Abstract 10974: Durable Reductions in Circulating Angiotensinogen and Blood Pressure Six Months After Single Doses of ALN-AGT, an RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, in Hypertensive Patients

Introduction: ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, is being evaluated as a novel treatment for hypertension in a multicenter, randomized, placebo-controlled single ascending dose study. Here we present new data on the long-term pharmacodynamic and antihypertensive effects of ALN-AGT six months after single-dose administration. Methods: As part of a Phase 1 program to assess the safety and tolerability of ALN-AGT, hypertensive patients (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after a washout of antihypertensive medications) were randomized 2:1 to ascending single doses of ALN-AGT (10-800 mg) or placebo. Change from baseline BP was measured by ambulatory BP monitoring (ABPM) at Week 8, Week 12, and Month 6. Interim results as of May 28, 2021 are reported. Results: 84 hypertensive patients (mean age 53 years, 61% male, 26% black, mean (SD) baseline 24-h SBP 140 (9) mm Hg) were enrolled in ascending single dose cohorts of ALN-AGT up to 800 mg SC. Dose-dependent and durable reductions in serum AGT levels were observed, with single doses ≥100 mg achieving serum AGT reductions >90% and 24-h SBP reductions >10 mm Hg (17 mm Hg in the 800 mg cohort) through Week 12. The 24-hour ABPM profile of ALN-AGT-treated patients showed sustained reductions of daytime BP with equally marked nighttime BP reduction. Notably, new data from follow-up visits show that all patients who received a single dose of 800 mg maintained serum AGT reductions >90% from Week 3 to Month 6, with a mean (SD) 24-h SBP reduction of 22 (15) mm Hg at Month 6 (5 of 8 patients without add-on antihypertensive treatment). There were no treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium. No patient required intervention for hypotension. Conclusions: Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in profound reductions in serum AGT and BP through Month 6. The durable reduction of serum AGT >90% with sustained 24-hour BP reduction over a period of 6 months after single dose SC administration of ALN-AGT 800 mg supports further evaluation of both quarterly and biannual dose administration.