New RNA therapy zilebesiran shows promise in lowering blood pressure

By Vijay Kumar MalesuFeb 19 2024Reviewed by Susha Cheriyedath, M.Sc.

In a recent study published in JAMA, researchers evaluated the efficacy and safety of zilebesiran doses in reducing mild to moderate hypertension.

Study: RNA Interference With Zilebesiran for Mild to Moderate Hypertension - The KARDIA-1 Randomized Clinical Trial. Image Credit: Ground Picture / Shutterstock

Background 

Hypertension is a major global health issue, leading to cardiovascular mortality and kidney disease progression, with up to 80% of patients failing to achieve recommended blood pressure (BP) targets. This condition's management is complicated by significant variability in BP and the challenges of ensuring adherence to daily, multi-drug treatment regimens. Zilebesiran, an innovative ribonucleic acid (RNA) interference therapeutic, targets the liver's production of angiotensinogen, a crucial component in BP regulation. Early phase studies showed promising results, with zilebesiran leading to sustained BP reductions. Further research is needed to fully understand the long-term effects, optimal dosing, and safety profile of zilebesiran in diverse patient populations.

About the study 

The present study was conducted across Canada, Ukraine, the United Kingdom (UK), and the United States (US) from July 2021 to June 2023 and adhered to ethical standards, requiring informed consent from participants. It targeted adults with hypertension, excluding those with certain conditions like severe renal impairment or poorly controlled diabetes. After a washout period for previous antihypertensives, participants were randomized to receive one of four zilebesiran dosing regimens or a placebo, with efforts to maintain blinding and stratification based on race and baseline systolic blood pressure (SBP).

The study's primary focus was on the change from baseline to month 3 in 24-hour mean ambulatory SBP among different zilebesiran doses compared to placebo. Secondary outcomes included office SBP changes, the percentage of patients achieving specific SBP criteria without additional medication, and various blood pressure metrics. Ambulatory and office BP measurements were conducted using standardized devices, and serum angiotensinogen levels were evaluated for pharmacodynamic assessment. Safety was monitored through adverse event reporting and laboratory tests.

The statistical analysis sought to identify significant SBP reductions across treatment groups, using a structured approach for handling multiple comparisons and missing data. It comprehensively evaluated zilebesiran's efficacy and safety in hypertension management across diverse demographics.

Study results 

In the study, 1,517 individuals were initially considered, with 394 ultimately randomized to receive either placebo or varying doses of zilebesiran: 150 mg, 300 mg every 6 months, 300 mg every 3 months, or 600 mg every 6 months. One patient did not receive the assigned treatment, leading to 393 participants being dosed. The analysis excluded data from 16 patients due to data collection issues related to the ongoing war in Ukraine, resulting in 377 individuals (302 on zilebesiran and 75 on placebo) being evaluated, with 347 completing the 6-month period.

The participants' demographics were diverse, with 44.3% female and 24.7% Black individuals and an average age of 56.8 years. Baseline BP averaged 142/82 mm Hg. The primary outcome showed significant reductions in 24-hour mean ambulatory SBP at 3 months across zilebesiran doses compared to placebo, with least-squares mean (LSM) changes from baseline of -7.3 mm Hg for 150 mg every 6 months, -10.0 mm Hg for 300 mg (both intervals), and -8.9 mm Hg for 600 mg every 6 months, versus a 6.8 mm Hg increase in the placebo group.

Secondary outcomes at 3 months mirrored these findings, with reductions in office SBP and consistent benefits observed at 6 months. Notably, zilebesiran significantly outperformed placebo in terms of participants meeting pre-defined BP response criteria. Additional benefits included substantial reductions in diastolic BP (DBP) and serum angiotensinogen levels, illustrating zilebesiran's potent and sustained action.

Exploratory analyses revealed a lower need for rescue antihypertensive medications in those treated with zilebesiran compared to placebo. Safety profiles were favorable, with serious adverse events (AEs) reported in a smaller percentage of zilebesiran-treated patients compared to placebo. Most AEs were mild to moderate, including injection site reactions and hyperkalemia. There were no significant liver function test abnormalities, and instances of hypotension and hyperkalemia were generally mild and manageable.

Body weight changes were minimal across all groups, and a slight increase in serum potassium levels was noted in some zilebesiran recipients, though these instances were typically transient and manageable. 

Conclusions 

To summarize, zilebesiran demonstrated significant BP reductions with the potential for biannual dosing. This novel treatment, leveraging RNA interference to decrease hepatic angiotensinogen, showed promise over a six-month period, particularly at doses of 300 mg or higher. AEs, mainly mild, included injection site reactions and hyperkalemia. The findings suggest that zilebesiran could simplify hypertension management, enhancing treatment adherence and efficacy. Further investigation is required to assess long-term safety and efficacy, including combination with other therapies, as explored in the ongoing KARDIA-2 study.