DOI: 10.1161/circ.148.suppl_1.17395 ISSN: 0009-7322

Abstract 17395: Effect of ION904, an Antisense Inhibitor of Angiotensinogen Production: Results of Phase 1 and Phase 2 Pilot Studies

Erin Morgan, Jason M Duran, Julia Weinland, Tao Lin, Adam E Mullick, Richard Geary, Sotirios Tsimikas
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Background: Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) act within the kidney and disturb tubuloglomerular feedback leading to renal dysfunction and hyperkalemia. We previously published that inhibiting angiotensinogen ( AGT ) mRNA in hepatocytes with GalNAc-modified antisense oligonucleotide (ASO)-IONIS-AGT-L Rx given subcutaneously (SC) weekly is effective in significantly reducing plasma angiotensinogen (AGT) with no on-target or off-target effects.

Objective: We aimed to develop a more potent and durable ASO targeting AGT . ION904 is a GalNAc-conjugated ASO that specifically reduces hepatic AGT production with minimal activity in the kidneys.

Methods: In a phase 1 study (PH1), healthy volunteers were treated with placebo saline (PBO) or ION904 SC with single ascending doses (PBO or 10-120 mg, n=56). A phase 2 (PH2) pilot study (n=48) in patients with uncontrolled hypertension (SBP > 130 - ≤ 170 mmHg) on at least 1 antihypertensive medication were randomized to PBO or 30, 60, or 90 mg of ION904 SC every 4 weeks for 3 months (3:1 randomization). The primary endpoint was plasma AGT reduction at Week 15. The study was not powered for SBP reduction.

Results: ION904 resulted in a significant mean percent reduction in plasma AGT levels compared to pooled PBO at Day 15 (-12% v. -76%, PBO v. 120 mg, p ≤ 0.001) in PH1. In PH2, the mean percent reduction in AGT levels were significantly greater in the ION904 group compared to PBO at the primary endpoint, Week 15, (-6% v. -79%, PBO v. 90 mg, p=0.001). Robust median AGT reductions were observed at the primary endpoint (-5% v. -86%, PBO v. 90 mg). A larger proportion of subjects (11/26, 42%) in the ION904 group achieved ≥ 10 mmHg reductions compared to PBO (3/10, 30%) at Week 15. No signals for hyperkalemia, renal dysfunction, hypotension (on target effect) or liver dysfunction or thrombocytopenia (off target effects) were noted. No drug-related serious adverse events occurred.

Conclusions: Monthly administration of ION904 demonstrated significant plasma AGT reductions with a favorable safety and tolerability profile supporting development in heart failure and hypertension.

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