- Cardiology
- Personalized medicine
Administration of a single dose of zilebesiran, in addition to standard antihypertensive therapy, significantly reduces blood pressure at 3 months, compared with placebo, in people whose blood pressure is not controlled with background medication. Zilebesiran is an RNA interference agent, which blocks the hepatic synthesis of angiotensinogen, the precursor of angiotensin. These are the results of the phase II KARDIA-2 trial, presented at this year’s meeting of the American College of Cardiology (ACC2024). 3 months after zilebesiran administration, blood pressure measured over 24 hours was:
- Reduced by 12 mmHg in subjects receiving indapamide as background therapy
- Reduced by 9.7 mmHg in people receiving amlodipine as background therapy
- Reduced by 4 mmHg in people receiving olmesartan as background therapy
The differences were statistically significant from the group that received placebo added to background therapy. The effects were maintained for up to 6 months in most patients, whether or not other antihypertensive drugs were added. The safety profile of zilebesiran therapy was also favorable.
“The fact that zilebesiran therapy led to significant reductions in blood pressure 3 months after each background treatment—which persisted for up to 6 months in many cases, even with additional drug therapy—suggests that it may be a very powerful new strategy to lower blood pressure while reducing the need for daily pills.”said Dr. Akshay Desai, who presented the study at ACC2024.
These results show that biannual administration of zilebesiran could be an appropriate strategy to additionally reduce blood pressure in combination with conventional antihypertensives. The phase 2 clinical study, however, is not enough to have definitive conclusions regarding the long-term safety of the new therapy.
In the United States, only about a quarter of patients who have been diagnosed with high blood pressure have adequate blood pressure control. Although there are many effective therapies against high blood pressure, most patients do not reach the levels recommended by blood pressure guidelines, so the risk of cardiovascular events remains high. These findings could be explained by areduced tolerance to multiple therapeutic combinations, which often require daily administration of numerous pills.
The KARDIA-2 study included 672 patients whose blood pressure remained elevated (mean 143 mmHg) following standard therapies for hypertension. After discontinuation of previously prescribed antihypertensives, study participants were randomized to one of the usual hypertension therapies: indapamide, amlodipine, and olmesartan. They have different mechanisms by which they reduce blood pressure.
After a minimum of 4 weeks, all patients were reevaluated, with blood pressure monitored for 24 hours. Following this investigation, study participants received either a skin injection of zilebesiran or a placebo. In the following 6 months they were monitored. After 3 months, additional medications were allowed to be added to achieve guideline-recommended blood pressure levels.
Among the adverse effects, there was a slight increase in potassium levels, hypotension and a reduction in the estimated glomerular filtration rate. Most episodes were transient, non-severe and resolved without intervention.
The KARDIA-3 follow-up study is further evaluating the efficacy and safety of zilebesiran in patients with uncontrolled hypertension on 2-4 blood pressure-lowering medications, who have high cardiovascular risk or advanced chronic kidney disease.
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Tags: ACC24 single dose RNA therapy zilebesiran lowers blood pressure months patients unresponsive standard treatment
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