SAFETY, PHARMACODYNAMICS, AND BLOOD PRESSURE EFFECTS OF ALN-AGT, AN RNA INTERFERENCE THERAPEUTIC TARGETING ANGIOTENSINOGEN, IN A RANDOMIZED SINGLE ASCENDING DOSE STUDY OF HYPERTENSIVE ADULTS

Abstract

Objective: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT, a subcutaneous investigational RNA interference (RNAi) therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Design and Method: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT, we conducted a multicenter study randomizing patients aged 18–65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of > 130 and ?165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of Oct 27, 2020. Design and method: Eighty-four patients (mean age 53 years, 39% female, mean baseline 24 h SBP 139.7 +/- 8.9 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg. Dose-related reductions in serum AGT levels were observed (figure), with mean reductions of > 90% at doses ?100 mg. AGT remained durably reduced through 12 weeks after single dose administration (data pending for 800 mg cohort). Concomitant reductions in BP from baseline were observed with AGT knockdown, with mean reductions in 24-hour SBP of > 10 mm Hg observed at Week 8 after single doses of 100 mg or higher. No treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium were seen. No patient required intervention for low blood pressure. Results: Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in dose-related reductions in serum AGT and BP over 8 weeks. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.