results Obicetrapib reduced MACE by 23% (HR 0.77, 95% CI 0.54–1.11; P = 0.16). LDL-C and Lp(a) were significant mediators individually and jointly mediated 84.5% of the obicetrapib effect on MACE. Conclusions Most of the obicetrapib benefit on MACE was attributable to reductions in LDL-C; reductions in Lp(a) also contributed meaningfully to its effect on MACE.Figures/Tables: 1

Setting:Prior to a cardiovascular outcomes trial (CVOT), novel cholesterol-lowering therapies undergo phase 2/3 studies for their lipid and atherosclerotic effects and safety (non-CVOTs). Since the occurrence of major adverse cardiovascular events (MACE) is part of the safety assessment, nominal reductions or increases may be observed prior to definitive testing of the effect in a CVOT. Study objective:To investigate if the observed MACE treatment effect in non-CVOT lipid-lowering registration studies holds value in predicting the outcome in a CVOT trial, typically reported later than the initial lipid-lowering studies. Design/participants/interventions:We reviewed recent development programs for cholesterol-lowering drugs that had completed non-CVOT and CVOT studies. MACE data were compared for phase 2/3 non-CVOT versus pivotal CVOT results. Main outcome measures:Our primary outcome was a qualitative comparison for directionally concordant consistency in MACE risk ratio treatment effects (harm, neutrality, or benefit). Correlation analysis was also performed. Results:Seven drugs were reviewed in 3 cholesterol-lowering classes: CETP inhibitors, bempedoic acid, and PCSK9 inhibitors. Concordance in non-CVOT vs CVOT results was seen in 6 of 7 drugs. One drug (dalcetrapib) had a trend for benefit observed, albeit with very small numbers, in early development, but showed a neutral CVOT. There was a moderate correlation between the risk reductions or increases from the non-CVOTs and CVOTs: r = 0.69, p = 0.0893. Conclusion:Within the limitations of the drugs studied and the variability in MACE definitions, there is value in the results of non-CVOTs to predict the CVOT outcome.

We recently showed that patients with atherosclerotic cardiovascular disease (ASCVD) carry a substantial but largely unrecognized burden of early Alzheimer's disease (AD) pathology. In the BROADWAY pivotal phase 3 lipid-lowering trial, nearly half of participants with high-risk ASCVD had plasma p-tau217 concentrations above thresholds associated with preclinical AD, yet none had undergone evaluation for cognitive impairment. In this population, apolipoprotein E ε4 (APOE4) carriers were disproportionately represented among those with the highest p-tau217 levels. These findings expose a critical gap between cardiovascular care and dementia prevention and raise the question whether interventions targeting shared pathophysiology could address both conditions simultaneously.Cholesteryl ester transfer protein (CETP) inhibition has emerged as a candidate for this dual role. In BROADWAY, obicetrapib reduced p-tau217 progression across the study population, with effects most pronounced in APOE4 carriers. In fact, treatment differences favoring obicetrapib were observed across all measured AD biomarkers in high-risk subgroups, including neurofilament light chain, glial fibrillary acidic protein, and the amyloid-beta (Aβ) 42:40 ratio. Unlike approaches that target downstream pathology, such as amyloid plaques already deposited in the brain or the inflammatory consequences of established disease, CETP inhibition may address the upstream processes involved in initiating the pathological cascade: lipid dysregulation, cholesterol ester accumulation in glial cells, impaired cholesterol efflux, lipid peroxidation, oxysterol formation, and deficient antioxidant transport.This review examines the biological rationale linking APOE4 status to disordered lipid metabolism in both peripheral and central compartments, the genetic and epidemiological evidence supporting CETP as a therapeutic target, the mechanisms through which CETP inhibition might confer neuroprotection, and the clinical data suggesting obicetrapib as the first oral agent associated with favorable changes in AD biomarkers across both amyloid and tau axes in individuals at high genetic risk for the development of AD.

The selective cholesteryl ester transfer protein (CETP) inhibitor obicetrapib is in clinical evaluation for dyslipidemia and cardiovascular risk reduction. This study investigated how obicetrapib alone and with ezetimibe reduces non-HDL-C, affects atherosclerotic lesion progression, and regression when added to background atorvastatin intervention. APOE∗3-Leiden.CETP mice received a Western-type diet (WTD) or this diet supplemented with obicetrapib, ezetimibe, or both. After 8 weeks, all interventions reduced non-HDL-C levels (obicetrapib: -53%; ezetimibe: -19%; combination: -75%). Obicetrapib mono and combination treatment blocked CETP activity (-99% and -98%), thereby increasing HDL-C levels (+286% and +256%). Very low-density lipoprotein (VLDL) cholesterol production was not affected, while obicetrapib and the combination with ezetimibe increased VLDL clearance (plasma half-life [14C]-cholesteryloleate: -44% and -57%) and LDL receptor expression (+63% and +74%), without increasing liver lipids. Atherosclerosis progression was evaluated after 28 weeks. All interventions reduced atherosclerotic lesion area (obicetrapib: -90%; ezetimibe: -50%; combination: -98%) and severity due to almost complete reductions in severe lesions (obicetrapib: -80%; combination: -98%). Non-HDL-C exposure (P < 0.001) was independently associated with lesion area, in contrast to HDL-C (P = 0.336). Combination treatment synergistically reduced non-HDL-C and atherosclerosis. For atherosclerosis regression, mice with advanced and established atherosclerosis received obicetrapib and ezetimibe on top of atorvastatin for 24 weeks. Triple therapy regressed lesion area (-44% vs. baseline) and increased healthy vessel segments, indicating potential for complete atherosclerosis resolution. In summary, obicetrapib, alone or combined with ezetimibe, lowers non-HDL cholesterol by enhancing LDL receptor-mediated VLDL clearance, thereby synergistically reducing atherosclerosis progression, while triple treatment with atorvastatin induces regression of established atherosclerotic lesions.

Funding Yes — NewAmsterdam Pharma Previously Published Yes — Submitted to EAS 2026 Background/Synopsis Obicetrapib, a highly selective cholesterol ester transfer protein (CETP) inhibitor in Phase III development for dyslipidemia, requires pharmacokinetic characterization in hepatic impairment for informed clinical use. Objective/Purpose To assess how moderate hepatic impairment affects the pharmacokinetics, safety, and tolerability of obicetrapib. Methods Phase I, open-label, parallel-group study (NCT06048302) enrolling participants with moderate hepatic impairment (Class B, Modified Child-Pugh; mean score 7.7; n = 10) and matched healthy controls (n = 8). All received a single 10 mg oral dose on Day 1, with blood sampling through 168 hours post-dose. Results Compared with healthy participants, those with moderate hepatic impairment exhibited lower Cmax (geometric mean ratio 71.58; 90% CI 60.23–85.07) and higher area under curve (AUC)(AUC0-last 111.25; 90% CI 90.12–137.34). Median time to Cmax was similar (6.0 h vs 5.5 h). Obicetrapib was safe and well tolerated in both groups. Conclusions Moderate hepatic impairment modestly increased obicetrapib exposure without affecting time to peak concentration. No dose adjustment is anticipated.

Funding NewAmsterdam Pharma. Background/Synopsis Increasing evidence implicates lipoprotein(a) [Lp(a)] in the causality of atherosclerotic cardiovascular disease (ASCVD). This has stimulated efforts to develop therapies that lower Lp(a) levels. While all patients with ASCVD require low-density lipoprotein cholesterol (LDL-C) lowering, 50% have Lp(a) levels greater than 50 nmol/L that are likely to promote residual risk. Therapies that lower both LDL-C and Lp(a) in this setting have the potential to produce cardiovascular benefit, since both are independent risk factors. The highly selective cholesteryl ester transfer protein (CETP) inhibitor, obicetrapib, reduced LDL-C by up to 51% and raised high-density lipoprotein cholesterol (HDL-C) up to 165% in early trials. The impact of obicetrapib on Lp(a) levels remains to be fully elucidated. Purpose Our analysis investigated the impact of obicetrapib on changes in Lp(a) levels in patients with baseline levels greater than 50 nmol/L. Methods A pooled analysis was performed evaluating the impact of obicetrapib on lipid levels which included the following clinical trials: (1) BROADWAY- evaluating obicetrapib and placebo in patients with heterozygous familial hypercholesterolemia (HeFH) or ASCVD, (2) BROOKLYN - evaluating obicetrapib and placebo in patients with HeFH and (3) TANDEM - evaluating the fixed dose combination of obicetrapib, ezetimibe, obicetrapib/ezetimibe and placebo in patients with or at high risk of ASCVD. Median differences in placebo-adjusted percentage and absolute changes in LDL-C and Lp(a) from baseline to day 84 were determined by Hodges-Lehman analyses. Results Patients (n=2538) had median baseline levels of LDL-C of 92 mg/dL and Lp(a) of 42.7 nmol/L. Obicetrapib produced placebo-adjusted reductions in LDL-C by 37.4% and 35.0 mg/dL. The correlation between absolute changes in apoB and LDL-C was r=0.88, however, the correlation between absolute change in apoB and Lp(a) was r=0.18. In patients with baseline Lp(a) levels ≥50 but below 150 nmol/L, obicetrapib produced placebo-adjusted percent reductions in Lp(a) by 44.8% and absolute reductions in Lp(a) by 37.4 nmol/L. While patients with baseline Lp(a) ≥150 nmol/L demonstrated a lower percentage reduction in Lp(a) with obicetrapib than those with baseline levels between 50 and 150 nmol/L, the absolute reduction in Lp(a) was similar in both groups (-33.1 vs. -37.4 nmol/L). (Table) Conclusion Obicetrapib administration results in reductions in levels of both LDL-C and Lp(a). The absolute reduction in Lp(a) was similar in patients with mildly elevated Lp(a) levels, who are unlikely to qualify for administration of RNA targeted Lp(a) lowering agents. The combined effects of obicetrapib on both LDL-C and Lp(a) have the potential to be an effective approach to lowering cardiovascular risk and is undergoing evaluation in a large cardiovascular outcomes trial.

BACKGROUND:Obicetrapib is a highly selective cholesteryl ester transfer protein inhibitor that reduces low-density lipoprotein (LDL) cholesterol levels. The efficacy and safety of obicetrapib have not been fully characterized among patients at high risk for cardiovascular events. METHODS:We conducted a multinational, randomized, placebo-controlled trial involving patients with heterozygous familial hypercholesterolemia or a history of atherosclerotic cardiovascular disease who were receiving maximum tolerated doses of lipid-lowering therapy. Patients with an LDL cholesterol level of 100 mg per deciliter or higher or a non-high-density lipoprotein (HDL) cholesterol level of 130 mg per deciliter or higher, as well as those with an LDL cholesterol level of 55 to 100 mg per deciliter or a non-HDL cholesterol level of 85 to 130 mg per deciliter and at least one additional cardiovascular risk factor, were eligible for inclusion. The patients were randomly assigned in a 2:1 ratio to receive either 10 mg of obicetrapib once daily or matching placebo for 365 days. The primary end point was the percent change in the LDL cholesterol level from baseline to day 84. RESULTS:A total of 2530 patients underwent randomization; 1686 patients were assigned to receive obicetrapib and 844 to receive placebo. The mean age of the patients was 65 years, 34% were women, and the mean baseline LDL cholesterol level was 98 mg per deciliter. The least-squares mean percent change from baseline to day 84 in the LDL cholesterol level was -29.9% (95% confidence interval [CI], -32.1 to -27.8) in the obicetrapib group, as compared with 2.7% (95% CI, -0.4 to 5.8) in the placebo group, for a between-group difference of -32.6 percentage points (95% CI, -35.8 to -29.5; P<0.001). The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS:Among patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia who were receiving maximum tolerated doses of lipid-lowering therapy and were at high risk for cardiovascular events, obicetrapib reduced LDL cholesterol levels by 29.9%. (Funded by NewAmsterdam Pharma; BROADWAY ClinicalTrials.gov number, NCT05142722.).

Funding Analyses funded by NewAmsterdam Pharma. Background/Synopsis HDL plays a role in the transport of lipophilic antioxidants but it is not yet understood how the CETP inhibitor obicetrapib impacts the distribution of lipophilic antioxidants in various lipoprotein fractions of the blood. Objective/Purpose We measured the concentration and distribution of lipophilic antioxidants in lipoproteins isolated from patients receiving a low dose of obicetrapib in a phase II study (ClinicalTrials.gov ID NCT05421078). Methods Patients were randomly assigned to one of four groups: placebo or obicetrapib 2.5, 5, or 10 mg per day for a 8-week treatment period. Two HDL subclasses (HDL2 and HDL3) were separated from non-HDL (LDL + VLDL) and protein fractionation was done with a TLA-100.4 rotor. Lipophilic antioxidants were quantified by UPLC MS-MS. Samples were obtained before treatment (V2), and after 2 weeks (V3) and 8 weeks (V5) of treatment. Results ApoA1, pre-beta1HDL (mApoA1), ApoE, cholesterol, and lipophilic antioxidants were unchanged in the ultracentrifugation fractions of plasma from the placebo group.In the HDL2 fraction, obicetrapib increased ApoA1 by 265.0% and 355.02% at V3 and V5, mApoA1 by 337.7% and 376.95% at V3 and V5, and cholesterol by 172.4% and 301.92% at V3 and V5 (all p < 0.0001). Obicetrapib treatment also increased cholesterol in HDL3 fraction by 26.1% and 49.7% at V3 and V5 (p = 0.062 and p = 0.0008).In the HDL2 fraction, obicetrapib increased lutein by 201.8% and 245.79% at V3 and V5 (p = 0.0033 and p = 0.0002), zeaxanthin by 202.5% and 301.97% at V3 and V5 (p < 0.0001 for both), and α-Tocopherol by 250.3% and 258.22% at V3 and V5 (p < 0.0001 for both). Obicetrapib treatment did not modify the amount of lutein or α-Tocopherol measured in the non-HDL, HDL3 and protein fractions.Obicetrapib treatment decreased (non-significantly) S1P in the non-HDL and protein fractions, but markedly increased S1P carried by HDL2 by 266.8% and 517.90% at V3 and V5 (p < 0.0001 for both).Obicetrapib shifted ApoE from the protein fraction (unbound or easily detachable) to the HDL fraction, particularly the HDL2 fraction at V5 (increase of 133.02%, p = 0.047). Unbound ApoE decreased significantly at V2 and V5 (78.1%, p = 0.005; and 65.91%, p = 0.01). Conclusions Obicetrapib treatment raised HDL2 cholesterol and ApoA1 and also shifted important lipophilic antioxidants, S1P, and ApoE to the HDL subfractions. These changes may have important therapeutic implications for CVD, AMD, and AD.Previously Published: Yes, Currently under review at EAS 2025 for presentation. Permission to ENCORE this abstract at NLA.

Funding NewAmsterdam Pharma. Background/Synopsis Obicetrapib is a cholesteryl ester transfer protein inhibitor in phase 3 development for the treatment of patients at risk for cardiovascular disease with elevated LDL-C. Objective/Purpose To investigate, in results from prior trials, the efficacy and safety of a potential fixed dose of obicetrapib with low-dose atorvastatin or rosuvastatin. Methods Two multi-center, randomized, double-blind, placebo-controlled phase 2 trials in the Netherlands and Denmark (TULIP; Hovingh et al. Lancet. 2015;386:452-60) and Japan (Harada-Shiba et al. J Atheroscler Thromb. 2024;31:1386-97) were conducted. TULIP included 364 adults not taking lipid-lowering treatment (or after washout) with LDL-C 96.7-174 mg/dL, HDL-C 30.9-69.6 mg/dL, and triglycerides < 399 mg/dL. For 12 weeks they received 1, 2.5, 5, or 10 mg obicetrapib or matching placebo; or 10 mg obicetrapib + 20 mg atorvastatin, 10 mg obicetrapib + 10 mg rosuvastatin, or 20 mg atorvastatin or 10 mg rosuvastatin alone. In the Japan trial, 102 Japanese adults with LDL-C > 70 mg/dL or non-HDL-C >100 mg/dL and triglycerides < 400 mg/dL while taking atorvastatin 10 or 20 mg/d or rosuvastatin 5 to 10 mg/d for ≥ 8 weeks received 2.5, 5, or 10 mg/d obicetrapib or matching placebo as an adjunct to stable statin for 8 weeks. Lipoprotein lipids and safety were assessed. Results In both trials, all atherogenic lipoproteins were significantly reduced and HDL-C was significantly increased from baseline in all obicetrapib monotherapy and combination therapy arms vs. their respective controls (all p < 0.01). In TULIP, LDL-C changes in the obicetrapib + atorvastatin and obicetrapib + rosuvastatin combination arms were -68.2% and -63.3%, respectively, vs. + 0.75% with placebo (least square means). Other respective changes in the TULIP combination arms and placebo were: ApoB -50.1%, -46.3%, and +1.10%; non-HDL-C -63.6%, -58.5%, and +0.80%; Lp(a) -25.0%,-25.4%, and -1.75%; and HDL-C +152%, +158%, and +2.20%. In the Japan trial, 10 mg obicetrapib + statin, compared to statin alone, significantly lowered LDL-C, ApoB, and non-HDL-C, and raised HDL-C by -45.8%, -29.7%, -37.0%, and +159% (medians), respectively. In both trials, obicetrapib was generally safe and well-tolerated when administered alone and in combination with statins. Conclusion A fixed dose combination of 10 mg obicetrapib with low-dose atorvastatin or rosuvastatin, which likely represents a more attractive treatment option to clinicians and patients than high-intensity statins, is expected to allow patients with dyslipidemia to substantially improve their lipid profile.