Investigational RNA interference therapeutic agent Zilebesiran effective for treatment of hypertension

Angiotensinogen has previously been assumed to be a passive substrate, however recent studies reveal an inherent conformational mechanism that is critical to the cleavage and release of the angiotensin peptides and consequently to the control of blood pressure.

A recent study in The New England Journal of Medicine reveals Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, that usually inhibits hepatic angiotensinogen synthesis showed that a single subcutaneous dose of zilebesiran of 200 mg or more is effective in decreasing serum angiotensinogen levels.

Researchers conducted a phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring.

The key findings of the study are

• A total of 107 patients were enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention.

• In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r=−0.56 at week 8; 95% confidence interval, −0.69 to −0.39).

• Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks.

• Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively.

The researchers concluded that “Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed.”

Reference: Desai AS, et al "Zilebesiran, an RNA interference therapeutic agent for hypertension" N Engl J Med 2023; DOI: 10.1056/NEJMoa2208391.