Roche and Alnylam Advance Zilebesiran to Phase III Cardiovascular Outcomes Trial Following Positive KARDIA-3 Results
Key Insights
Zilebesiran demonstrated clinically meaningful reductions in office systolic blood pressure (-5.0 mmHg) at three months in patients with uncontrolled hypertension (search) and high cardiovascular risk.
The investigational RNAi therapeutic showed sustained blood pressure control through six months with twice-yearly subcutaneous dosing and encouraging safety when combined with multiple antihypertensives.
Based on comprehensive KARDIA Phase II data, Roche and Alnylam will initiate the global ZENITH Phase III cardiovascular outcomes trial enrolling approximately 11,000 patients by year-end 2025.
Roche and Alnylam announced plans to advance zilebesiran into a global Phase III cardiovascular outcomes trial following encouraging results from the KARDIA-3 Phase II study presented at the European Society of Cardiology Congress 2025. The investigational RNAi therapeutic demonstrated clinically meaningful blood pressure reductions in patients with uncontrolled hypertension (search) despite multiple background therapies.
KARDIA-3 Study Results Show Sustained Blood Pressure Control
The KARDIA-3 study evaluated zilebesiran in 270 patients with uncontrolled hypertension (search) and high cardiovascular risk receiving two to four standard antihypertensive medications. Results showed that a single 300 mg dose of zilebesiran administered subcutaneously every six months produced a placebo-adjusted reduction in office systolic blood pressure of -5.0 mmHg (p=0.0431) at the three-month primary endpoint, with sustained benefits continuing through six months (-3.9 mmHg; 95% CI: -8.5, 0.7).
The 600 mg dose showed no additional benefits over the 300 mg dose at either timepoint. While the study did not meet the pre-specified definition for statistical significance due to multiplicity testing requirements, it successfully identified the patient population that could benefit most from zilebesiran treatment.
"Zilebesiran has the potential to become a best-in-disease treatment for many patients with uncontrolled hypertension (search). Its blood pressure-lowering effects and twice-yearly dosing could reduce the risk of serious health complications and death," said Levi Garraway, MD, PhD, Roche's chief medical officer and head of Global Product Development.
Enhanced Effects with Diuretic Combinations
Consistent with findings from the earlier KARDIA-2 study, zilebesiran showed particularly robust benefits when combined with diuretics (search). In patients receiving diuretics with baseline blood pressure >140 mmHg, the placebo-adjusted reduction was -9.2 mmHg at three months and -8.3 mmHg at six months, demonstrating the synergistic effects of this combination approach.
At baseline, approximately 66% of patients were taking diuretics (search), 91% were receiving ACE inhibitors (search) or ARBs (search), and 58% were on calcium channel blockers. The mean baseline office and 24-hour ambulatory systolic blood pressure were 143.6 mmHg and 142.4 mmHg, respectively.
Encouraging Safety Profile Across Multiple Therapies
Zilebesiran demonstrated an encouraging safety profile when added to multiple background antihypertensive therapies. Most adverse events were mild or moderate, non-serious, and transient with few requiring intervention. Rates of hyperkalemia, kidney dysfunction, and hypotension remained low. Serious adverse events occurred in 3.8% of zilebesiran-treated patients compared to 4.5% in the placebo group, with no deaths reported during the six-month study period.
"The KARDIA-3 results demonstrate that a single dose of zilebesiran provided continuous control of blood pressure over the 24-hour period, day and night, for up to six months, while also showing the potential to improve cardiac and renal biomarkers independent of blood pressure reduction," said Pushkal Garg, M.D., Chief Research and Development Officer of Alnylam.
ZENITH Phase III Trial Design
Based on the comprehensive KARDIA Phase II program data, the companies will initiate the ZENITH (ZilebEsiraN CardIovascular OuTcome Study in Hypertension (search)) Phase III trial by the end of 2025. This event-driven study will enroll approximately 11,000 patients across more than 30 countries to evaluate zilebesiran 300 mg every six months compared to placebo.
The trial will focus on patients with uncontrolled hypertension (search) despite treatment with at least two standard antihypertensives (one being a diuretic) who have either established cardiovascular disease (search) or are at high risk for cardiovascular disease. The primary objective will assess zilebesiran's impact on reducing the risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure events.
Addressing Significant Unmet Medical Need
Hypertension (search) affects an estimated one in three adults worldwide, representing over 1.2 billion people. Despite the wide availability of antihypertensive medications, up to 80% of patients do not achieve adequate blood pressure control, with poor adherence to daily oral therapies contributing significantly to suboptimal outcomes.
"Patients with uncontrolled hypertension (search) despite the use of multiple background therapies are at the highest risk of major adverse cardiovascular events. It is well known that reductions in systolic blood pressure of five mmHg or more can result in a reduction in cardiovascular risk," said Neha Pagidipati, M.D., MPH, FACC, Associate Professor of Medicine, Cardiology, Duke Clinical Research Institute, and KARDIA-3 Lead Investigator.
Mechanism of Action and Technology Platform
Zilebesiran targets angiotensinogen (search) (AGT), the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS (search)), which plays a central role in blood pressure regulation. By inhibiting AGT synthesis in the liver, zilebesiran potentially leads to durable reductions in AGT protein and ultimately in the vasoconstrictor angiotensin II.
The therapeutic utilizes Alnylam's Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, enabling the infrequent biannual subcutaneous dosing regimen and increased selectivity. This RNAi approach represents a differentiated mechanism compared to existing antihypertensive therapies by targeting the most upstream component of the RAAS (search) pathway.