RNA interference with zilebesiran shows therapeutic potential in mild-to-moderate hypertension

Zilebesiran, an investigational RNA interference therapeutic agent that targets hepatic angiotensinogen synthesis, appears to have a promising blood pressure (BP)-lowering effect in adults with mild-to-moderate hypertension, as shown in the phase II KARDIA-1 trial.

KARDIA-1 included 377 adults (mean age 57 years, 44.3 percent women, 24.7 percent Black) with daytime mean ambulatory systolic BP (SBP) of 135–160 mm Hg. Following an antihypertensive washout period, the participants were randomly assigned to receive placebo (once every 3 months, n=75) or one of the following subcutaneous zilebesiran regimens (n=302): 150 mg, 300 mg, or 600 mg once every 6 months or 300 mg once every 3 months. Treatment was given for 6 months.

The primary endpoint of least-squares mean (LSM) changes from baseline to month 3 in 24-hour mean ambulatory SBP were −7.3 mm Hg with zilebesiran 150 mg once every 6 months, −10.0 mm Hg with 300 mg once every 3 months or every 6 months, −8.9 mm Hg with 600 mg once every 6 months, and 6.8 mm Hg with placebo.

The difference in LSM changes relative to placebo was significant across the zilebesiran doses evaluated: −14.1 mm Hg with 150 mg once every 6 months (p<0.001), −16.7 mm Hg with 300 mg once every 3 months or every 6 months (p<0.001), and −15.7 mm Hg with 600 mg once every 6 months (p<0.001).

Over 6 months, adverse events occurred in 60.9 percent of patients in the combined zilebesiran groups and in 50.7 percent of patients in the placebo group. The respective frequencies of serious adverse events were 3.6 percent and 6.7 percent, respectively. Nonserious drug-related adverse events occurred in 16.9 percent of zilebesiran-treated patients (mostly injection site reactions and mild hyperkalemia) and in 8.0 percent of placebo-treated patients.