Will zilebesiran, an RNA interference therapy, be effective, safe, and improve the treatment of hypertension?

Introduction: Less than half of the subjects with hypertension have been diagnosed and treated, with only 21% having their blood pressure under control. Many of the subjects find it difficult to adhere to daily antihypertensives. Zilebesiran reduces hepatic angiotensinogen messenger RNA levels to inhibit the renin-angiotensin-aldosterone system and is being developed as a long-acting anti-hypertensive agent.

Areas covered: KARDIA-1; a phase 2 clinical trial of zilebesiran in mild to moderate hypertension. Most doses of zilebesiran (150-600 mg) modestly reduced blood pressure from baseline to month 3. Adverse events included hyperkalemia and kidney failure.

Expert opinion: The main problem with zilebesiran is that it only has a modest effect on blood pressure, and it is likely to have to be used as add-on therapy, which will probably reduce any benefits on adherence it has. It was also difficult to reliably interpret the results of KARDIA-1 as blood pressure went up significantly in the placebo group. KARDIA-1 did not answer previous concerns about zilebesiran; (i) what happens during volume depletion, sepsis, and pregnancy when angiotensinogen is inhibited long-term or (ii) will it be effective in a high sodium diet.