Small Targets Equal Big Gains for Treating Hypertension

Volume 29, Issue 2

Small interfering RNA [siRNA] technology has the potential to revolutionize how chronic diseases are managed. One such agent, inclisiran, is already approved by the US Food and Drug Administration to lower low-density lipoproteins (LDLs). This drug can produce profound reductions in LDL with 2 annual infusions administered 6 months apart. 

Hypertension continues to inflict significant morbidity and mortality on the adult population worldwide. This is due in part to the natural attrition in medication adherence that results from prolonged administration of once- or twice-daily oral medications. 

Zilebesiran is an investigational siRNA covalently linked to an N-acetylgalactosamine [GalNAc] ligand that binds with high affinity to the hepatic asialoglycoprotein receptor. Through a reduction in hepatic angiotensinogen mRNA levels, this agent can hinder the production of angiotensinogen and lower blood pressure. With hepatocyte-targeted delivery, extrahepatic angiotensinogen expression may be spared, which could improve tolerability. 

In this week’s issue of Talking Therapeutics, we explore a phase 1 study of zilebesiran for managing hypertension. 

Point 1: Strong Preliminary Signal

In this new paper, patients with hypertension were randomized 2:1 to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo. Researchers also investigated the effect of 800-mg zilebesiran on blood pressure in patients with either low- or high-salt diets, as well as outcomes associated with 800-mg zilebesiran when coadministered with irbesartan. 

By week 8, the researchers found associations between single doses of zilebesiran (≥200 mg) and reductions in both systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg). 

“These changes were consistent throughout the diurnal cycle and were sustained at 24 weeks,” researchers said. 

The results further showed that a high-salt diet blunted zilebesiran’s effect on blood pressure, and coadministration with irbesartan augmented blood pressure reduction.  

Importantly, there were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. 

Point 2: Is This a Glimpse of the Future?

The results of this trial, which must be viewed through the lens of a phase 1 study, are most impressive. Administration of this very targeted agent was able to lower blood pressure without imparting significant toxicity on patients. Also striking, a single dose of zilebesiran lowered blood pressure effectively for 24 weeks, which could greatly improve compliance. 

These findings, if confirmed in subsequent phase 2 and 3 trials, could have wide-ranging public health outcomes and could signal the beginning of a new era in managing hypertension.