Injectable antihypertensive drug lowers blood pressure for up to 6 months
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Key takeaways:
- Zilebesiran lowered systolic BP for 3 months, a reduction sustained at 6 months.
- Rates of major adverse events were low.
PHILADELPHIA — Zilebesiran, an investigational subcutaneous RNA interference therapeutic, lowered systolic blood pressure at 3 months and sustained the reduction to 6 months, according to results of the phase 2 KARDIA-1 trial.
The agent “targets hepatic angiotensinogen synthesis,” Healio | Cardiology Today Editorial Board Member George L. Bakris, MD, FAHA, FASN, professor of medicine and director of the American Heart Association Comprehensive Hypertension Center at the University of Chicago Medicine, said during a press conference at the AHA Scientific Sessions. “This is a phase 2 study and it tests the hypothesis that the use of an agent that results in a sustained reduction of serum angiotensinogen levels will result in a dose-dependent reduction of blood pressure that can be sustained over a 24-week period following a single dose.”
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Bakris and colleagues randomly assigned 394 people (mean age, 57 years; 49% to 60% men per treatment group; 25% Black) with daytime mean ambulatory systolic BP of 135 mm Hg to 160 mm Hg to one of five regimens: zilebesiran (Alnylam) 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.
The primary endpoint was change from baseline to month 3 in 24-hour mean ambulatory systolic BP.
Researchers reported dose-dependent reductions in serum angiotensinogen levels through 6 months in the zilebesiran groups, ranging from 88% to 98%, and at 6 months, serum angiotensinogen reduction was correlated with systolic BP change (r = 0.354; 95% CI, 0.298-0.408), Bakris said during the press conference.
All zilebesiran groups had reductions in systolic BP at 3 months that remained almost identical at 6 months, he said. At 6 months, the 24-hour mean ambulatory systolic BP reductions for zilebesiran compared with placebo were as follows:
- 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; and
- 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.
All zilebesiran groups had reduced office systolic BP at 6 months compared with placebo, with the 300 mg groups having the greatest reductions, Bakris said.
There were no drug-related adverse events classified as serious or severe, and four patients discontinued zilebesiran for drug-related reasons, he said, noting there were no clinically relevant changes in renal or hepatic function. “Taken together, the drug is well tolerated with minimal side effects,” he said.
“Single subcutaneous doses of zilebesiran resulted in clinically meaningful and significant reductions in 24-hour ambulatory systolic blood pressure compared to placebo at month 3 and sustained out to month 6,” Bakris said. “Zilebesiran demonstrated an encouraging safety profile over 6 months. Rates of serious or severe adverse events were low, and only mild to moderate drug-related [adverse events] were observed across the different groups. Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study.”
Perspective
Back to TopSandra J. Taler, MD
I didn’t think we would see a subcutaneous hypertension treatment. A 3-month or 6-month subcutaneous injection for hypertension is remarkable. There is an unmet need. There has been interest in renal denervation, which is an invasive approach to block the signals that raise blood pressure. There is a subgroup of hypertensive patients who don’t like pills or want as few pills as possible. There will be a line of people who will ask when is this going to be ready.
The data are beautiful, but very early. I thought the 3-month injection group did a little better than the 6-month injection groups, so we will have to see how that turns out. Even if this does not last longer than 6 months, it could be very well received.
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Bakris GL, et al. LBS.04. Using drugs, diet and delivery to optimize hypertension outcomes. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
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