Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx: Results of Phase 1 and Phase 2 Studies
- PMID: 34222719
- PMCID: PMC8246029
- DOI: 10.1016/j.jacbts.2021.04.004
Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx: Results of Phase 1 and Phase 2 Studies
Abstract
Targeting angiotensinogen (AGT) may provide a novel approach to more optimally inhibit the renin-angiotensin-aldosterone system pathway. Double-blind, placebo-controlled clinical trials were performed in subjects with hypertension as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with IONIS-AGT-LRx versus placebo up to 2 months. IONIS-AGT-LRx was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function. IONIS-AGT-LRx significantly reduced AGT levels compared with placebo in all 3 studies. Although not powered for this endpoint, trends were noted in blood pressure reduction. In conclusion, IONIS-AGT-LRx significantly reduces AGT with a favorable safety, tolerability, and on-target profile. (A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx; NCT04083222; A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure; NCT03714776; Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ionis AGT-LRx in Healthy Volunteers; NCT03101878).
Keywords: ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; AGT, angiotensinogen; ASO, antisense oligonucleotide; CI, confidence interval; DBP, diastolic blood pressure; EDTA, ethylenediaminetetraacetic acid; GalNAc3, triantennary N-acetyl galactosamine; K+, potassium; PS, phosphorothioate; RAAS; RAAS, renin-angiotensin-aldosterone system; SBP, systolic blood pressure; angiotensinogen; antisense; hepatocyte; hypertension; oligonucleotide.
© 2021 The Authors.
Conflict of interest statement
This work was supported by Ionis Pharmaceuticals. Dr. Tsimikas is a co-inventor of and receives royalties from patents owned by University of California, San Diego, on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins; and is a co-founder and has an equity interest in Oxitope, Inc and its affiliates, Kleanthi Diagnostics, LLC, and Covicept Therapeutics, Inc. Dr. Bakris has been a consultant to Ionis Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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Comment in
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An antisense oligonucleotide to target the RAAS.Nat Rev Cardiol. 2021 Aug;18(8):544. doi: 10.1038/s41569-021-00574-9. Nat Rev Cardiol. 2021. PMID: 34040182 No abstract available.
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