Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

Background: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF).
Objective: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes.
Methods: TRANSLATE-TIMI 70 was a randomized, placebo-controlled trial testing 7 dosing regimens of vupanorsen in 286 adults with hyperlipidemia. A total of 227 patients had HFF measured at baseline and 24 weeks and were included in this analysis.
Results: The median HFF at baseline was 8.5%. Vupanorsen led to dose-dependent relative increases in HFF of up to 76% at 24 weeks (p < 0.001), corresponding to an absolute increase of up to 7.0% at the highest dose (p < 0.001). Increases in HFF were numerically greater in patients who had elevated baseline HFF, body mass index, triglycerides, or diabetes. Vupanorsen also increased liver enzymes in a dose-dependent manner, and changes in HFF were moderately positively correlated with changes in aspartate transaminase (AST) (rho = 0.49, p < 0.001) and alanine transaminase (ALT) (rho = 0.50, p < 0.001).
Conclusion: Vupanorsen, an inhibitor of ANGPTL3 protein synthesis, caused dose-dependent increases in HFF. Increases in HFF were only moderately correlated with elevations in AST and ALT, suggesting that liver enzymes are an imperfect indicator to detect increases in hepatic fat. These results highlight the need to monitor HFF in clinical trials of therapies targeting intracellular ANGPTL3 inhibition, especially those that are targeted to the liver.
Competing Interests: Declaration of competing interest A.Z, S.D.W, J.G.P, S.A.M., X.R., A.J., J.F.K., M.S.S., B.A.B., and N.A.M. are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Saghmos Therapeutics, Inc., Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc., Zora Biosciences. S.D.W. reports grants from Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi; and consulting fees from Arena, AstraZeneca, Aegerion, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St Jude Medical, and Xoma. His spouse, Dr Caroline Fox, is an employee of Merck. C.R.B., M.C., V.R. and S.G.T. are employees and shareholders of Pfizer. S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc, and Sanofi. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. W.W. reports lecture fees from Pfizer, Astra Zeneca, and Boehringer Ingelheim. M.S.S. reports research grant support through Brigham and Women's Hospital from: Abbott; Amgen; Anthos Therapeutics; AstraZeneca; Boehringer Ingelheim; Daiichi-Sankyo; Ionis; Merck; Novartis; Pfizer; Saghmos Therapeutics; Verve Therapeutics. M.S.S. reports consulting for: Amgen; Anthos Therapeutics; AstraZeneca; Beren Therapeutics; Boehringer Ingelheim; Dr. Reddy's Laboratories; Merck; Moderna; Novo Nordisk; Precision BioSciences; Silence Therapeutics. B.A.B. reports grant support through the Brigham and Women's Hospital: Pfizer, Ionis, AstraZeneca, and Abbott Vascular; and consulting/personal fees from Abiomed, CSI, Philips, Abbott Vascular, Servier, DaiichiSankyo, Janssen, and Quark. N.A.M. reports funds through a National Institutes of Health grant (K08HL153950) and is involved in clinical trials with Amgen, Pfizer, Ionis, Novartis, and AstraZeneca without personals fees, payments, or increase in salary. The other authors report no conflicts.
(Copyright © 2023. Published by Elsevier Inc.)