RNA interference therapy targeting hepatic angiotensinogen for the treatment of hypertension and cardiovascular disease: a first-in-human and proof-of-concept study

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Abstract Introduction Hypertension remains a leading cause of cardiovascular diseases and death. Angiotensinogen (AGT) is the sole precursor protein in the renin-angiotensin-aldosterone system pathway, predominantly secreted by the liver. Targeting AGT with GalNAc-siRNA has the potential to overcome angiotensin escape and offer an effective, long-acting treatment that could improve the well-recognized real-world challenges of patient adherence and compliance. QCZ484 is a GalNAc-siRNA, designed to specifically target the AGT mRNA in the liver. Purpose To evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) of QCZ484 in healthy subjects (HS) and in patients with mild hypertension (HTN). Methods This was a double-blind, placebo-controlled, single ascending dose, first-in-human study consisting of 2 parts. In Part A, 8 HS in each cohort received either QCZ484 (50, 150, 300, and 600 mg) or placebo in a 3:1 ratio. In Part B, 12 patients with HTN in each cohort received either QCZ484 (300 or 150 mg) or placebo in a 2:1 ratio. Study endpoints included safety, PK, and PD (AGT and BP). Blood pressure (BP) was measured with ambulatory BP monitoring (ABPM; first measurement was week 4) in Part B. All subjects, except for those receiving placebo in Part B (who completed the study at Day 57), were followed until week 48. Results In Part A, 32 HS in total received either QCZ484 or placebo: 24 received QCZ484 (50, 150, 300, 600 mg) and 8 received placebo. In Part B, 24 patients in total received either QCZ484 (150 or 300 mg) or placebo: 9 received 300 mg, 8 received 150 mg, and 7 received placebo. In HS, QCZ484 at doses of ≥150 mg resulted in >90% AGT inhibition starting on Day 29, and >80% AGT inhibition was sustained for ≥Week 24. No notable changes in systolic BP, diastolic BP and HR (office vital signs measurement) were found across QCZ484 dose cohorts in HS. In patients with HTN, QCZ484 (150 and 300 mg) led to >90% AGT inhibition, and >80% AGT inhibition was sustained for up to Week 24. In patients with HTN, maximal reductions in 24-hr ABPM SBP (>12 mmHg) and DBP (>5 mmHg) were observed at Week 4 in both 150 mg and 300 mg groups; more importantly, BP-lowering effects were sustained for up to 6 months. Similar BP-lowering effects were observed in patients with HTN using office BP measurement. Similar BP-lowering effects of QCZ484 during daytime and nighttime were observed. QCZ484 was generally safe and well tolerated; most adverse events were of mild intensity. Conclusions The sustained BP-lowering effects for up to 6 months and the favorable safety of QCZ484 highlight its potential for the treatment of patients with uncontrolled HTN, at a convenient dosing regimen. The similar BP-lowering effects of QCZ484 during nighttime are especially advantageous for managing nocturnal hypertension, because nighttime BP is a strong predictor of future cardiovascular and kidney events.