zilebesiran (ALN-AGT) / Alnylam, Roche - LARVOL DELTA

Efficacy of Zilebesiran in Hypertension: A Meta-analysis with Dose-Response and Angiotensinogen Correlation from KARDIA Trials (AHA 2025) - "Zilebesiran significantly reduces 24-hour systolic blood pressure across dosing regimens. However, no clear dose-response relationship or direct link between AGT suppression and SBP reduction was observed. These findings highlight the need for further trials with harmonized dosing and biomarker reporting to clarify predictors of response."

Retrospective data • Cardiovascular • Hypertension

Zilebesiran as an Innovative siRNA-Based Therapeutic Approach for Hypertension: Emerging Perspectives in Cardiovascular Medicine. (PubMed, Int J Mol Sci) - "In conclusion, zilebesiran represents a promising siRNA-based therapy that may redefine the management of difficult-to-control hypertension, offering durable, targeted, and patient-friendly treatment with broad cardiovascular benefits. Future studies will clarify its long-term safety, efficacy across diverse populations, and integration into personalized hypertension management strategies."

Journal • Review • Cardiovascular • Hypertension

KARDIA-3: A randomized trial of zilebesiran versus placebo on top of standard care for patients with hypertension and established cardiovascular disease or high cardiovascular risk with or without chronic kidney disease (AHA 2025) - P2 | "Results of the KARDIA-3 trial, including patients with CKD, will characterize the efficacy and safety profile of zilebesiran in patients with uncontrolled hypertension despite standard care who are at high CV risk and will inform the design of a planned CVOT."

Clinical • Cardiovascular • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Hypertension • Metabolic Disorders • Nephrology • Renal Disease

Zilebesiran-Small Interfering RNAs as Prospective New Drug in the Treatment of Hypertension. (PubMed, J Clin Med) - "In hypertensive patients, a long-term reduction in blood pressure by more than 10 mmHg compared to placebo has been observed after a single dose of zilebesiran. Despite the promising results of the previous studies, further observations are still necessary regarding side effects and long-term effectiveness, as well as the possibility of developing resistance to treatment."

Journal • Review • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension

RNA-targeted therapeutics in arterial hypertension. (PubMed, Eur Heart J Qual Care Clin Outcomes) - "On the one hand, zilebesiran (formerly ALN-AGT01) is currently in phase 2 clinical trials and targets the hepatic synthesis of angiotensinogen through a novel mechanism of action. On the other hand, IONIS-AGT-LRX is a hepatocyte-directed antisense oligonucleotide designed to target AGT mRNA in hepatocytes, thereby reducing angiotensinogen synthesis and circulating plasma levels...However, these therapies are not suitable for the acute management of hypertensive emergencies or urgencies, and evidence regarding their effects on cardiovascular outcomes, target organ protection, and mortality is still lacking. Further studies are warranted to define their role in clinical practice."

Journal • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension

Efficacy and Safety of Zilebesiran for the Management of Hypertension: An Updated Systematic Review and Meta-Analysis of Randomised Controlled Trials. (PubMed, Cureus) - "This meta-analysis confirms that Zilebesiran is consistently associated with significant reductions in both ambulatory and office blood pressure over 12 to 24 weeks, with an acceptable safety profile. Further trials are needed to evaluate the efficacy, dosing, and safety outcomes of Zilebesiran across diverse hypertensive populations."

Journal • Retrospective data • Review • Cardiovascular • Hypertension

Zilebesiran Add-On Treatment for Inadequately Controlled Hypertension. (PubMed, JAMA) - No abstract available

Journal • Cardiovascular • Hypertension

Zilebesiran Add-On Treatment for Inadequately Controlled Hypertension-Reply. (PubMed, JAMA) - No abstract available

Journal • Cardiovascular • Hypertension

A Study to Evaluate ALN-AGT01 RVR in Adult Healthy Volunteers (clinicaltrials.gov) - P1 | N=42 | Completed | Sponsor: Alnylam Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion

ZENITH: Zilebesiran in Patients With Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease (clinicaltrials.gov) - P3 | N=11000 | Recruiting | Sponsor: Alnylam Pharmaceuticals

Adverse events • New P3 trial • Cardiovascular • Congestive Heart Failure • Hypertension

KARDIA-3: Zilebesiran as Add-on Therapy in Adults with Hypertension and Established Cardiovascular Disease or at High Cardiovascular Risk (ESC-WCC 2025) - No abstract available

Clinical • Cardiovascular • Hypertension

Add-on treatment with zilebesiran for inadequately controlled hypertension: KARDIA-2 RCT (ESC-WCC 2025) - "Joint session with JAMA and JAMA Cardiology"

Cardiovascular • Hypertension

Impact of zilebesiran, an investigational RNA interference therapeutic targeting hepatic angiotensinogen, on renin-angiotensin system biomarkers in patients with mild-to-moderate hypertension (ESC-WCC 2025) - "AGT reductions with biannual and quarterly doses of zilebesiran were observed to Month 6 and were accompanied by decreases in serum angiotensin I and II concentrations and subsequent increases in plasma renin concentration, consistent with disruption of negative angiotensin II feedback on renin secretion with angiotensinogen inhibition. Pharmacodynamic effects were sustained for 6 months, without evidence of angiotensin escape, which together with previously reported long-lasting blood pressure-lowering effects, support a biannual dosing regimen for zilebesiran."

Biomarker • Clinical • Cardiovascular • Hypertension

ALN-AGT01-006: A Study to Evaluate Zilebesiran in Japanese Patients With Mild to Moderate Hypertension (clinicaltrials.gov) - P1/2 | N=36 | Completed | Sponsor: Alnylam Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Hypertension

Results of KARDIA-3 showed that a single dose of zilebesiran (300 mg every six months, subcutaneous injection) resulted in clinically meaningful placebo-adjusted reductions of office systolic blood pressure (SBP) in all comers at the month three primary endpoint (-5.0 mmHg; p=0.0431) with sustained benefits out to month six (-3.9 mmHg; 95% CI: [-8.5, 0.7]). (Roche Press Release) - "There were no additional benefits 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 overall KARDIA-3 study did not meet the pre-specified definition for statistical significance, because of a multiplicity statistical testing approach...In an analysis of patients that were on diuretics and had a baseline BP >140 mm Hg, the placebo-adjusted reduction was -9.2mmHg; (-17.3, -1.2) at month three and -8.3mmHg (-16.4, -0.2) at month six."

P3 data • Hypertension

The ZENITH (ZilebEsiraN CardIovascular OuTcome Study in Hypertension) Phase III trial has been submitted to global regulators and is expected to be initiated by the end of 2025. (Roche Press Release) - "ZENITH will be a CVOT enrolling approximately 11,000 patients and evaluating zilebesiran (300 mg) every six months compared to placebo in patients with uncontrolled hypertension with either established CV disease or at high risk for CV disease on two or more antihypertensives, one being a diuretic."

New P3 trial • Hypertension

A Study to Evaluate ALN-AGT01 RVR in Adult Healthy Volunteers (clinicaltrials.gov) - P1 | N=42 | Active, not recruiting | Sponsor: Alnylam Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=78 ➔ 42

Enrollment change • Enrollment closed

Key Upcoming Events (Businesswire) - "Alnylam announces today that it will present results from the KARDIA-3 Phase 2 trial of zilebesiran in patients with hypertension during a Hot Line Session at the European Society of Cardiology (ESC) Congress in Madrid, Spain on August 30, 2025...In addition, in the second half of 2025, Alnylam expects to: Initiate a Phase 3 cardiovascular outcomes trial of zilebesiran, in collaboration with its partner Roche; Initiate the TRITON-PN Phase 3 trial of nucresiran in hATTR-PN; Initiate a Phase 2 trial of mivelsiran in Alzheimer’s disease....In addition, Alnylam's partner, Regeneron Pharmaceuticals, plans to share results from the Phase 3 trial of cemdisiran tested as a monotherapy and in combination with pozelimab in patients with myasthenia gravis in the second half of 2025."

Clinical data • New P2 trial • New P3 trial • Alzheimer's Disease • Amyloidosis • Cardiovascular • Hypertension • Myasthenia Gravis

Advancing antihypertensive drug development. (PubMed, Br J Pharmacol) - "RNA-based therapies, like zilebesiran, provide a novel approach to suppress angiotensinogen, offering durable antihypertensive effects with less frequent dosing...These emerging therapies not only aim to lower blood pressure but also address underlying pathophysiological mechanisms, offering a precision-focussed approach to treatment. By critically analysing these developments, this review provides insights into how novel strategies can overcome existing challenges in hypertension management, reduce the global disease burden and improve patient outcomes."

Journal • Review • Cardiovascular • Hypertension • Hypotension

Zilebesiran: A Novel RNA Interference Therapeutic for Hypertension. (PubMed, Cardiol Rev) - "Therapeutic applications under investigation include use as monotherapy in patients with essential hypertension and as an adjunct for patients with resistant hypertension or high cardiovascular risk. This manuscript provides a comprehensive overview of zilebesiran's mechanism of action, pharmacokinetics/pharmacodynamics, clinical trial evidence, potential role in hypertension management and related conditions, as well as its safety and tolerability profile, based on current peer-reviewed data."

Journal • Cardiovascular • Hypertension • Hypotension • Renal Disease

Add-On Treatment With Zilebesiran for Inadequately Controlled Hypertension: The KARDIA-2 Randomized Clinical Trial. (PubMed, JAMA) - P2 | "In patients with uncontrolled hypertension despite treatment with indapamide, amlodipine, or olmesartan, the addition of single-dose zilebesiran resulted in significant SBP reductions compared with placebo at 3 months, with low rates of serious adverse events. ClinicalTrials.gov Identifier: NCT05103332."

Clinical • Journal • Acute Kidney Injury • Cardiovascular • Hypertension • Hypotension • Nephrology • Renal Disease

Novel Antihypertensive Medications to Target the Renin-Angiotensin System: Mechanisms and Research. (PubMed, Rev Cardiovasc Med) - "The current overview presents the latest research findings on the mechanisms through which novel anti-hypertensive medications target the RAS. These include zilebesiran (targeting angiotensinogen), PRO20 (targeting the renin/(pro)renin/PRR axis), sacubitril/valsartan (targeting the renin/ACE/Ang II/AT1R axis), GSK2586881, Ang (1-7) and AVE0991 (targeting the renin/ACE2/Ang (1-7)/MasR axis), alamandine (targeting the alamandine/MrgD receptor axis), C21 and β-Pro7-Ang III (targeting the renin/ACE/Ang II/AT2R axis), EC33, and firibastat and NI956 (targeting brain Ang III)."

Journal • Review • Cardiovascular • CNS Disorders • Hypertension • Vascular Neurology

Key Upcoming Events (Businesswire) - "Alnylam intends to initiate the TRITON-CM Phase 3 clinical trial of nucresiran in patients with ATTR-CM in the first half of 2025...Alnylam anticipates regulatory approval for AMVUTTRA for ATTR-CM in Japan in Q2 and in the European Union in Q3 of 2025...Alnylam also intends to release data from the KARDIA-3 Phase 2 clinical trial evaluating zilebesiran in combination with at least two antihypertensives in high cardiovascular risk patients with uncontrolled hypertension in the second half of 2025. These results will further inform the design of a Phase 3 cardiovascular outcomes trial for zilebesiran that Alnylam intends to initiate in the second half of 2025."

EMA approval • Japan approval • New P3 trial • P2 data • Amyloidosis • Cardiomyopathy • Cardiovascular • Hypertension

Novel approaches in antihypertensive pharmacotherapeutics. (PubMed, Curr Opin Nephrol Hypertens) - "Pharmacotherapeutic management options for hypertension is a growing field of research with potential clinical implications for multiple agents in upcoming years. Such novel approaches have the potential to improve clinical outcomes of hypertension management."

Journal • Cardiovascular • Hypertension

Advancing hypertension management: the role of zilebesiran as an siRNA therapeutic agent. (PubMed, Ann Med Surg (Lond)) - "Its emergence highlights the ongoing evolution of cardiovascular pharmacology and underscores the importance of innovative approaches to address the global burden of hypertension. Moving forward, concerted efforts in research and clinical practice are necessary to realize the benefits of zilebesiran into hypertension management protocols, ultimately advancing cardiovascular health worldwide."

Journal • Review • Cardiovascular • Hypertension • ASGR