RNA interference agents against angiotensinogen – potentially safeand effective therapies to address key issues in hypertension

抄録

Small interfering RNAs (siRNA) have emerged as important new therapeutics thatcan knock down previously undruggable targets in an efficient and long-lastingmanner. Initially exploited for rare diseases, licensing of inclisiran inhypercholesterolemia positions them as viable approaches in common conditions.Zilebesiran is an siRNA that knocks down angiotensinogen (AGT) in the liver, thesole precursor of angiotensin peptides. It has now completed phase I studies.Patients with hypertension were randomly assigned in a 2:1 ratio (n=12/dose) toreceive either a single ascending sc dose of zilebesiran (10, 25, 50, 100, 200,400 or 800mg) or placebo and followed for 24 weeks (Part A). Phase I alsoassessed the effect of 800mg on BP under low- or high-salt diet (Part B), andwhen given with irbesartan (Part C). Endpoints included safety, PK & PD,and change from baseline in ambulatory systolic (SBP) and diastolic BP (DBP)measured over 24-h. Of 107 patients enrolled, 5 had mild, transientinjection-site reactions. There were no significant reports of hypotension,hyperkalemia, or worsened renal function. In Part A, zilebesiran decreased serumAGT dose-dependently. Single doses (≥200 mg) were associated with decreased SBP(>10 mm Hg) and DBP (>5 mm Hg) by week 8. These changes were consistentthroughout the diurnal cycle and sustained at 24 weeks. Results from Parts B andC were consistent with modulation of BP: attenuated by a high-salt diet;augmented by irbesartan. Based on impressive efficacy, and acceptable safety,phase II studies are underway (KARDIA I examines dose and dosing interval;KARDIA 2 explores combination with other agents). Safety data in larger cohorts,with broader co-morbidities are needed, but targeting AGT seems a powerful wayto inhibit the renin-angiotensin system and may have potential beyondhypertension, such as in chronic heart and kidney disease. The long action ofzilebesiran may potentially be beneficial for adherence and BP stability.