Roche and Alnylam Push Zilebesiran into Phase III Trial Despite Mixed Phase II Hypertension Data

Roche and Alnylam announced the decision to move zilebesiran, an investigational RNAi therapy, into a global Phase III cardiovascular outcomes trial (ZENITH) for patients with uncontrolled hypertension despite KARDIA-3 Phase II results missing pre-specified statistical significance barriers123.

KARDIA-3, the latest Phase II study, showed a single 300 mg dose of zilebesiran provided a placebo-adjusted reduction of office systolic blood pressure (SBP) by -5.0 mmHg at three months (p=0.0431) and maintained benefit at six months (-3.9 mmHg)13.

The 600 mg dose offered no additional benefit, and overall the study did not achieve its pre-specified definition for statistical significance due to multiplicity testing1.

Despite this, Roche and Alnylam found the safety data and blood pressure reduction to be clinically meaningful and sufficient to identify the most likely to benefit subgroup, prompting the Phase III trial launch13.

The upcoming Phase III ZENITH trial will enroll approximately 11,000 patients globally and aims to determine zilebesiran’s ability to reduce major adverse cardiovascular events in high-risk, uncontrolled hypertension patients23.

Zilebesiran targets angiotensinogen (AGT) in the liver, reducing the renin-angiotensin-aldosterone system activation, with biannual subcutaneous dosing made possible by Alnylam’s Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology2.

Sources:

1. https://www.roche.com/media/releases/med-cor-2025-08-30

2. https://www.ainvest.com/news/roche-alnylam-launch-phase-3-study-hypertension-drug-2508/

3. https://trial.medpath.com/news/e7dd7872e9b983f1/roche-and-alnylam-advance-zilebesiran-to-phase-iii-cardiovascular-outcomes-trial-following-positive-kardia-3-results