‘Exciting’ siRNA Therapy for Hypertension Passes First Hurdle

Patients with hypertension successfully dialed down their angiotensinogen levels and had lasting reductions in blood pressure (BP) following one injection of an investigational small interfering RNA (siRNA) therapy, according to a phase I study.

In this first-in-human, placebo-controlled study, patients who received zilebesiran showed dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory BP after a single subcutaneous dose, reported Akshay Desai, MD, MPH, of Brigham and Women’s Hospital and Harvard University in Boston, and colleagues.

Higher doses resulted in drops of at least 10 mm Hg in systolic BP and 5 mm Hg in diastolic BP by week 8 that persisted up to week 24, and the changes were consistent throughout the day, they noted in the New England Journal of Medicine.

Adverse events occurred in 72% and 88% of zilebesiran and placebo groups, respectively, and the most common events were headache, injection site reaction, and upper respiratory tract infection, mostly mild or moderate in severity. There were no reports of hypotension, hyperkalemia, or worsening renal function resulting in medical intervention in either group, Desai and team reported.

“Overall, these preliminary data regarding efficacy and safety support the potential for further study of quarterly or twice-yearly administration of zilebesiran as a treatment for patients with hypertension,” they wrote, noting that investigation of zilebesiran is continuing in two phase II trials: KARDIA-1 and KARDIA-2.

Zilebesiran is an RNA interference agent that inhibits synthesis of hepatic angiotensinogen, the precursor for all angiotensin metabolites. Such upstream renin-angiotensin-aldosterone system (RAAS) inhibition is thought to have the advantage of overcoming compensatory RAAS activation that is a concern with existing antihypertensives.

“Angiotensinogen suppression in the liver by siRNA is a novel and exciting means of targeting the renin-angiotensin system: it offers specificity, long-term efficacy, and sustained blood-pressure lowering,” commented Rhian Touyz, MBBCh, PhD, of McGill University Health Centre in Montreal, in an accompanying editorial.

“Although zilebesiran offers new possibilities as an antihypertensive agent, it may also have therapeutic benefit in other conditions associated with activation of the renin-angiotensin system, such as kidney and heart disease,” she wrote.

Touyz noted that acute activation of the renin-angiotensin system may be needed in some emergency cases, such as shock and pregnancy. However, siRNA activity can be reversed using the dedicated REVERSIR platform or, for the purpose of relieving the inhibition of angiotensinogen, by opting for vasopressors, salt, and fludrocortisone.

High BP is very common and is a major risk factor for heart disease and stroke. By one estimate, nearly half of U.S. adults have hypertension, defined as a BP over 130/80 mm Hg or use of hypertension medication. Advances in population-level BP control have seen setbacks in recent years.

“Factors that contribute to the suboptimal control of hypertension include poor adherence, the need for multiple antihypertensive drugs, difficulty in adopting healthy lifestyles, health disparities, and physician apathy,” Touyz noted.

“RNA therapeutic agents are particularly interesting in the context of nonadherence, because they may be administered as a single injection every few months,” she added.

Conducted at four sites in the U.K., the phase I study on zilebesiran included adults up to age 65 with treated or untreated hypertension and no serious coexisting conditions. This report included 107 participants (mean age 53.5 years, 62% men), spread over three parts of the study.

Part A included patients randomized to a range of zilebesiran (n=56) doses versus placebo (n=28).

Part B put people on the 800-mg dose of zilebesiran (n=8) versus placebo (n=4) and showed that dietary salt intake can modulate the BP-lowering effects of zilebesiran: treatment plus administration of a low-salt diet together conferred a greater reduction in BP than a low-salt diet alone.

Finally, Part E included 10 zilebesiran 800 mg recipients with a persistent ambulatory systolic BP of 120 mm Hg or more at week 6 taking additional treatment with irbesartan (300 mg once daily for 2 weeks). Compared with six comparators on zilebesiran alone, dual therapy was associated with incremental BP reductions averaging 6.3/3.0 mm Hg at week 8.

After the conclusion of the treatment period at week 12 for Parts A, B, and E, patients entered an extended safety follow-up period.

Desai and colleagues acknowledged the small sample and short follow-up in their report. Results may not be generalizable, as exclusion criteria included secondary hypertension, postural hypotension, diabetes, previous cardiovascular events, and current or anticipated treatment with beta-adrenergic receptor-blocking drugs.

Moreover, it is unknown if the teratogenic effects of other renin-angiotensin system inhibitors might apply to zilebesiran, they added.