IONIS-AGT-LRx / Ionis - LARVOL DELTA

Exploratory Studies on RNAi-Based Therapies Targeting Angiotensinogen in Hypertension: Scoping Review. (PubMed, J Pers Med) - "Focusing on the efficacy and safety of RNAi-based therapies, this review discusses several key approaches, including antisense oligonucleotides (IONIS-AGT-LRx), small interfering RNA (siRNAs; zilebesiran), and adeno-associated viruses carrying short hairpin RNAs. They offer long-term BP control with fewer doses, potentially improving patient adherence and outcome. Although these therapies address several limitations of current antihypertensive treatments, further studies are required to confirm their long-term safety and efficacy."

Journal • Review • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension

Will zilebesiran, an RNA interference therapy, be effective, safe, and improve the treatment of hypertension? (PubMed, Expert Opin Biol Ther) - "It was also difficult to reliably interpret the results of KARDIA-1 as blood pressure went up significantly in the placebo group. KARDIA-1 did not answer previous concerns about zilebesiran; (i) what happens during volume depletion, sepsis, and pregnancy when angiotensinogen is inhibited long-term or (ii) will it be effective in a high sodium diet."

Journal • Review • Cardiovascular • Hypertension • Infectious Disease • Renal Disease • Septic Shock

Injectable angiotensinogen inhibition therapy for hypertension: a systematic review and meta-analysis (ESC 2024) - "Purpose We aimed to perform a systematic review and meta-analysis to investigate the role of injectable angiotensinogen (AGT) inhibitors, such as Zilebesiran and IONIS-AGT-LRx, in the treatment of hypertension. Conclusions In this meta-analysis of RCTs, injectable AGT inhibitors were associated with a significant decrease in mean AGT, SBP, and DBP as compared with placebo. There were no significant differences between groups in serious adverse events, although injection site reaction was more common in patients treated with injectable AGT inhibitors."

Retrospective data • Review • Cardiovascular • Hypertension • Hypotension

Effect of ION904, an Antisense Inhibitor of Angiotensinogen Production: Results of Phase 1 and Phase 2 Pilot Studies (AHA 2023) - "We previously published that inhibiting angiotensinogen (AGT) mRNA in hepatocytes with GalNAc-modified antisense oligonucleotide (ASO)-IONIS-AGT-LRx given subcutaneously (SC) weekly is effective in significantly reducing plasma angiotensinogen (AGT) with no on-target or off-target effects. Monthly administration of ION904 demonstrated significant plasma AGT reductions with a favorable safety and tolerability profile supporting development in heart failure and hypertension."

Clinical • P1 data • P2 data • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Hepatology • Hypertension • Hypotension • Liver Failure • Nephrology • Renal Disease • Thrombocytopenia

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ASTRAAS: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure (clinicaltrials.gov) - P2 | N=160 | Completed | Sponsor: Ionis Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Hypertension

ASTRAAS-HF: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Participants With Chronic Heart Failure With Reduced Ejection Fraction (clinicaltrials.gov) - P2 | N=72 | Completed | Sponsor: Ionis Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure • Heart Failure

ASTRAAS: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure (clinicaltrials.gov) - P2 | N=136 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Jan 2023 ➔ Sep 2022

Trial completion date • Cardiovascular • Hypertension

ASTRAAS-HF: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Participants With Chronic Heart Failure With Reduced Ejection Fraction (clinicaltrials.gov) - P2 | N=72 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Congestive Heart Failure • Heart Failure

ASTRAAS: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure (clinicaltrials.gov) - P2 | N=136 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hypertension

ASTRAAS: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: May 2022 ➔ Jan 2023 | Trial primary completion date: May 2022 ➔ Oct 2022

Trial completion date • Trial primary completion date • Hypertension

ASTRAAS-HF: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Participants With Chronic Heart Failure With Reduced Ejection Fraction (clinicaltrials.gov) - P2 | N=72 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Sep 2022 ➔ Jan 2023

Trial completion date • Cardiovascular • Congestive Heart Failure • Heart Failure

Antisense Inhibition of Angiotensinogen With IONIS-AGT-L: Results of Phase 1 and Phase 2 Studies. (PubMed, JACC Basic Transl Sci) - P1, P2 | "In conclusion, IONIS-AGT-L 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)."

Clinical • Journal • P1 data • P2 data • Hypertension

[VIRTUAL] EFFECT OF IONIS-AGT-LRX, AN ANTISENSE INHIBITOR OF ANGIOTENSINOGEN PRODUCTION, IN HEALTHY VOLUNTEERS AND IN SUBJECTS WITH HYPERTENSION: RESULTS OF PHASE 1 AND PHASE 2 STUDIES (ACC 2021) - "IONIS-AGT-LRX results in significant AGT reductions with favorable safety and tolerability profile. As monotherapy, proof of principle was demonstrated as evidenced by reduction in SBP thereby providing support to proceed to larger phase 2 trials in patients with resistant hypertension and heart failure."

Clinical • P1 data • P2 data • Congestive Heart Failure • Heart Failure • Hypertension • Hypotension

[VIRTUAL] EFFECT OF IONIS-AGT-LRX IN SUBJECTS WITH UNCONTROLLED HYPERTENSION ON 2-3 MEDICATIONS: RESULTS OF A PHASE 2 STUDY (ACC 2021) - "IONIS-AGT-LRX results in significant AGT reductions with favorable trends in SBP and DBP reduction in subjects with uncontrolled HTN with concomitant RAAS blockade. No on-target effects were observed. A dose-ranging, Ph2B study is underway in subjects with resistant HTN on ≥ 3 meds, as well a Ph2 study in patients with heart failure with reduced ejection fraction."

Clinical • P2 data • Acute Kidney Injury • Congestive Heart Failure • Heart Failure • Hypertension • Hypotension • Nephrology • Renal Disease

A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Participants With Chronic Heart Failure With Reduced Ejection Fraction (clinicaltrials.gov) - P2; N=72; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Participants With Chronic Heart Failure With Reduced Ejection Fraction (clinicaltrials.gov) - P2; N=72; Not yet recruiting; Sponsor: Ionis Pharmaceuticals, Inc.

New P2 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure (clinicaltrials.gov) - P2; N=150; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Hypertension

A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure (clinicaltrials.gov) - P2; N=150; Not yet recruiting; Sponsor: Ionis Pharmaceuticals, Inc.

Clinical • New P2 trial • Hypertension

A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx (clinicaltrials.gov) - P2; N=26; Completed; Sponsor: Ionis Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed; Trial completion date: Jan 2021 ➔ Jul 2020

Clinical • Trial completion • Trial completion date • Hypertension

A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx (clinicaltrials.gov) - P2; N=26; Active, not recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Cardiovascular • Hypertension

A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx (clinicaltrials.gov) - P2; N=30; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx (clinicaltrials.gov) - P2; N=30; Not yet recruiting; Sponsor: Ionis Pharmaceuticals, Inc.

Clinical • New P2 trial

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 (clinicaltrials.gov) - P2; N=25; Active, not recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

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 (clinicaltrials.gov) - P2; N=30; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open