Abstract 116: Safety And Tolerability Of Zilebesiran, An RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, In Obese Patients With Hypertension

Abstract

Introduction: Single subcutaneous (SC) doses of zilebesiran, an investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, have been shown to reduce serum AGT levels and blood pressure (BP) in patients with mild-moderate hypertension based on results from phase 1 studies. Limited data are available on the safety, pharmacodynamics, and efficacy of multiple dosing or administration of zilebesiran in patients with Class II/III obesity. Methods: Patients with hypertension (mean seated office systolic BP (SBP) of >130 and ≤165 mmHg after washout of antihypertensive medication) and Class II/III obesity (BMI >35 kg/m 2 and ≤50 kg/m 2 ) without diabetes were randomized 2:1 to zilebesiran or irbesartan in a double-blind, double-dummy design. Patients received either sequential doses of zilebesiran 800 mg SC (Day 1 and 85) and daily oral placebo, or sequential SC doses of saline (Day 1 and 85) and daily 150mg oral irbesartan. Key endpoints included safety, change in AGT level from baseline to week 24 (using an enzyme-linked immunosorbent assay), and change in BP from baseline to week 24 (by 24-h ambulatory BP monitoring). Results: Twelve patients were enrolled (zilebesiran, N=8; irbesartan, N=4; median (range) age 56 (46-64) years, 67% female, mean ± SD BMI 40 ± 4 kg/m 2 , baseline 24-h mean ± SD [systolic/diastolic] BP 144 ± 10 / 88 ± 9 mmHg). At least one adverse event (AE) was reported in 6 zilebesiran patients and 4 irbesartan patients, most of which were mild or moderate; one serious AE occurred with zilebesiran and was considered unrelated. There were no episodes of hypotension requiring intervention in either arm. AGT levels did not change with irbesartan but were reduced with zilebesiran by 99% from week 4 to week 24. Change in SBP from baseline to week 24 was -27 ± 8 mmHg with zilebesiran versus -19 ± 6 mmHg with irbesartan. Conclusions: In this Phase 1 study of obese patients with hypertension, administration of two sequential doses of zilebesiran was associated with durable reductions in serum AGT levels and sustained reductions in BP persisting to 24 weeks. Zilebesiran was also generally well tolerated in this patient population. These data suggest that pharmacodynamics, efficacy, and safety of zilebesiran may not be influenced by BMI.