Experimental RNA Therapy Significantly Reduces Blood Pressure up to 6 Months, Study Says

Among adults with mild to moderate hypertension, zilebesiran significantly reduced 24-hour mean ambulatory systolic blood pressure (SBP) at month 3, according to a study published in JAMA.

This held true for all 4 subcutaneous zilebesiran regimens in the study: 150 mg, 300 mg, or 600 mg once every 6 months, or 300 mg once every 3 months for 6 months. These findings are in comparison with taking placebo once every 3 months for 6 months.

Angiotensinogen serves as the primary precursor within the renin-angiotensin-aldosterone system (RAAS), playing a pivotal role in regulating BP. Zilebesiran, an experimental RNA interference therapy, specifically targets the production of angiotensinogen in the liver. Previous studies have shown zilebesiran can reduce levels of angiotensinogen in the blood and lower BP in people with mild to moderate hypertension.

The KARDIA-1 phase 2 trial, which is part of the drug's development process, aimed to assess the effectiveness and safety of different dosing schedules of zilebesiran compared with placebo in patients with mild to moderate hypertension. The double-blinded study was conducted across 78 sites in 4 countries: Canada, Ukraine, the United Kingdom, and the US. Mild to moderate hypertension was defined as daytime mean SBP between 135 and 160 mm Hg following antihypertensive washout, and adult patients were enrolled in the study after discontinuing their existing BP medications.

Blood pressure monitor | Image credit: Photo Sesaon – stock.adobe.com

The analysis included 377 total patients with a mean (SD) age of 57 (11) years, with 302 receiving zilebesiran in some form and 75 receiving placebo. Overall, the mean 24-hour ambulatory SBP at baseline was 142 (8) mm Hg, while diastolic BP (DBP) was 82 (8) mm Hg. The full cohort originally had 394 patients, but 16 patients in Ukraine were excluded due to data collection challenges arising from the Russia-Ukraine war, and 1 other patient did not receive the study drug.

Of the 302 patients taking zilebesiran:

• 79 received 150 mg once every 6 months
• 78 received 300 mg once every 6 months
• 79 received 600 mg once every 6 months
• 79 received 300 mg once every 3 months

For the 150 mg every 6 months regimen, the 24-hour mean ambulatory SBP change from baseline to month 3 was –7.3 mm Hg (95% CI, –10.3 to –4.4). Patients taking zilebesiran 600 mg once every 6 months saw a slightly greater decrease in SBP, with a reduction of –8.9 mm Hg (95% CI, –11.9 to –6.0) at month 3. Meanwhile, patients taking the 300 mg dose saw the greatest decrease at month 3, regardless of whether they were taking it once every 3 or 6 months, with a SBP reduction of –10.0 mm Hg (95% CI, –12.0 to –7.9). In comparison, the 3-month change for placebo was 6.8 mm Hg (95% CI, 3.6-9.9), making it the only cohort that actually saw an increase in ambulatory SBP.

Patients who received any dosage of zilebesiran experienced a greater reduction in serum angiotensinogen from baseline to both month 3 and month 6 compared with those who received placebo. Specifically, a decrease of over 90% from baseline persisted up to month 6 after a single administration of either 300 mg or 600 mg of zilebesiran.

The study authors also measured the least-squares mean (LSM) change in 24-hour ambulatory SBP between baseline and month 3. These differences were:

• –14.1 mm Hg (95% CI, −19.2 to −9.0) for zilebesiran 150 mg every 6 months
• –16.7 mm Hg (95% CI, −21.2 to −12.3) for zilebesiran 300 mg every 3 or 6 months
• –15.7 mm Hg (95% CI, −20.8 to −10.6) for zilebesiran 600 mg every 6 months

The authors noted consistent treatment differences across prespecified subgroups.

During the 6-month period, a higher proportion of patients treated with zilebesiran (60.9%) experienced adverse events compared with those receiving placebo (50.7%). Additionally, the incidence of serious adverse events was lower in the zilebesiran group (3.6%) compared with the placebo group (6.7%). Nonserious adverse events related to the drug were reported in 16.9% of patients taking zilebesiran, primarily consisting of injection site reactions and mild hyperkalemia, compared with 8.0% in the placebo group.

These findings build upon the initial phase 1 study results for zilebesiran, demonstrating its efficacy, safety, and pharmacodynamic effects. According to the authors, they confirm its ability to significantly reduce serum angiotensinogen levels, leading to sustained reductions in BP over a 24-hour period, even 6 months post-treatment. Notably, lower doses of 300 mg or greate—compared with the 800 mg dose at month 6 in the phase 1 study—achieved durable reductions in angiotensinogen levels, suggesting potential efficacy at lower doses than initially thought. While dose-related reductions were observed, maximal BP reduction occurred with doses of 300 mg or higher, indicating that angiotensinogen reduction exceeding 90% may be key for optimal and sustained BP control.

The consistent effects across different dosing regimens—300 mg every 3 months, 300 mg every 6 months, and 600 mg every 6 months—suggest that quarterly or biannual subcutaneous doses of zilebesiran can effectively lower BP, although further studies are needed to confirm these findings over longer periods.

“It is conceivable that dosing on this schedule could be accomplished in the clinical setting for many patients as part of routine scheduled follow-up, reducing the complexity of oral drug regimens (which often include as many as 3 or 4 antihypertensive drugs) and limiting the potential for inadvertent missed doses,” the authors added. “Moreover, tonic BP control with consistent reduction during daytime and nighttime lasting for 6 months may prove to be a strategy for addressing the residual risk associated with between-visit variability that complicates current oral antihypertensive treatment.”

The study's findings are subject to several important limitations. First, since the research focused on individuals with mild to moderate hypertension after discontinuing antihypertensive medications, the results may not fully reflect outcomes in broader patient populations, especially those with severe BP issues or those on ongoing antihypertensive therapy. Second, the follow-up period was limited to 6 months, raising questions about the durability of zilebesiran's effects over longer treatment durations and potential changes to its safety profile. However, the authors said ongoing assessment in the extension phase of the study will provide insights into the longer-term impact. Lastly, while the observed reductions in SBP could theoretically lower cardiovascular risk, definitive evidence on long-term outcomes awaits larger clinical trials with extended follow-up periods.

Reference

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