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08/30/2025 – 10:30 AM
– Phase III trial informed by comprehensive KARDIA data set generated through three Phase II studies: KARDIA-1, KARDIA-2 and KARDIA-3 –
– In the Phase II KARDIA-3 study, presented today as a late breaker at the European Society of Cardiology Congress 2025, zilebesiran demonstrated clinically meaningful reductions in office systolic blood pressure at month three with continuous control through month six –
– Zilebesiran, a potential best-in-disease RNAi antihypertensive with twice-yearly subcutaneous dosing, demonstrated encouraging safety when combined with two or more antihypertensives –
– Phase III cardiovascular outcomes trial expected to be initiated by the end of the year –
SOUTH SAN FRANCISCO, Calif. — Biotech giants Genentech (a Roche Group member) and Alnylam are gearing up for a Phase III showdown with zilebesiran, an RNAi therapeutic poised to disrupt the hypertension market. The companies announced plans to initiate a cardiovascular outcomes trial (CVOT) to gauge the drug’s ability to slash the risk of major adverse cardiovascular events in patients grappling with uncontrolled hypertension.
The decision comes on the heels of a comprehensive KARDIA Phase II program, encompassing the KARDIA-1, KARDIA-2, and the newly unveiled KARDIA-3 studies. These trials rigorously assessed zilebesiran’s efficacy and safety in patients battling uncontrolled hypertension and elevated cardiovascular risk, even while on a regimen of two to four standard-of-care antihypertensives. Notably, KARDIA-3 was designed to pinpoint the patient population most likely to benefit from zilebesiran in the upcoming Phase III trial.
The KARDIA-3 results revealed that a single 300 mg dose of zilebesiran, administered via subcutaneous injection every six months, yielded clinically significant, placebo-adjusted reductions in office systolic blood pressure (SBP) at the month three primary endpoint (-5.0 mmHg; p=0.0431). This effect sustained through month six (-3.9 mmHg; 95% CI: [-8.5, 0.7]). Interestingly, the 600 mg dose did not offer additional benefits at either month three (-3.3 mmHg; p=0.1830) or month six (-3.6 mmHg; 95% CI: [-8.2, 1.0]). While KARDIA-3, due to a stringent statistical testing approach, didn’t hit the pre-specified definition for statistical significance, it successfully identified the patient profile that could potentially reap the greatest rewards from zilebesiran. Moreover, the study showcased encouraging safety data and clinically meaningful reductions in blood pressure.
Echoing the findings of the KARDIA-2 Phase II study, KARDIA-3 data bolstered the case for combining zilebesiran with a diuretic, a common antihypertensive. In a subgroup analysis of patients on diuretics with a baseline BP exceeding 140 mmHg, the placebo-adjusted reduction was a notable -9.2 mmHg (-17.3, -1.2) at month three and -8.3 mmHg (-16.4, -0.2) at month six. This type of combination therapy has established precedent for enhanced blood pressure reduction, supported by both scientific literature and clinical practice.
“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,” asserted 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 also exhibited encouraging safety profiles in patients with comorbidities on multiple background therapies – with over 90% receiving treatment with an ACE inhibitor or an Angiotensin Receptor Blocker (ARB). These findings underscore confidence in zilebesiran’s potential for seamless integration with standard-of-care antihypertensives.
Consequently, the global ZENITH (Zilebesiran cardiovascular outcome study in Hypertension) Phase III trial has been submitted to global regulators and is expected to be unleashed by the end of 2025. ZENITH, an event-driven CVOT, aims to enroll approximately 11,000 patients, evaluating zilebesiran (300 mg) every six months compared to placebo. Participants will be patients with uncontrolled hypertension, either with preexisting CV disease or at high risk, and already on two or more antihypertensives, one of which must be a diuretic.
Hypertension, the primary culprit and most manageable risk factor for cardiovascular disease, affects an estimated one in three adults worldwide – over 1.2 billion people. Despite the widespread availability of antihypertensives, a staggering 80% fail to achieve adequate blood pressure control. A major contributing factor is poor adherence to daily oral therapies. An effective, long-acting therapy offering continuous blood pressure control could be instrumental in reducing the burden of uncontrolled hypertension.
With an expanding cardiometabolic portfolio and robust diagnostic capabilities, Genentech seeks to advance transformative standards of care, improving the lives of individuals grappling with cardiometabolic diseases, while simultaneously alleviating the strain on healthcare systems and society.
About the KARDIA-3 Study
KARDIA-3 (NCT06272487), the third Phase II study in the KARDIA program, included two Cohorts (A and B). Cohort A assessed zilebesiran in patients with eGFR ≥ 45 mL/min/1.73m2, while Cohort B included patients with advanced kidney dysfunction (i.e., eGFR between 30 and
At baseline, 144 (53.3%), 96 (35.6%) and 30 (11.1%) patients were on two, three, or over three antihypertensives, respectively, with ~91% of patients taking ACE inhibitors/ARBs, ~66% of patients taking a diuretic, and ~58% of patients taking calcium channel blockers. The mean baseline office and 24-hour mean ambulatory SBP were 143.6 mmHg and 142.4 mmHg, respectively (N= 270).
KARDIA-3 Cohort A Primary Results (Placebo-Adjusted Changes from Baseline):
|
Cohort A Study population |
Endpoint |
Month three change (censored)* † |
Month six change (all collected) ** † |
|
Overall study population (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 analysis excludes patients who intensified antihypertensive use within two weeks of visits at month three **All collected analysis includes all available patient data, regardless of medication changes, through visits at month six The statistical testing procedure, The Hochberg Method, was used for multiplicity control, requiring both doses to have a p †The placebo adjusted SBP changes are shown as LS mean (95% CI) |
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In summary, in the Cohort A overall study population, zilebesiran 300 mg achieved clinically meaningful reductions in office SBP at month three, with sustained benefits out to month six, compared to placebo. No incremental SBP reductions were observed with zilebesiran 600 mg at months three or six. Post-hoc analyses suggest that a greater blood pressure-lowering effect with zilebesiran was observed in patients on diuretic therapy and uncontrolled hypertension at baseline (with office SBP ≥140). Reductions in blood pressure were sustained over six months, and the entire 24-hour period. Incremental reductions were also observed at nighttime, a period during which blood pressure elevations is a strong predictor of cardiovascular risk.
Consistent with prior studies, zilebesiran demonstrated an encouraging safety profile when added to two or more background antihypertensives (over 90% of whom were receiving treatment with an ACE inhibitor or an ARB). Most adverse events were mild or moderate, non-serious, and transient with few requiring intervention; rates of hyperkalaemia, kidney dysfunction, and hypotension were low. Across study arms, serious adverse events were observed in 3.8% and 4.5% in zilebesiran and placebo-treated patients, respectively. No deaths were reported during the six-month double-blind period.
Results from KARDIA-3 Cohort B are expected to be presented at an upcoming medical meeting.
About the ZENITH CVOT
The global Phase III ZENITH CVOT is an event-driven study that will enroll approximately 11,000 patients in over 30 countries to evaluate zilebesiran 300 mg in patients with uncontrolled hypertension, despite the use of at least two standard of care antihypertensives (one being a diuretic), and with either established cardiovascular disease (CVD) or at high risk for CVD. The primary objective will be to assess the impact of zilebesiran on reducing the risk of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or heart failure (HF) events (hospitalization for HF or urgent HF visit), compared to placebo.
About Zilebesiran
Zilebesiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of hypertension to reduce cardiovascular risk in high unmet need populations. Zilebesiran targets angiotensinogen (AGT), the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a role in blood pressure (BP) regulation. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein, and ultimately, in the vasoconstrictor angiotensin (Ang) II. Zilebesiran utilizes Alnylam’s Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables infrequent biannual subcutaneous dosing and increased selectivity. Zilebesiran has demonstrated the ability to provide continuous control of blood pressure with biannual dosing in patients with mild-to-moderate hypertension as a monotherapy and in combination with standard-of-care antihypertensives, as well as in patients with high cardiovascular risk and uncontrolled hypertension despite the use of multiple background therapies. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA or any other health authority. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche.
Zilebesiran Phase II clinical development overview:
|
Study |
Overview of protocol |
|
KARDIA-1 [NCT04936035] |
Evaluated zilebesiran monotherapy in people with mild to moderate hypertension. Met primary endpoint of the study demonstrating a clinically significant reduction of systolic blood pressure at three months of treatment compared with placebo (>15 mmHg reduction of 24h mean Systolic Blood Pressure (SBP) at 3 months vs. placebo at two highest doses (300 mg, 600 mg), p |
|
KARDIA-2 [NCT05103332] |
Evaluated zilebesiran when added to a standard of care hypertension medication in people with mild to moderate hypertension. Met primary endpoint demonstrating that zilebesiran resulted in clinically and statistically significant additive, placebo-adjusted reductions in 24-hour mean systolic blood pressure (SBP) of up to 12.1 mmHg at month three (measured per ABPM). |
|
KARDIA-3 [NCT06272487] |
Evaluated zilebesiran when added to two to four hypertension medications in people with uncontrolled hypertension at high cardiovascular risk. Among individuals with CV disease or at high CV risk who have uncontrolled HTN, a single dose of zilebesiran 300 mg and 600 mg led to respective 5.0 mmHg and 3.3 mmHg reductions in office systolic BP at three months compared with placebo, although statistical significance was not reached. |
About Cardiovascular Disease and Hypertension
Cardiovascular disease (CVD) is a global health crisis and a leading cause of death worldwide, responsible for approximately 20 million deaths annually. Hypertension is the primary cause of and number one modifiable risk factor for CVD. An estimated one in three adults worldwide have hypertension and despite wide availability of antihypertensives, up to 80% of all patients and up to a third of treated patients do not reach and maintain blood pressure (BP) targets. Even when blood pressure appears well managed, continuous control of BP may remain suboptimal, leading to variability in BP during the 24-hour period and in the long-term, putting patients at greater risk of cardiovascular events and end organ damage. These patients require novel approaches that not only reduce BP but also lower overall cardiovascular risk.
About Genentech
Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.
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