A subcutaneous injection of the novel drug zilebesiran, when added to a standard antihypertensive agent, significantly reduces both 24-hour mean ambulatory and office systolic blood pressure (SBP) compared with placebo at three months in patients with uncontrolled hypertension, according to results from the KARDIA-2 trial published May 28 in JAMA.

In this phase 2 international multicenter study, Akshay S. Desai, MD, FACC, et al., evaluated the efficacy and safety of adding zilebesiran, which blocks production of angiotensinogen, in 663 patients (58 years old, 43% women, 29% Black). Their mean SBP was 143.4 mm Hg at baseline, with most patients taking one or two antihypertensive drugs.

After a run-in period of at least four weeks during which participants received once-daily doses of either indapamide 2.5 mg (n=130), amlodipine 5 mg (n=240) or olmesartan 40 mg (n=293), adherent patients with 24-hour mean ambulatory SBP of 130-160 mm Hg were randomized to a single injection of zilebesiran 600 mg or placebo.

Results showed significant additional reductions in 24-hour mean ambulatory SBP with zilebesiran vs. placebo for each background therapy at three months. The least-squares mean difference was −12.1 mm Hg for indapamide (p<0.001), −9.7 mm Hg for amlodipine (p<0.001) and −4.5 mm Hg for olmesartan (p=0.02).

Moreover, the difference in office SBP at three months was even greater for zilebesiran vs. placebo for each background therapy, at −18.5 mm Hg for indapamide, −10.2 mm Hg for amlodipine and −6.7 mm Hg for olmesartan.

Of note, at six months, significant SBP reductions persisted with zilebesiran in the indapamide and amlodipine cohorts, but not the olmesartan cohort. The time-adjusted change favored zilebesiran in the olmesartan cohort for office SBP but not for 24-hour mean ambulatory SBP.

Serious adverse events were low overall but were more prevalent in the zilebesiran vs. placebo group (hyperkalemia 5.5% vs. 1.8%, hypotension 4.3% vs. 2.1 and acute kidney failure 4.9% vs. 1.5%). Most events were mild and resolved with no medical intervention.

Desai and colleagues write that "although further study is needed to establish the long-term safety profile of zilebesiran, these results add to the growing corpus of evidence supporting a role for RNA interference therapeutics targeting hepatic angiotensinogen as a novel strategy for managing hypertension in clinical practice."

They add that the ongoing KARDIA-3 study, which includes patients with high cardiovascular risk and hypertension, "will shed further light on the balance of efficacy and safety of zilebesiran as an add-on therapy."