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

Visual Abstract

Highlights

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  Targeting AGT is a novel approach to inhibit the RAAS pathway.

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  AGT is primarily synthesized in the liver.

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  IONIS-AGT-L _Rx is an ASO directed to hepatocyte-derived AGT.

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  In 2 phase 2 trials as monotherapy and as an add-on to 2 to 3 medications for hypertension, IONIS-AGT-L _Rx was well tolerated with a significant reduction in plasma AGT levels.

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  IONIS-AGT-L _Rx is being developed for hypertension and heart failure indications.

Summary

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)