Impact of zilebesiran, an investigational RNA interference therapeutic targeting hepatic angiotensinogen, on renin-angiotensin system biomarkers in patients with mild-to-moderate hypertension

Abstract Background Zilebesiran is an investigational RNA interference therapeutic targeting hepatic synthesis of angiotensinogen (AGT), the most upstream precursor of the renin–angiotensin system (RAS). By targeting AGT, zilebesiran may lead to downstream suppression of the RAS and offer a new mechanism for providing continuous control of blood pressure. Purpose To assess the effect of zilebesiran on RAS biomarkers in patients with mild-to-moderate hypertension to demonstrate the mechanism of action clinically. Methods KARDIA-1 was a Phase 2, double-blind, placebo-controlled, dose-ranging study assessing efficacy and safety of zilebesiran in patients with mild-to-moderate hypertension. Eligible patients discontinued prior antihypertensive therapy for at least two weeks, and those with mean daytime ambulatory systolic blood pressure (SBP) 135–160 mmHg were randomized to zilebesiran (150, 300, or 600 mg subcutaneously (SC) once every 6 months Q6M or 300 mg SC once every 3 months Q3M) or placebo. The primary endpoint was reduction in 24-hour mean ambulatory SBP at Month 3. Change in levels of serum AGT (secondary endpoint), plasma renin concentration, serum angiotensin I, and serum angiotensin II (exploratory endpoints) from baseline to Months 3 and 6 were analysed descriptively. Blood samples for RAS biomarker assessment were collected in the morning and in an upright position. Results The study included 377 patients (median age range 58.0 22–75 years; 55.7% male; 24.7% Black). Baseline levels of RAS biomarkers were comparable across groups (Table 1). Placebo-adjusted reductions in blood pressure from baseline were up to 16.7 mmHg, and each dose of zilebesiran was associated with decreases from baseline in levels of serum AGT, as previously reported. There was a concomitant increase in plasma renin concentration (up to a median of 433.94% at Month 6), and decrease in levels of serum angiotensin I and II (up to median 61.62% and 79.43% reductions at Month 6, respectively); levels of these biomarkers in those treated with placebo were relatively unchanged from baseline. Greater changes in RAS biomarker levels were seen with zilebesiran 300 mg and 600 mg than with the 150 mg dose. Conclusion AGT reductions with biannual and quarterly doses of zilebesiran were observed to Month 6 and were accompanied by decreases in serum angiotensin I and II concentrations and subsequent increases in plasma renin concentration, consistent with disruption of negative angiotensin II feedback on renin secretion with angiotensinogen inhibition. Pharmacodynamic effects were sustained for 6 months, without evidence of angiotensin escape, which together with previously reported long-lasting blood pressure-lowering effects, support a biannual dosing regimen for zilebesiran.