Genentech: Press Releases | Saturday, Aug 30, 2025

Saturday, Aug 30, 2025

Genentech and Alnylam Advance Zilebesiran Into Global Phase III Cardiovascular Outcomes Trial for People With Uncontrolled Hypertension

Phase III trial knowledgeable by complete KARDIA knowledge set generated via three Phase II research KARDIA-1, KARDIA-2 and KARDIA-3

In the Phase II KARDIA-3 examine, offered right now as a late breaker on the European Society of Cardiology Congress 2025, zilebesiran demonstrated clinically significant reductions in workplace systolic blood stress at month three with steady management via month six

Zilebesiran, a possible best-in-disease RNAi antihypertensive with twice-yearly subcutaneous dosing, demonstrated encouraging security when mixed with two or extra antihypertensives

Phase III cardiovascular outcomes trial anticipated to be initiated by the top of the 12 months

South San Francisco, CA — August 30, 2025 —

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY) and Alnylam (Nasdaq: ALNY) right now introduced the choice to provoke a Phase III cardiovascular outcomes trial (CVOT) to guage the flexibility of zilebesiran, an RNAi therapeutic, to cut back the danger of main opposed cardiovascular occasions in sufferers with uncontrolled hypertension. This choice was knowledgeable by the great KARDIA Phase II program, together with KARDIA-1, KARDIA-2 and the latest KARDIA-3 examine evaluating the efficacy and security of zilebesiran in sufferers with uncontrolled hypertension and excessive cardiovascular (CV) threat, on two to 4 commonplace of care antihypertensives. In explicit, KARDIA-3 aimed to outline the affected person inhabitants to be investigated within the Phase III CV outcomes trial.

Results of KARDIA-3 confirmed a single dose of zilebesiran (300 mg each six months, subcutaneous injection) resulted in clinically significant placebo-adjusted reductions of workplace systolic blood stress (SBP) in all comers on the month three main endpoint (-5.0 mmHg; p=0.0431) with sustained advantages out to month six (-3.9 mmHg; 95% CI: [-8.5, 0.7]). There had been no extra advantages of the 600 mg dose at month three (-3.3 mmHg; p=0.1830) or month six (-3.6 mmHg; 95% CI: [-8.2, 1.0]). The general KARDIA-3 examine didn’t meet the pre-specified definition for statistical significance, due to a multiplicity statistical testing strategy. However the examine met the goal of figuring out the affected person inhabitants that would doubtlessly profit essentially the most from zilebesiran and likewise confirmed encouraging security and clinically significant placebo adjusted reductions in blood stress.

As noticed within the KARDIA-2 Phase II examine, the KARDIA-3 outcomes assist a strong profit of mixing zilebesiran with a diuretic, a generally used antihypertensive. In an evaluation of sufferers that had been on diuretics and had a baseline BP > 140 mmHg, the placebo-adjusted discount was -9.2 mmHg; (-17.3, -1.2) at month three and -8.3 mmHg (-16.4, -0.2) at month six. A precedent for enhanced blood stress discount conferred by this sort of mixture is established in each literature and scientific apply. 

“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,” stated Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. “Detailed analysis of our comprehensive Phase II clinical trials have informed our decision to move zilebesiran into Phase III. 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.”

Zilebesiran additionally demonstrated encouraging security in sufferers with comorbidities on a number of background therapies – over 90% of whom had been receiving therapy with an ACE inhibitor or an Angiotensin Receptor Blocker (ARB). These findings reinforce confidence in zilebesiran’s capacity to be mixed with commonplace of care antihypertensives.

As a outcome, the worldwide ZENITH (ZilebEsiraN cardIovascular ouTcome examine in Hypertension) Phase III trial has been submitted to international regulators and is predicted to be initiated by the top of 2025. ZENITH will likely be a CVOT enrolling roughly 11,000 sufferers and evaluating zilebesiran (300 mg) each six months in comparison with placebo in sufferers with uncontrolled hypertension with both established CV illness or at excessive threat for CV illness on two or extra antihypertensives, one being a diuretic.

Hypertension is the first reason for and primary modifiable threat issue for heart problems. An estimated one in three adults, over 1.2 billion individuals worldwide, have hypertension and regardless of the large availability of antihypertensives, as much as 80% of them don’t obtain sufficient blood stress management. Poor adherence to every day oral therapies is a crucial contributor to poor blood stress management and CV outcomes. An efficient long-acting remedy that gives steady management of blood stress could assist to cut back the burden of uncontrolled hypertension.

With its rising cardiometabolic portfolio and robust diagnostic experience, Genentech is advancing transformative requirements of care to enhance the lives of individuals dwelling with cardiometabolic ailments in addition to lowering the numerous burden on healthcare programs and society.

About the KARDIA-3 Study

KARDIA-3 (NCT06272487), the third Phase II examine within the KARDIA program, included two Cohorts (A and B). Cohort A assessed zilebesiran in sufferers with eGFR ≥ 45 mL/min/1.73m2, whereas Cohort B included sufferers with superior kidney dysfunction (i.e., eGFR between 30 and <45 mL/min/1.73m2). Cohort A enrolled 270 sufferers who had been randomized to therapy with zilebesiran (300 mg or 600 mg) or placebo. Randomization was stratified by background diuretic use, baseline blood stress, and race. The main endpoint was change in workplace SBP at month three. Key secondary endpoints had been modifications in workplace SBP at month six and alter in 24-hour imply ambulatory SBP at months three and 6.

 

At baseline, 144 (53.3%), 96 (35.6%) and 30 (11.1%) sufferers had been on two, three, or over three antihypertensives, respectively, with ~91% of sufferers taking ACE inhibitors/ARBs, ~66% of sufferers taking a diuretic, and ~58% of sufferers taking calcium channel blockers. The imply baseline workplace and 24-hour imply ambulatory SBP had been 143.6 mmHg and 142.4 mmHg, respectively (N= 270).

 

KARDIA-3 Cohort A Primary Results (Placebo-Adjusted Changes from Baseline):

Cohort A Study inhabitants	Endpoint	Month three change (censored)* †	Month six change (all collected) ** †
Overall examine inhabitants (N=270)	Office SBP (300 mg)	-5.0 (-9.9, -0.2) p=0.0431	-3.9 (-8.5, 0.7)
	24-Hour Mean Ambulatory SBP (300 mg)	-3.6 (-7.7, 0.4)	-5.5 (-9.4, -1.5)
Subgroup (N=110) (Diuretics and with baseline SBP≥140mmHg) ***	Office SBP (300 mg)	-9.2 (-17.3, -1.2)	-8.3 (-16.4, -0.2)
	24-Hour Mean Ambulatory SBP (300 mg)	-6.8 (-13.9, -0.2)	-6.6 (-13.3, -0.0)
*** Post hoc Analysis	*Censored evaluation excludes sufferers who intensified antihypertensive use inside two weeks of visits at month three **All collected evaluation contains all obtainable affected person knowledge, no matter treatment modifications, via visits at month six   The statistical testing process, The Hochberg Method, was used for multiplicity management, requiring each doses to have a p<0.05 or one dose to have a p<0.025 to be thought of statistically important. As the first endpoint was not important, statistical significance couldn’t be claimed for secondary endpoints. †The placebo adjusted SBP modifications are proven as LS imply (95% CI)

In abstract, within the Cohort A general examine inhabitants, zilebesiran 300 mg achieved clinically significant reductions in workplace SBP at month three, with sustained advantages out to month six, in comparison with placebo. No incremental SBP reductions had been noticed with zilebesiran 600 mg at months three or six. Post-hoc analyses counsel {that a} larger blood pressure-lowering impact with zilebesiran was noticed in sufferers on diuretic remedy and uncontrolled hypertension at baseline (with workplace SBP ≥140). Reductions in blood stress had been sustained over six months, and the whole 24-hour interval. Incremental reductions had been additionally noticed at nighttime, a interval throughout which blood stress elevations is a robust predictor of cardiovascular threat. 

 

Consistent with prior research, zilebesiran demonstrated an encouraging security profile when added to 2 or extra background antihypertensives (over 90% of whom had been receiving therapy with an ACE inhibitor or an ARB).  Most opposed occasions had been delicate or reasonable, non-serious, and transient with few requiring intervention; charges of hyperkalaemia, kidney dysfunction, and hypotension had been low. Across examine arms, severe opposed occasions had been noticed in 3.8% and 4.5% in zilebesiran and placebo-treated sufferers, respectively. No deaths had been reported throughout the six-month double-blind interval.

 

Results from KARDIA-3 Cohort B are anticipated to be offered at an upcoming medical assembly.

 

About the ZENITH CVOT
The international Phase III ZENITH CVOT is an event-driven examine that can enroll roughly 11,000 sufferers in over 30 nations to guage zilebesiran 300 mg in sufferers with uncontrolled hypertension, regardless of using a minimum of two commonplace of care antihypertensives (one being a diuretic), and with both established heart problems (CVD) or at excessive threat for CVD. The main goal will likely be to evaluate the impression of zilebesiran on lowering the danger of CV dying, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary heart failure (HF) occasions (hospitalization for HF or pressing HF go to), in comparison with placebo.

 

About Zilebesiran

Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic in improvement for the therapy of hypertension to cut back cardiovascular threat in excessive unmet want populations. Zilebesiran targets angiotensinogen (AGT), essentially the most upstream precursor within the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a task in blood stress (BP) regulation. Zilebesiran inhibits the synthesis of AGT within the liver, doubtlessly resulting in sturdy reductions in AGT protein, and in the end, within the vasoconstrictor angiotensin (Ang) II. Zilebesiran makes use of Alnylam’s Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate know-how, which allows rare biannual subcutaneous dosing and elevated selectivity. Zilebesiran has demonstrated the flexibility to offer steady management of blood stress with biannual dosing in sufferers with mild-to-moderate hypertension as a monotherapy and together with standard-of-care antihypertensives, in addition to in sufferers with excessive cardiovascular threat and uncontrolled hypertension regardless of using a number of background therapies. The security and efficacy of zilebesiran haven’t been established or evaluated by the FDA, EMA or some other well being authority. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche.

 

Zilebesiran Phase II scientific improvement overview:

Study	Overview of protocol
KARDIA-1 [NCT04936035]	Evaluated zilebesiran monotherapy in individuals with delicate to reasonable hypertension. Met main endpoint of the examine demonstrating a clinically important discount of systolic blood stress at three months of therapy in contrast with placebo (>15 mmHg discount of 24h imply Systolic Blood Pressure (SBP) at 3 months vs. placebo at two highest doses (300 mg, 600 mg), p<0.0001).
KARDIA-2 [NCT05103332]	Evaluated zilebesiran when added to a regular of care hypertension treatment in individuals with delicate to reasonable hypertension. Met main endpoint demonstrating that zilebesiran resulted in clinically and statistically important additive, placebo-adjusted reductions in 24-hour imply systolic blood stress (SBP) of as much as 12.1 mmHg at month three (measured per ABPM).
KARDIA-3 [NCT06272487]	Evaluated zilebesiran when added to 2 to 4 hypertension drugs in individuals with uncontrolled hypertension at excessive cardiovascular threat. Among people with CV illness or at excessive CV threat who’ve uncontrolled HTN, a single dose of zilebesiran 300 mg and 600 mg led to respective 5.0 mmHg and three.3 mmHg reductions in workplace systolic BP at three months in contrast with placebo, though statistical significance was not reached.

 

About Cardiovascular Disease and Hypertension

Cardiovascular illness (CVD) is a world well being disaster and a number one reason for dying worldwide, liable for roughly 20 million deaths yearly. Hypertension is the first reason for and primary modifiable threat issue for CVD. An estimated one in three adults worldwide have hypertension and regardless of large availability of antihypertensives, as much as 80% of all sufferers and as much as a 3rd of handled sufferers don’t attain and preserve blood stress (BP) targets. Even when blood stress seems nicely managed, steady management of BP could stay suboptimal, resulting in variability in BP throughout the 24-hour interval and within the long-term, placing sufferers at larger threat of cardiovascular occasions and finish organ harm. These sufferers require novel approaches that not solely cut back BP but additionally decrease general cardiovascular threat. 

 

About Genentech

Founded greater than 40 years in the past, Genentech is a number one biotechnology firm that discovers, develops, manufactures and commercializes medicines to deal with sufferers with severe and life-threatening medical situations. The firm, a member of the Roche Group, has headquarters in South San Francisco, California. For extra details about the corporate, please go to
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