Roche and Alnylam are launching the Phase III ZENITH cardiovascular outcomes trial (CVOT) to evaluate zilebesiran in patients with uncontrolled hypertension. The RNAi therapeutic was designed to reduce the risk of major adverse cardiovascular events in this patient population.

The trial follows the comprehensive Phase II KARDIA program, including KARDIA-1, KARDIA-2, and KARDIA-3, which evaluated the efficacy and safety of zilebesiran in patients on two to four standard antihypertensives.

How could Zilebesiran Improve Long-Term Blood Pressure Control and Cardiovascular Outcomes?

Roche noted that KARDIA-3 identified the target patient population for Phase III and demonstrated that a single 300 mg subcutaneous dose every six months produced clinically meaningful reductions in office systolic blood pressure at three months with sustained effects at six months. Additionally, analyses from KARDIA-2 and KARDIA-3 showed that combining zilebesiran with a diuretic can provide more robust blood pressure reductions.¹

“Zilebesiran has the potential to become a best-in-disease treatment for many patients with uncontrolled hypertension. Its blood pressure-lowering effects and twice-yearly dosing could reduce the risk of serious health complications and death,” said Levi Garraway, MD, PhD, chief medical officer, head, global product development, Roche, in a press release.

ZENITH Phase III Trial Design

• The global ZENITH CVOT is expected to evaluate 300 mg of zilebesiran in an estimated 11,000 patients with uncontrolled hypertension, despite the use of at least two standard of care antihypertensives and with either established cardiovascular disease (CVD) or at high risk for CVD.
• The primary endpoint of the trial will be to assess the impact of zilebesiran on reducing the risk of CV death, nonfatal myocardial infarction, nonfatal stroke, and heart failure events compared to placebo.¹

Hypertension Burden in the United States

• According to Million Hearts, approximately 119.9 million people in the United States are currently living with hypertension, with only one-quarter of these individuals having the condition under control.
• Four out of every five adults with hypertension are recommended to take prescription medication.²

Global Hypertension Statistics

• According to the World Health Organization, approximately 1.28 billion people between 30 and 79 years of age are currently living with hypertension, most of whom live in low- and middle-income countries.
• Close to 46% of people with hypertension are unaware that they have it and only one in five adults have their diagnosis under control.³

Unmet Need and Treatment Challenges

• Hypertension is the leading driver of CVD and the most significant modifiable risk factor.
• Nearly 80% of people with hypertension fail to achieve proper blood pressure control despite access to existing antihypertensive drugs.
• According to Roche, a major challenge is poor adherence to daily oral medications, which contributes to inadequate management and worse cardiovascular outcomes.
• A long-acting therapy that delivers sustained blood pressure control could play a key role in addressing the global burden of uncontrolled hypertension.

Safety Profile and Combination Potential

Roche stated that zilebesiran showed a favorable safety profile in patients with comorbidities who were already on multiple background treatments, with more than 90% receiving an ACE inhibitor or an angiotensin receptor blocker. The company noted that these results strengthen confidence in the therapy’s potential to be used alongside standard antihypertensive regimens.¹

“Detailed analysis of our comprehensive Phase II clinical trials have informed our decision to move zilbesiran into Phase III,” continued Garraway, in the press release. “Despite current treatment options, up to 80% of people with hypertension do not achieve adequate blood pressure control putting them at higher risk of cardiovascular events. Therefore, additional treatment options are needed."

References

1. Roche and Alnylam advance zilebesiran into global phase III cardiovascular outcomes trial for people with uncontrolled hypertension. Roche. August 29, 2025. Accessed September 2, 2025. https://www.roche.com/media/releases/med-cor-2025-08-30
2. Estimated Hypertension Prevalence, Treatment, and Control Among U.S. Adults. Million Hearts. Accessed September 2, 2025. https://millionhearts.hhs.gov/data-reports/hypertension-prevalence.html
3. Hypertension. WHO. Accessed September 2, 2025. https://www.who.int/news-room/fact-sheets/detail/hypertension