Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May 3;6(6):485-496.
doi: 10.1016/j.jacbts.2021.04.004. eCollection 2021 Jun.

Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx: Results of Phase 1 and Phase 2 Studies

Erin S Morgan  1 , Yvonne Tami  1 , Kuolung Hu  1 , Michela Brambatti  1 , Adam E Mullick  1 , Richard S Geary  1 , George L Bakris  2 , Sotirios Tsimikas  1   3
Affiliations

Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx: Results of Phase 1 and Phase 2 Studies

Erin S Morgan et al. JACC Basic Transl Sci. .

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.

PubMed Disclaimer

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.

Figures

None
Graphical abstract
Figure 1
Figure 1
Mean Percent Changes in AGT Over Time in IONIS-AGT-LRx Versus Placebo in the Monotherapy Study The shaded area represents the dosing window, the arrowheads show the timepoint when the dose was given, and the unshaded area shows the follow-up period. The primary endpoint was at day 43. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001 IONIS-AGT-LRx versus placebo at the specified timepoint. AGT = angiotensinogen.
Figure 2
Figure 2
Mean Percent Changes in AGT Over Time in IONIS-AGT-LRx Versus Placebo in the Add-On Study The shaded area represents the dosing window, the arrowheads show the timepoint when the dose was given, and the unshaded area shows the follow-up period. The primary endpoint was at day 57. ∗p < 0.05; ∗∗p < 0.01, ∗∗∗p < 0.001 IONIS-AGT-LRx versus placebo at the specified timepoint. Abbreviation as in Figure 1.
Figure 3
Figure 3
Waterfall Plots of the SBP and DBP in the Monotherapy and Add-On Trials (A) Systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) in the monotherapy trial. (C) SBP and (D) DBP in the add-on trial.
Figure 4
Figure 4
Impact of IONIS-AGT-LRx on UAGT Versus Plasma AGT Levels AGT was measured in plasma and in spot urine and plotted over time during the treatment phase and in recovery off-drug. A gradient was noted in urine and plasma that resolved in recovery when IONIS-AGT-LRx was beginning to wear off. The p values represent comparisons of either urine AGT (UAGT) or plasma AGT versus placebo based on the analysis of covariance or Van Elteren test. The shaded area represents the dosing window, the arrowheads show the timepoint when the dose was given, and the unshaded area shows the follow-up period. ∗p < 0.05; ∗∗p < 0.01; and ∗∗∗p < 0.001. AGT = angiotensinogen. Abbreviations as in Figure 1.
Figure 5
Figure 5
Ligand-Conjugated Antisense Technology GalNAc-conjugate moiety delivers the ASO to the hepatocytes where hepatic AGT is made. Targeting the top of RAAS pathway by reducing liver-derived AGT is a novel mechanism for RAAS inhibition. This GalNAc conjugation will minimize renal AGT reduction and thereby potentially provide a better safety profile than other RAAS inhibitors. AGT = angiotensinogen; ASGR = asialoglycoprotein receptor; ASO = antisense oligonucleotide; GaINAc3 = triantennary N-acetyl galactosamine; mRNA = messenger RNA; RAAS = renin-angiotensin-aldosterone system.
See this image and copyright information in PMC

Comment in

References

    1. Ferrario C.M., Strawn W.B. Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol. 2006;98:121–128. - PubMed
    1. Weber K.T. Aldosterone in congestive heart failure. N Engl J Med. 2001;345:1689–1697. - PubMed
    1. Cohn J.N., Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–1675. - PubMed
    1. Swedberg K., Kjekshus J. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) Am J Cardiol. 1988;62:60–66a. - PubMed
    1. Pfeffer M.A., Swedberg K., Granger C.B. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759–766. - PubMed

Associated data