Abstract
Most patients with heterozygous familial hypercholesterolemia fail to achieve adequate low-density lipoprotein (LDL) cholesterol lowering. Here we carried out a randomized trial to test the safety and efficacy of obicetrapib, a highly selective cholesteryl ester transfer protein inhibitor that lowers LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia and an LDL cholesterol level ≥70 mg dl−1 on maximally tolerated lipid-lowering therapy. The trial enrolled 354 patients (190 women, 164 men) with a mean LDL cholesterol level of 122 mg dl−1 (87% on statins) who were randomized (2:1) to receive obicetrapib 10 mg or placebo daily for 365 days. For the primary endpoint, the change in LDL cholesterol from baseline to day 84, obicetrapib treatment resulted in a placebo-adjusted change in LDL cholesterol of −36.3% (95% confidence interval −42.2% to −30.4%, P < 0.0001). In analyses of secondary endpoints at day 84, treatment with obicetrapib resulted in placebo-adjusted reductions in apolipoprotein B of −24.4%, non-HDL cholesterol of −34.5% and lipoprotein(a) of −45.9%, as well as a placebo-adjusted increase in high-density lipoprotein cholesterol of +138.7%. Obicetrapib was well tolerated. These findings suggest that obicetrapib is an effective therapy for additional lipid lowering in patients with heterozygous familial hypercholesterolemia. ClinicalTrials.gov registration: NCT05425745.
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Data availability
The authors declare that all data supporting the findings of this analysis are available within the article and its Supplementary Information. NewAmsterdam Pharma is committed to sharing, with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. Data requests should be submitted to stephen.nicholls@monash.edu. These requests are reviewed and approved by an independent review and panel on the basis of scientific merit. Researchers can expect a response within 30 business days. Access is subject to approval of a research proposal, execution of a data sharing agreement and compliance with patient privacy regulations. All data provided are anonymized to respect the privacy of patients in accordance with GDPR and in line with applicable laws and regulations.
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Acknowledgements
This study was funded by NewAmsterdam Pharma. We thank all patients who participated in the BROOKLYN trial and the site investigators, coordinators and research staff for their contributions. We acknowledge the independent data monitoring committee for their oversight and the contract research organization Medpace for trial operations support.
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S.J.N. wrote the first draft of the paper. S.J.N., M.D., J.J.P.K. and M.H.D. designed the study. M.D., E.W., A.L.N., D.K. and A.H. coordinated trial operations and data collection. V.B. and M.S. performed the statistical analyses, with M.S. providing statistical oversight. S.J.N., A.J.N. and J.B. supervised site activities and data collection. S.J.N., A.J.N., C.M.B., K.K.R., A.M.N., S.E.N., A.C.G., L.R.B., B.A.F., U.L., M.B., R.M., A.L.C. and M.H.D. enrolled patients and collected data. All authors contributed to data interpretation, critically reviewed and revised the paper and approved the final version for submission. S.J.N. had full access to all trial data and takes responsibility for the integrity of the data and accuracy of the data analysis.
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S.J.N. received grant and/or research support from AstraZeneca, NewAmsterdam Pharma, Amgen, Anthera, Cyclarity, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience; and was a consultant for Abcentra, AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, Daiichi Sankyo, Silence Therapeutics, CSL Seqirus and Vaxxinity. A.J.N. has received research support from AstraZeneca, Amgen, Eli Lilly and Novartis; and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Seqirus, Eli Lilly, GSK, Novartis, Novo Nordisk, Sanofi Pasteur and Vaxxinity. C.M.B. has received grants or research support from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Ionis, Merck, NewAmsterdam Pharma, Novartis, Novo Nordisk, Roche Diagnostic, NIH, AHA and ADA; and is a consultant for 89Bio, Abbott Diagnostics, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Illumina, Ionis, Eli Lilly, Merck, NewAmsterdam Pharma, Novartis, Novo Nordisk and Roche Diagnostic. K.K.R. reports research grants from Amgen, Amarin, Sanofi, Daiichi Sankyo and Ultragenyx to Imperial College London; consultancy to Novartis, Daiichi Sankyo, Kowa, Esperion, Novo Nordisk, MSD, Eli Lilly, Silence Therapeutics, AZ, New Amsterdam Pharma, Bayer, Beren Therapeutics, Cleerly, EmendoBio, Scribe, NodThera, CRISPR, Vaxxinity and Sanofi; fees for lectures from Novartis, BI, AZ, Novo Nordisk, Viatris, Amarin, Sanofi, Amgen, Esperion, Daiichi Sankyo, Dr Reddy’s, Mankind and Macleods Pharma for symposia at international meetings; and holding stock options from NewAmsterdam Pharma, Scribe Therapeutics and Pemi31. A.M.N. has received research support to her institution from Amgen and Esperion; and personal fees for consulting from Amgen, Arrowhead, AstraZeneca, Bayer, Eli Lilly, Esperion, Janssen, Merck, NewAmsterdam, Novartis, Novo Nordisk, Pfizer, Roche and Silence Therapeutics. S.E.N. has received research funding to perform clinical trials from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, Esperion Therapeutics, Medtronic, MyoKardia, NewAmsterdam Pharma, Novartis, Pfizer and Silence Therapeutics. A.C.G. has received research support to her institution from Amgen, Arrowhead, Esperion, Ionis, NewAmsterdam Pharma, Novartis, 89Bio Inc. and Sanofi; and personal fees for consulting from Ionis, NewAmsterdam Pharma, Regeneron and Eli Lilly. L.R.B. reports receiving research grants or consulting fees from Amgen, Sanofi, Novartis, HLS Therapeutics, Ionis and NewAmsterdam Pharma. B.A.F. has received research grants and consulting fees from Amgen, AstraZeneca, CiVi Biopharma, Daiichi Sankyo, DalCor, Eli Lilly, Esperion, Ionis Pharmaceuticals, Krka Pharmaceuticals, Merck, Mylan, NewAmsterdam Pharma, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, The Medicines Company and Viatris. U.L. has received fees for consulting or lectures from Amgen, Boehringer, Daiichi Sankyo, NewAmsterdam Pharma, Novartis, Sanofi; Leipzig University received research funding from Amgen, Daiichi Sankyo, Novartis and Sanofi. M.B. has received grant(s) and/or research support from Amgen, Daiichi Sankyo, Mylan/Viatris and Sanofi; and has served as a consultant and/or received speaker fees from Adamed, Amgen, Exceed Pharma, Daiichi Sankyo, Esperion, Kogen, KRKA, Lilly, MSD, Mylan/Viatris, NewAmsterdam Pharma, Novartis, Novo Nordisk, Polpharma, Sanofi, Teva and Zentiva. R.M. reports institutional research payments from Abbott, Alleviant Medical, Beth Israel Deaconess Medical Center, Concept Medical, Cordis, Elixir Medical, Faraday Pharmaceuticals, Idorsia Pharmaceuticals, Janssen, MedAlliance, MediaSphere Medical, Medtronic, Novartis, Protembis GmbH, RM Global BioAccess Fund Management and Sanofi US Services, Inc.; has received personal fees from Elixir Medical, IQVIA, Medtronic, Medscape/WebMD Global and Novo Nordisk; and has equity in Elixir Medical, Stel and ControlRad (spouse). A.L.C. has received honoraria, lecture fees or research grants from Amarin, Amgen, AstraZeneca, Chiesi, Daiichi Sankyo, Eli Lilly, Esperion, Ionis Pharmaceutical, Medscape, Menarini, MSD, Novartis, Novo Nordisk, Regeneron, Sanofi, Ultragenyx and Viatris. M.S. serves as a consultant for and/or has received research support from Lexicon, Amarin, NewAmsterdam Pharma, Silence, Sanofi, Regeneron and Tourmaline; and receives salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado, which receives or has received research grant/consulting funding between July 2021 and July 2024 from Abbott Laboratories, Agios Pharmaceuticals, Inc., Alexion Pharma Godo Kaisha, Amgen Inc., Anthos Therapeutics, Inc., ARCA biopharma, Inc., Arrowhead Pharmaceuticals, AstraZeneca Pharma India, AstraZeneca UK Ltd, Bayer, Bayer Aktiengesellschaft, Bayer Pharma AG, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute LLC, Bristol Myers Squibb, Cleerly, Inc., Colorado Dept. of Public Health and Environment, Congress Inc., Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc., EPG Communication Holdings Ltd., Esperion Therapeutics, Inc., Faraday Pharmaceuticals, Inc., HeartFlow Inc., Insmed, Ionis Pharmaceuticals, IQVIA Inc., Janssen Pharmaceuticals, Inc., Janssen Research & Development, LLC, Janssen Scientific Affairs LLC, Lexicon Pharmaceuticals, Inc., Medpace, Inc., Medscape, Merck Sharp & Dohme Corp., Nectero Medical, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer, PPD Development, L.P., Prothena Biosciences Limited, Regeneron, Regents of the University of Colorado (aka UCD), Sanifit Therapeutics S.A., Sanofi, Silence Therapeutics PLC, Stanford University, Stealth BioTherapeutics Inc., The Brigham and Women’s Hospital, Thrombosis Research Institute, Tourmaline Bio, Inc., University of Colorado, University of Colorado Denver, University of Pittsburgh, VarmX, Verve Therapeutics and WraSer, LLC. V.B. is an employee of Medpace. M.D., J.J.P.K., E.W., A.L.N., D.K., A.H. and M.H.D. are employees of NewAmsterdam Pharma and hold stocks or options. J.B. declares no competing interests.
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Extended data
Extended Data Fig. 1 Atherogenic Lipid Goal Achievement.
Achievement of treatment goals for LDL cholesterol, non-HDL cholesterol and apoB in patients treated with placebo or obicetrapib at days 84 and 365. The primary endpoint of the study was the percentage change in LDL cholesterol from baseline to day 84. Error bars represent 95% confidence intervals. Sample size: n = 118 (placebo), n = 236 (obicetrapib) representing biological replicates (individual patients). apoB, apolipoprotein B; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
Extended Data Fig. 2 Median LDL cholesterol percent changes in subgroups (demographics).
Least squares mean (95% confidence intervals) treatment group differences in percent changes in LDL cholesterol with obicetrapib at day 84 in patient subgroups of demographics, medical history and statin use. Apo, apolipoprotein; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein. Sample sizes vary by subgroup. All data represent biological replicates (individual patients with heterozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy).
Extended Data Fig. 3 Change in lipid and lipoprotein parameters.
Least squares (LS) mean (95% confidence interval) percent change from baseline in apolipoprotein B (apoB, upper left panel), non-high-density lipoprotein (HDL) cholesterol (upper right panel), HDL cholesterol (lower left panel) and triglycerides (lower right panel) in patients treated with placebo or obicetrapib. Sample size: n = 118 (placebo), n = 236 (obicetrapib) representing biological replicates (individual patients with heterozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy).
Extended Data Fig. 4 Change in lipoprotein(a).
Least square (LS) mean (95% confidence interval) percent change in lipoprotein(a) in patients treated with obicetrapib or placebo (upper left panel) and LS mean placebo-adjusted changes in lipoprotein(a) with obicetrapib at days 84 and 365 (upper right panel). Waterfall plots demonstrating individual percentage change in lipoprotein(a) from baseline in patients treated with placebo or obicetrapib (lower panels). Sample size: n = 118 (placebo), n = 236 (obicetrapib) representing biological replicates (individual patients with heterozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy).
Extended Data Fig. 5 Trough plasma obicetrapib levels.
Median (interquartile range) trough plasma obicetrapib levels in patients treated with obicetrapib at baseline, days 84, 180 and 365 and at 35 days following the last administration of study drug. Sample size: n = 236 (obicetrapib group only). Each data point represents median trough plasma concentration from biological replicates (individual patients) at specified timepoints.
Extended Data Fig. 6 Percent change in NMR lipoprotein measures.
Least squares (LS) mean percent change in concentration of lipoprotein subclasses in patients treated with placebo or obicetrapib. HDL, high-density lipoproteins; IDL, intermediate density lipoproteins; LDL, low-density lipoproteins; VLDL, very low-density lipoproteins. Error bars represent 95% confidence intervals. Sample size: n = 118 (placebo), n = 236 (obicetrapib) representing biological replicates (individual patients with heterozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy).
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Nicholls, S.J., Nelson, A.J., Ditmarsch, M. et al. Obicetrapib in patients with heterozygous familial hypercholesterolemia: the BROOKLYN randomized clinical trial. Nat Med (2026). https://doi.org/10.1038/s41591-025-04179-4
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DOI: https://doi.org/10.1038/s41591-025-04179-4
