Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early Human Studies
- PMID: 40158211
- DOI: 10.1016/j.jacc.2025.03.005
Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early Human Studies
Abstract
Background: The residual cardiovascular risk associated with hypertriglyceridemia and remnant particles supports efforts to develop effective novel therapeutic approaches. Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases, and Mendelian randomization studies associate lower ANGPTL3 activity with lower triglycerides, and lower cardiovascular risk.
Objectives: The aim of this study was to evaluate the impact of solbinsiran, an N-acetylgalactosamine-conjugated small interfering RNA developed to inhibit hepatic translation of ANGPTL3 messenger RNA (mRNA), on ANGPTL3 and lipid levels in preclinical models and humans.
Methods: In preclinical studies, the impact of solbinsiran on ANGPTL3 levels was assessed in mouse and nonhuman primate models. The phase 1 clinical study enrolled participants with mixed dyslipidemia. In the single-ascending-dose study, participants received single subcutaneous doses of solbinsiran (24-960 mg) or matching placebo. In the repeat-dose study, subcutaneous solbinsiran (208 or 480 mg) or matching placebo on days 1 and 29 was evaluated. Safety, pharmacokinetics, and effect on levels of ANGPTL3 and lipid parameters were evaluated over 169 days.
Results: In mice transiently expressing human ANGPTL3, a single dose of solbinsiran reduced hepatocyte ANGPTL3 mRNA expression by 65% vs vehicle-treated mice. In cynomolgus monkeys, mean ± SEM reductions in hepatic ANGPTL3 mRNA expression up to 73% ± 2% (P < 0.0001) and serum ANGPTL3 protein expression up to 69% ± 4% (P < 0.001) were seen vs vehicle-treated monkeys. In humans, a single dose of solbinsiran resulted in dose-dependent mean percentage reductions from baseline in ANGPTL3 up to 86% ± 4%, triglycerides up to 73% ± 7%, low-density lipoprotein (LDL) cholesterol up to 30% ± 16%, non-high-density lipoprotein cholesterol up to 41% ± 12%, and apolipoprotein B up to 30% ± 11%, with sustained effects at higher doses (P < 0.0001 for all). The repeat-dose study demonstrated reductions in ANGPTL3 of 89% ± 6%, triglycerides up to 70% ± 13%, LDL cholesterol up to 42% ± 14%, non-high-density lipoprotein cholesterol up to 46% ± 14%, and apolipoprotein B up to 36% ± 13% (P < 0.0001 for all). Nuclear magnetic resonance lipoprotein analysis demonstrated reductions in the total number of triglyceride-rich lipoprotein and LDL particles with solbinsiran. Adverse events were mostly mild in severity, with similar incidence in solbinsiran- and placebo-treated participants.
Conclusions: Solbinsiran inhibits hepatic ANGPTL3 translation and results in significant reductions in all atherogenic lipoproteins in mixed dyslipidemia. The impact of this approach on cardiovascular outcomes remains to be determined. (A Study of LY3561774 in Participants With Dyslipidemia; NCT04644809).
Keywords: ANGPTL3; LDL-C; dyslipidemia; solbinsiran; triglycerides.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Funding Support and Author Disclosures These studies were funded by Eli Lilly & Company, manufacturer and licensee of LY3561774. Eli Lilly was involved in the study design, data collection, data analysis, and preparation of the manuscript. Dr Ray is supported by the National Institute for Health and Care Research Imperial Biomedical Research Centre. As per Good Publication Practice 2022, all sources of financial support (including disclosure of funding for medical writing services), roles of the funding source or sponsor, roles of the contributors, and conflicts of interest should be disclosed appropriately, even if this information is not requested by the journal. Medical writing assistance was provided by Charlie Bellinger, BSc, and Clare Weston, MSc, of ProScribe–Envision Pharma Group and was funded Eli Lilly & Company. ProScribe’s services complied with international guidelines for Good Publication Practice. Dr Ray has received research grants from Amarin, Amgen, Daiichi-Sankyo, Merck Sharp & Dohme, Pfizer, Regeneron, and Sanofi; and is a consultant for Abbott, Amarin, Amgen, AstraZeneca, Bayer, Biologix Pharma, Boehringer Ingelheim, Cargene Therapeutics, CRISPR, CSL Behring, Eli Lilly & Company, Esperion Therapeutics, Kowa Pharmaceuticals, NewAmsterdam Pharma, Novartis, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Scribe Therapeutics, Silence Therapeutics, Vaxxinity, and Viatris; has received honoraria for lectures from Amarin, Amgen, AstraZeneca, Biologix Pharma, Boehringer Ingelheim, Daiichi-Sankyo, Esperion, Macleod, Novartis, Novo Nordisk, Sanofi, and Viatris; and has stock options from NewAmsterdam Pharma, Pemi 31, and Scribe Therapeutics. Drs Linnebjerg, Michael, Shen, Ma, Lim, Zhen, and Ruotolo are employees and shareholders of Eli Lilly & Company. Drs Dudek, Saxena, and Turanov are employees and shareholders of Novo Nordisk and former employees of Dicerna. Dr Abrams is a former employee of Dicerna. Dr Nicholls has received research support from Amgen, Anthera Pharmaceuticals, AstraZeneca, Cerenis Therapeutics, CSL Behring, Eli Lilly & Company, Esperion Therapeutics, Infraredx, NewAmsterdam Pharma, Novartis, Resverlogix, and Sanofi Regeneron; and is a consultant for Akcea Therapeutics, Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, Eli Lilly & Company, Esperion Therapeutics, Kowa Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sanofi Regeneron, and Takeda.
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