The phase II KARDIA studies of zilebesiran have shown BP reductions, with a manageable safety profile.A pooled analysis of data from the phase II KARDIA 2 and 3 studies shows the blood pressure (BP)-lowering potential of zilebesiran, an investigational, long-acting RNA interference therapeutic, when added to a renin–angiotensin–aldosterone system inhibitor (RAASi) in patients with hypertension (HTN).
“In patients receiving zilebesiran on top of a background RAASi, zilebesiran demonstrated low rates of hypotension, kidney dysfunction, and hyperkalaemia,” noted Dr David Wheeler from the University College London, UK, at ERA 2026.
Compared with the placebo group, the zilebesiran group had slightly higher rates of participants with at least one adverse event (AE; 54.1 percent vs 47.6 percent), dizziness (3.7 percent vs 1.6 percent), and at least one hypotension event (2.6 percent vs 1.2 percent). [ERA 2026, abstract 181]
“[Nonetheless,] there was a very reasonable balance in the safety parameters,” Wheeler noted. Most AEs were mild or moderate in severity, were transient, and resolved without intervention.
Looking at renal safety, the zilebesiran group had numerically higher rates of estimated glomerular filtration rate (eGFR) decline ≥30 percent and final eGFR <60 mL/min/1.73 m2 (7.7 percent vs 3.3 percent), as well as potassium >5.5 mmol/L (7.7 percent vs 3.7 percent). “There was a slight excess of the events we would expect when we block the RAAS, but there were no major safety signals,” Wheeler said, adding that most renal AEs were mild and easily managed.
Descriptive office BP data also show a numerically greater reduction in office systolic BP (SBP) with zilebesiran vs placebo (mean change from baseline, –10.4 vs –5.8 mm Hg). Wheeler noted that the additional BP-lowering effect was particularly suggested in participants on zilebesiran 300 or 600 mg.
The KARDIA programme
Many individuals with HTN do not achieve and maintain their BP targets despite effective treatments. [Hypertension 2022;79:e1-e14] “Treatment options are particularly restricted in patients with chronic kidney disease (CKD). BP control gets more difficult, and we need more agents to manage HTN in [these patients]. Therefore, the availability of long-acting agents will, I think, be welcomed by many [clinicians],” Wheeler said.
The KARDIA studies sought to evaluate the potential of subcutaneous zilebesiran as monotherapy in adults with mild-to-moderate HTN (KARDIA 1); as add-on therapy in adults with HTN inadequately controlled with amlodipine, indapamide, or olmesartan (KARDIA 2); or as add-on therapy in adults with uncontrolled HTN on 2–4 antihypertensives and with cardiovascular (CV) disease or high CV risk.
RAASis: Safety concerns
Dual RAAS inhibition has presented prior safety concerns. [N Engl J Med 2008;358:1547-1559; N Engl J Med 2012;367:2204-2213; N Engl J Med 2016;374:1521-1532] “In contrast to RAASIs, zilebesiran targets angiotensinogen, the most upstream substrate in the RAAS pathway,” Wheeler noted.
This pooled analysis included KARDIA 2 and 3 participants who were on a background RAASi. The safety cohort (n=625) comprised individuals receiving zilebesiran 150, 300, or 600 mg (n=379; mean age 64.5 years, 54.1 percent men) or placebo Q6M (n=246; mean age 61.4 years, 60.6 percent men) on top of olmesartan (KARDIA 2), or an angiotensin–converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB; KARDIA 3). The efficacy cohort excluded the zilebesiran 150-mg group (n=601).
The baseline eGFR was similar between the zilebesiran and placebo groups (median, 75.6 and 78 mL/min/1.73 m2, respectively), as were the urine albumin-to-creatinine ratio (median, 15 and 16 mg/g) and office SBP (mean, 144.5 and 145.3 mm Hg).
“[In summary,] the phase II studies of zilebesiran have shown BP reductions, with a manageable safety profile. When we pooled patients on [background ACEis/ARBs] … we did not see any major [safety concerns]. We think that the addition of zilebesiran led to further BP reductions,” Wheeler said.
The phase III ZENITH trial will evaluate the effect of zilebesiran Q6M in addition to standard-of-care antihypertensives on CV outcomes in patients with uncontrolled HTN and established CVD or high CV risk, including those with CKD.