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

Erin S Morgan; Yvonne Tami; Kuolung Hu; Michela Brambatti; Adam E Mullick; Richard S Geary; George L Bakris; Sotirios Tsimikas

doi:10.1016/j.jacbts.2021.04.004

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

JACC Basic Transl Sci. 2021 May 3;6(6):485-496. doi: 10.1016/j.jacbts.2021.04.004. eCollection 2021 Jun.

Authors

Erin S Morgan¹, Yvonne Tami¹, Kuolung Hu¹, Michela Brambatti¹, Adam E Mullick¹, Richard S Geary¹, George L Bakris², Sotirios Tsimikas^{1

3}

Affiliations

¹ Ionis Pharmaceuticals, Carlsbad, California, USA.
² Department of Medicine, University of Chicago Medicine, Chicago, Illinois, USA.
³ Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, California, USA.

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-L_Rx versus placebo up to 2 months. IONIS-AGT-L_Rx was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function. IONIS-AGT-L_Rx 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-L_Rx 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.

Associated data

ClinicalTrials.gov/NCT03101878