What is the clinical evidence from this study?

Study design: RCT. Population: Hypertension (n=51). Intervention: IONIS-AGT-LRx vs. Placebo. Primary outcome: Percent change from baseline to study week 9 in plasma angiotensinogen (Add-on study) (p=<0.001).

May 3, 2021Open Access

Antisense Inhibition of Angiotensinogen With IONIS-AGT-LRx

Q: What are the key findings of this study?

IONIS-AGT-LRx significantly reduced plasma angiotensinogen levels compared to placebo in patients with controlled hypertension after washout (-54%) and in patients with uncontrolled hypertension on 2 to 3 medications (-67%).

Key Result

IONIS-AGT-LRx significantly reduced plasma angiotensinogen levels compared to placebo in patients with controlled hypertension after washout (-54%) and in patients with uncontrolled hypertension on 2 to 3 medications (-67%).

Study Design

Type

RCT (n=51)

Blinding

Double-blind

Randomization

2:1

Multicenter

Yes

Structured PICO

Does IONIS-AGT-LRx reduce angiotensinogen levels and blood pressure in subjects with hypertension?

Population

51 adults with hypertension participated in two Phase 2 randomized trials evaluating IONIS-AGT-LRx as monotherapy or as an add-on to standard of care for up to 8 weeks.

Intervention

IONIS-AGT-LRx (antisense inhibitor of angiotensinogen) administered subcutaneously as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers for up to 2 months

Comparator

Placebo

Outcome

Angiotensinogen (AGT) levelssurrogate

IONIS-AGT-LRx safely and effectively reduces angiotensinogen levels in hypertensive patients, representing a novel approach to RAAS inhibition.

Main Result

Absolute Event Rate: -67% vs 3.4%

p-value: p=<0.001

Limitations

The monotherapy and add-on studies were small in sample size and were not powered for blood pressure endpoints.
Short treatment duration indicates larger studies with longer follow-up are needed.
The analytical measuring range of the plasma AGT assay had a lower limit of detection of 4.7 μg/ml, meaning several patients had undetectable levels, which may have underestimated the mean percent reductions in AGT.

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)

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Cite This Study

Morgan et al. (Mon,) conducted a rct in Hypertension (n=51). IONIS-AGT-LRx vs. Placebo was evaluated on Percent change from baseline to study week 9 in plasma angiotensinogen (Add-on study) (p=<0.001). IONIS-AGT-LRx significantly reduced plasma angiotensinogen levels compared to placebo in patients with controlled hypertension after washout (-54%) and in patients with uncontrolled hypertension on 2 to 3 medications (-67%).

synapsesocial.com/papers/6a4d93f46c3ae3769c077c2b https://doi.org/https://doi.org/10.1016/j.jacbts.2021.04.004

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