Novel RNA interference therapeutic Zilebesiran results in dose-dependent sustained BP reduction

By Leah Kosyakovsky on

Key Points:

  • Uncontrolled hypertension is a major public health concern, and this condition is often primarily driven by the renin-angiotensin (RAAS) pathway.
  • A new RNA interference therapy, Zilebesiran, was developed to target to most upstream precursor of the RAAS pathway (angiotensinogen). This study was a Phase 2 study examining the safety and efficacy of zilebesiran.
  • A single dose of subcutaneous zilebesiran resulted in sustained BP reduction with low rates of adverse events over 6 months.

Uncontrolled hypertension is a major contributor to long-term morbidity and mortality, with major contributions from the renin-angiotensin system (RAAS). There has yet to be a therapy directly targeting angiotensinogen (AGT), the most upstream precursor of the RAAS pathway. In a breaking presentation at the 2023 AHA Scientific Sessions today,  Dr. George Bakris (University of Chicago) and his team presented their study: “Sustained BP reduction with the RNA interference therapeutic, Zilebesiran,” or the KARDIA-1 study.

The KARDIA-1 study (NCT04936035) randomized 394 adults (18-75 years) with a daytime mean sBP 135-160 mm Hg by ambulatory BPM, after washout of prior antihypertensive medication for 2-4 weeks prior to enrollment. Relevant exclusion criteria were secondary hypertension, elevated liver enzymes, hyperkalemia, and eGFR <30ml/min. Patients were randomized 1:1:1:1:1 to placebo and zilebesiran doses of 150mg q6M SC, 300mg q6M SC, 300mg q3M SC, and 600mg q6M SC. The primary outcome was change from baseline at month 3 in 24-hour ambulatory SBP. Secondary outcomes included change from baseline at month 6 in 24-hour ambulatory SBP, change from baseline in office SBP at month 3 or 6, and proportion of patients with 24-hour mean SBP <130mm Hg or reduction ≥ 20 mm Hg at month 6, without additional antihypertensives. Safety endpoints (frequency of adverse events) were also observed.

The median age was 57, with 44% women. A sustained, dose-dependent reduction in serum angiotensinogen, AGT, was observed through 6 months, with a peak reduction observed at 2 months. At 6 months, there were reductions of 88% for 150mg q6 M, 93% for 300mg q6M, 98% for 300mg q3M, and 96% for 600mg q6M. At 6 months there were also sustained BP reductions observed across all doses compared to placebo, with observed reductions of 11.1 (-15.8, -6.4) mm Hg, 14.5 (-19.1, -9.9) mm Hg, 14.1 (-18.9, -9.4) mm Hg, and 14.2 -18.9, -9.5) mm Hg observed for escalating doses of zilebesiran (all p<0.05). Similar results were obtained for office SBP readings at 6 months (p<0.05 for all doses). The proportion of patients achieving a 24-hour mean SBP <130mm Hg or reduction ≥ 20 mm Hg at month 6 was higher across all doses (all p<0.05). Zilebesiran also had a favorable safety profile over 6 months, with no serious or severe drug-related adverse events noted. Drug-related adverse events which resulted in drug discontinuation included orthostatic hypotension (n=2), ISR (n=1), and BP elevation (n=1).

When discussing the clinical implications of the study at the Scientific Sessions, Dr. Bakris stated: “In KARDIA-1, single subcutaneous doses of zilebesiran resulted in clinically meaningful and significant reductions in 24-hour mean SBP compared with placebo at Month 3, that were sustained through Month 6…these data further support the potential for quarterly or biannual dosing of SC zilebesiran in achieving a consistent pharmacodynamic effect and effective BP reduction through 6 months… is being further evaluated as an add-on therapy for the treatment of hypertension in the ongoing KARDIA-2 study.”