Experimental RNA Drug Zilebesiran Delivers Six-Month Blood Pressure Control with Single Injection
Key Insights
Zilebesiran, an investigational RNA interference therapeutic, demonstrated sustained systolic blood pressure reductions of 10-15 mm Hg for up to six months following a single subcutaneous injection in the phase 2 KARDIA-1 trial.
The drug targets hepatic angiotensinogen synthesis and achieved dose-dependent reductions in serum angiotensinogen levels ranging from 88% to 98% across treatment groups.
Safety profile was encouraging with only mild to moderate drug-related adverse events reported and no clinically relevant changes in renal or hepatic function observed.
A single injection of the experimental RNA interference drug zilebesiran safely and effectively lowered blood pressure in adults with mild-to-moderate hypertension for up to six months, according to results from the phase 2 KARDIA-1 trial presented at the American Heart Association's Scientific Sessions 2023.
The investigational therapeutic, developed by Alnylam, targets hepatic angiotensinogen synthesis and represents a potential breakthrough in hypertension management through sustained blood pressure control with infrequent dosing.
Trial Design and Patient Population
The global, placebo-controlled, randomized, double-blind trial enrolled 394 patients with daytime mean ambulatory systolic blood pressure of 135 mm Hg to 160 mm Hg. Participants had an average age of 57 years, with 49% to 60% men per treatment group and 25% Black participants. The average baseline blood pressure was 141.8/81.8 mm Hg.
Patients were randomly assigned to one of five regimens: zilebesiran 150 mg once every 6 months, zilebesiran 300 mg once every 3 months, zilebesiran 300 mg once every 6 months, zilebesiran 600 mg once every 6 months, or placebo once every 3 months. The assigned regimen began after a 2-to-4-week washout of existing antihypertensive medications.
Sustained Blood Pressure Reductions
The primary endpoint was change from baseline to month 3 in 24-hour mean ambulatory systolic blood pressure. All zilebesiran groups demonstrated dose-dependent reductions in serum angiotensinogen levels through 6 months, ranging from 88% to 98%. At 6 months, serum angiotensinogen reduction was correlated with systolic blood pressure change (r = 0.354; 95% CI, 0.298-0.408).
"All zilebesiran groups had reductions in systolic BP at 3 months that remained almost identical at 6 months," said lead study author George L. Bakris, MD, FAHA, professor of medicine and director of the American Heart Association Comprehensive Hypertension Center at the University of Chicago Medicine.
At 6 months, the 24-hour mean ambulatory systolic blood pressure reductions for zilebesiran compared with placebo were:
- 150 mg once every 6 months: least squares mean difference, −11.1 mm Hg (95% CI, −15.8 to −6.4; P = 4.5 x 10-6)
- 300 mg once every 6 months: least squares mean difference, −14.5 mm Hg (95% CI, −19.1 to −9.9; P = 1.8 x 10-9)
- 300 mg once every 3 months: least squares mean difference, −14.1 mm Hg (95% CI, −18.9 to −9.4; P = 9.1 x 10-9)
- 600 mg once every 6 months: least squares mean difference, −14.2 mm Hg (95% CI, −18.9 to −9.5; P = 5.8 x 10-9)
Participants in groups that received the 300 mg and 600 mg doses had 24-hour average systolic blood pressure lowered by 15 mm Hg or more at the three-month follow-up. After six months, people receiving zilebesiran were significantly more likely to experience 24-hour average systolic blood pressure reductions of 20 mm Hg or more without taking additional high blood pressure medications.
Safety Profile and Tolerability
The safety profile was encouraging throughout the six-month study period. There were no drug-related adverse events classified as serious or severe, and only four patients discontinued zilebesiran for drug-related reasons. The most common adverse events were mild reactions at the injection site.
"There were no clinically relevant changes in renal or hepatic function," Bakris noted. "Taken together, the drug is well tolerated with minimal side effects."
Four non-serious, related adverse reactions led to discontinuation in the zilebesiran groups: two instances of orthostatic hypotension, one of blood pressure elevation, and one of injection site reaction. No adverse reactions occurred in the placebo group.
Clinical Implications
"Uncontrolled high blood pressure is a leading cause of death and disease, so there is a need for new treatments that provide sustained blood pressure control over longer periods of time," Bakris said. According to the American Heart Association's 2023 Statistical Update, heart disease continues to be the number one cause of death in the United States and nearly half of adults in the U.S. have high blood pressure.
The results demonstrate that reductions in systolic blood pressure of greater than or equal to 5 mm Hg are linked to a reduction in cardiovascular risk. "These results reinforce the potential of zilebesiran to provide sustained blood pressure control, improve adherence to medication via infrequent dosing, and in turn, improve outcomes for people with high blood pressure," Bakris said.
Future Development
Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study. The current findings are limited to people with mild-to-moderate hypertension and the six-month placebo-controlled period. Longer-term safety and impact on cardiovascular outcomes will be assessed in future research.
The six-month, placebo-controlled treatment period of the Phase 2 trial was conducted from July 2021 to June 2023 at sites in Canada, Ukraine, the United Kingdom and the U.S., with 78% of participants living in the U.S.