Twice-a-Year RNA Interference Blood Pressure Shot Clearly Lowers 24-Hour Blood Pressure in Phase 2

Blood pressure medicines must be taken every day, and many patients stop taking them. Professor George L. Bakris of the University of Chicago Medicine in the United States and colleagues published in JAMA the results of the phase 2 KARDIA-1 trial of zilebesiran, a small interfering RNA (siRNA) drug given as a subcutaneous injection once every 3 to 6 months. The drug stops the liver from making angiotensinogen, the uppermost substance in the renin-angiotensin-aldosterone system (RAAS), a blood pressure regulation pathway.

Dose-Finding Phase 2 at 78 Sites in 4 Countries

Adults whose daytime ambulatory systolic blood pressure was 135 to 160 mmHg after stopping their previous blood pressure medicines (394 people) were randomized to four zilebesiran regimens (150, 300 or 600 mg once every 6 months, or 300 mg once every 3 months) or placebo, given double-blind for 6 months. The primary endpoint was the change in 24-hour mean ambulatory systolic blood pressure at 3 months. In 377 people analyzed, the difference from placebo ranged from -14.1 to -16.7 mmHg depending on the regimen, and all were statistically significant.

Over the 6 months, adverse events occurred in 60.9% of the zilebesiran group and 50.7% of the placebo group, and serious adverse events in 3.6% and 6.7%, respectively. Drug-related nonserious adverse events (16.9% vs. 8.0%) were mainly injection-site reactions and mild hyperkalemia.

Significance and Limits

A single shot keeps working for several months, drawing attention as an alternative that could reduce the problem of medication adherence. However, because this was a 6-month phase 2 trial, outcome measures such as stroke and heart attack were not evaluated, and the risks of hyperkalemia and low blood pressure with long-term RAAS suppression, as well as the effect of combining it with existing drugs, must be examined in phase 3.