RNA Silencer Zilebesiran: Infrequent Injections Bring Down BP

In people with mild to moderate hypertension taken off antihypertensive treatment, quarterly and biannual injections of novel RNA silencer zilebesiran showed promise for safely reducing systolic blood pressure (BP), the phase II KARDIA-1 study showed.

Effects on 24-hour mean ambulatory systolic BP were apparent by month 3, ranging from 14.1- to 16.7-mm Hg greater reductions than with placebo, depending on the dose in the 6-month randomized trial led by George Bakris, MD, of the University of Chicago Medicine.

“Consistent clinical and pharmacodynamic effects of 300 mg every 3 months, 300 mg every 6 months, and 600 mg every 6 months doses indicate that these regimens achieve effective BP reduction, although this needs to be confirmed in future studies and over longer duration of follow-up,” the investigators reported in JAMA.

Indeed, they said that longer follow-up is planned for study participants. Additionally, the ongoing KARDIA-2 study is studying zilebesiran as add-on therapy in patients with hypertension that is inadequately controlled with olmesartan, amlodipine, or indapamide.

Zilebesiran is an investigational small interfering RNA (siRNA) therapeutic that works by targeting hepatic angiotensinogen synthesis. Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system that regulates BP.

A phase I study previously showed that a single injection of zilebesiran took angiotensinogen and BP levels down in patients with mild to moderate hypertension. Higher doses resulted in drops of at least 10 mm Hg in systolic BP and 5 mm Hg in diastolic BP by week 8, which persisted up to week 24 in that study.

“Notably, durable reductions of angiotensinogen levels (by greater than 90%) were achieved at month 6 in this study with doses of 300 mg or greater, rather than the 800-mg dose seen at month 6 in the previous phase 1 study, signifying the potential for efficacy at lower doses than suggested in the phase 1 study,” Bakris and colleagues noted of KARDIA-1.

“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. This may be particularly important in light of substantial data suggesting that challenges with adherence to prescribed oral antihypertensive therapies may be an important contributor to inadequate BP control to guideline-recommended targets in clinical practice,” they wrote.

As for safety in KARDIA-1, the authors reported mild to moderate drug-related adverse events, namely transient injection site reactions and hyperkalemia, affecting 16.9% of zilebesiran-treated patients compared with 8.0% of the placebo group.

Altogether, total adverse events reached 60.9% and 50.7% of zilebesiran and placebo groups, respectively, with serious adverse events in 3.6% and 6.7%, although none of the latter were deemed related to the siRNA-based drug.

Fears that patients would develop refractory hypotension from zilebesiran treatment did not come to fruition in the study.

Ernesto Schiffrin, MD, PhD, of Jewish General Hospital in Montreal, stressed the clinical benefit of sustained BP reductions for patients with hypertension.

“There is little doubt that lack of adherence to treatment is a major cause of not achieving goal BP during treatment with antihypertensive agents. An agent that can be administered, even if by injection, with few adverse effects every 6 months that produces a sustained lowering of BP represents an important potential advance in relation to adherence to therapy,” Schiffrin wrote in an accompanying editorial.

The initial KARDIA-1 report had been presented at the American Heart Association meeting last fall.

This dose-ranging study, conducted at 78 sites in four countries, enrolled 394 adults with mild to moderate hypertension and randomly assigned them to various subcutaneous doses of zilebesiran (150, 300, or 600 mg once every 6 months, or 300 mg once every 3 months) or placebo for 6 months.

Eligible patients had to be either untreated or treated with a stable regimen of up to two antihypertensive therapies and have a daytime mean ambulatory systolic BP of 135-160 mm Hg following washout of background antihypertensive medications.

Study participants averaged age 57; and 44.3% were women. Approximately a quarter were Black patients. At baseline, 24-hour mean ambulatory BP was 142/82 mm Hg.

Bakris’ group acknowledged that it remains unknown how the siRNA therapy would perform in a broader population of unselected patients, including those treated with antihypertensives or those with more severe BP elevations.

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