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Quarterly, Semiannual Zilebesiran Injection Improves Blood Pressure Control – Renal and Urology News

For patients with mild to moderate hypertension, a single injection of zilebesiran every 3 or 6 months may lower blood pressure while enabling greater medication adherence.

Zilebesiran, a small interfering RNA that specifically decreases angiotensinogen production by the liver, showed early success in a phase 1 trial.

In the phase 2 KARDIA-1 randomized clinical trial (ClinicalTrials.gov Identifier: NCT04936035), investigators tested various dosing regimens in 394 adults who had a mean ambulatory systolic blood pressure (SBP) of 135 to 160 mmHg without use of any antihypertensive medication. Patients received subcutaneous zilebesiran doses of 150, 300, or 600 mg every 6 months or 300 mg every 3 months or placebo. The primary end point was change from baseline to month 3 in 24-hour mean ambulatory SBP.

At 3 months, 24-hour mean ambulatory SBP significantly decreased by 7.3, 10.0, and 8.9 mmHg from baseline after a single zilebesiran dose of 150 mg every 6 months, 300 mg every 3 or 6 months, and 600 mg every 6 months, respectively, George L. Bakris, MD, of the American Heart Association Comprehensive Hypertension Center at The University of Chicago Medicine in Illinois, and colleagues reported in JAMA. Mean SBP increased 6.8 mmHg from baseline with placebo. Blood pressure reductions appeared mostly consistent over day or night in a 24-hour period.

Compared with placebo, each zilebesiran dosing regimen significantly decreased ambulatory SBP at 3 months by 14.1, 16.7, and 15.7 mmHg, respectively.

Serum angiotensinogen decreased by more than 90% from baseline to month 6 after single 300 or 600 mg doses of zilebesiran.

[Zilebesiran] could represent a significant advance in hypertension therapeutics

By 6 months, a greater proportion of the zilebesiran than placebo groups had experienced any adverse events (60.9% vs 50.7%), but a lower proportion had endured serious adverse events (AEs; 3.6% vs 6.7%). Among the intervention groups, mild to moderate AEs occurred such as injection site reaction in 6.3%, hyperkalemia in 6.3%, hepatic AEs in 3.0%, hypotension in 4.3%, and acute kidney failure in 1.3%. Three patients receiving zilebesiran were treated with potassium binders. The drug was discontinued in 2 patients with orthostatic hypotension, 1 patient with elevated blood pressure, and 1 patient with injection site reaction.

“These data highlight an opportunity to provide durable BP reductions with biannual dosing of zilebesiran, which could be augmented with dosing of other antihypertensive agents,” Dr Bakris’ team wrote.

Further research is needed to establish the long-term efficacy and safety of zilebesiran, including the possibility of refractory hypotension and severe hyperkalemia with monotherapy or combination antihypertensive therapy. The ongoing KARDIA-2 study (NCT05103332) will investigate the efficacy of zilebesiran as add-on therapy in patients with hypertension that is inadequately controlled with olmesartan, amlodipine, or indapamide.

Of the analyzed population, 167 patients (44.3%) were women and 93 (24.7%) were Black. Mean age at baseline was 56.8 years.

The KARDIA-1 trial excluded patients with secondary hypertension, type 1 or type 2 diabetes, an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m2 or less, orthostatic hypotension, or a serum potassium concentration greater than 5 mEq/L.

“If sustained BP reduction is confirmed with few adverse effects, zilebesiran administration every 6 months could represent a significant advance in hypertension therapeutics because it could potentially overcome lack of adherence to treatment, which remains to be demonstrated,” Ernesto L. Schiffrin, MD, PhD, of Lady Davis Institute of Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, in Montréal, Quebec, Canada, wrote in an accompanying editorial.

Disclosure: This research was supported by Alnylam Pharmaceuticals. Please see the original reference for a full list of disclosures.

References:

Bakris GL, Saxena M, Gupta A, et al. RNA interference with zilebesiran for mild to moderate hypertension: The KARDIA-1 randomized clinical trial. JAMA. Published online February 16, 2024. doi:10.1001/jama.2024.0728

Schiffrin EL. RNA injection every 6 months to improve adherence and lower blood pressure in patients with hypertension. JAMA. Published online February 16, 2024. doi:10.1001/jama.2023.26071