Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension

Hibo Abud, PharmD, Goodrich Pharmacy

Background: Blood pressure control is an important factor in reducing cardiovascular events. There are many factors that prevent patients from achieving adequate blood pressure goals, including suboptimal therapy and adherence. Newer antihypertensive agents are being introduced with novel mechanisms, including Zilebesiran. Zilebesiran is an investigational small interfering RNA agent that works to decrease angiotensinogen synthesis in the liver by reducing angiotensinogen mRNA levels. Traditional RAAS targeting treatment options for HTN  have a long term effect of compensatory increase in angiotensin activation. This phenomenon could be prevented with this new class of therapy. Additionally, zilebesiran and other small interfering RNA agents have a long duration of action that would allow for less frequent dosing of the medication. 

Objective: To determine the efficacy and safety of zilebesiran in patients with HTN

Study design: This was a phase 1, randomized, multicenter, four-part trial conducted in the United Kingdom. A total of 107 patients were enrolled and 84 were in part A, 12 in part B, and 16 in part E. Eligible patients included those 18-65 years of age, with treated or untreated HTN. Patients were also included based on mean seated systolic blood pressure measured using automatic cuff of more than 130-165 mmHg (parts A and B) or more than 135-165 mmHg (part E) and a systolic blood pressure of 130 mmHg or more using 24-hour ambulatory blood pressure monitoring following a 2 week washout period of antihypertensive drugs. Patients were excluded if they had secondary HTN, postural hypotension, diabetes, prior cardiovascular events, and current or future treatment with beta blockers. The Primary endpoint of the study was the frequency of adverse events. Secondary endpoints looked at change from baseline in serum angiotensinogen level and pharmacokinetic characteristics. The study also looked at exploratory endpoints such as changes from baseline in systolic and diastolic blood pressure as measured by 24-hour ambulatory monitoring. In part A, patients were randomly assigned in a 2:1 ratio to either single dose zilebesiran at various doses (10 mg, 25 mg, 50 mg, 100 mg, 200 mg,  400 mg, or 800 mg) or placebo. In part B, patients were first exposed to a low salt diet followed by a high salt diet for 2 weeks, then randomly assigned in 2:1 ratio to a single 800 mg dose of zilebesiran or placebo and then re-challenged with the same diet protocol. Part E was an open label study in which all patients received 800 mg of zilebesiran and patients with systolic blood pressure of 120 mmHg or greater at week 6 received additional treatment with irbesartan 300 mg for 2 weeks. All patients were followed for 12 weeks. Formal statistical hypothesis testing was not performed in this study. In part A of the study, a log linear model was used to determine the relationship between angiotensinogen levels and 24-hour mean systolic blood pressure.

Results: In the primary endpoint of adverse events, the only significant adverse event associated with zilebesiran was injection site reactions, which occurred in 5 patients overall in the treatment group. In part A of the study, there was a negative correlation seen between zilebesiran doses and angiotensinogen levels. At doses of 100 mg or more, there was a mean decrease of more than 90% in angiotensinogen levels that were maintained from week 3 to 12. At 800 mg of zilebesiran, decreases in angiotensinogen levels were maintained through week 24. In part B, administration of 800 mg of zilebesiran with a low salt diet yielded a change in systolic and diastolic blood pressure of -18.8+4.3 and -8.4+2.5 mmHg, respectively. In part E, 6 patients had a significant decrease in systolic blood pressure at week 6 (21.8+2.9 mmHg) while 10 had persistent systolic blood pressure above 120 mmHg at 6 weeks and subsequently received additional irbesartan therapy. Those patients only saw a slight change in systolic and diastolic blood pressure at -6.3+3.1 and 03.0+1.9 mmHg at week 8.

Conclusions: A decrease in both angiotensinogen levels and blood pressure were observed with the use of zilebesiran in the treatment of HTN. In this phase 1 study, mild and transient injection site reactions were observed in a few patients, while other major adverse events were absent. The study was not large or long enough to fully encompass all adverse events. 

Key point: Zilebesiran could be a key treatment option for patients in the management of HTN. This study showed a correlation of the drug to decreasing angiotensinogen levels and blood pressure. Due to the nature of being a phase 1 trial, we are not able to analyze the effects of the medication in patients with other comorbid conditions, such as diabetes. The drug is still undergoing phase 2 trials, which would be essential in determining effective dosing and a full adverse effects profile. Zilebesiran could be especially beneficial in patients who have adherence issues with currently available antihypertensives in the future. 


  1. Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N Engl J Med. 2023;389(3):228-238. doi:10.1056/NEJMoa2208391
  2. Ranasinghe P, Addison ML, Webb DJ. Small interfering RNA therapeutics in hypertension: a viewpoint on vasopressor and vasopressor-sparing strategies for counteracting blood pressure lowering by angiotensinogen-targeting small interfering RNA. J Am Heart Assoc. 2022;11(20):e027694. doi:10.1161/JAHA.122.027694