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

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) - No abstract available

Biomarker • Clinical • Cardiovascular • Hypertension

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

Safety and Efficacy of Novel RNA Interference Therapeutic Agent Zilebesiran in People With Hypertension: A Systematic Review and Meta-Analysis. (PubMed, Cureus) - "This limits the generalizability of the results and highlights the need for further trials with a larger and more diverse study population. Further long-term investigations are also needed to establish the drug's impact on body weight, blood glucose levels, lipid profile, cardiovascular and hepatic health, and its efficacy when used alongside conventional antihypertensive medications."

Journal • Retrospective data • Review • Cardiovascular • Dermatology • Hypertension • Nephrology • Pain • Renal Disease

Alnylam Announces Preliminary Fourth Quarter and Full Year 2024 Global Net Product Revenues and Provides 2025 Combined Net Product Revenue Guidance and Pipeline Goals (Businesswire) - "Zilebesiran – an investigational RNAi therapeutic in development for the treatment of hypertension, in collaboration with Roche. Alnylam expects to: Report results from the KARDIA-3 Phase 2 study in the second half of 2025.Initiate a Phase 3 cardiovascular outcomes trial in the second half of 2025...ALN-6400 – an investigational RNAi therapeutic in development for the treatment of bleeding disorders. Alnylam expects to: Initiate a Phase 2 study in a bleeding disorder in the second half of 2025. In addition, the Company plans to file Investigational New Drug (IND) applications for four new Alnylam-led programs by the end of 2025."

IND • New P2 trial • New P3 trial • P2 data • Cardiovascular • Hematological Disorders • Hypertension

Exploratory Studies on RNAi-Based Therapies Targeting Angiotensinogen in Hypertension: Scoping Review. (PubMed, J Pers Med) - "Focusing on the efficacy and safety of RNAi-based therapies, this review discusses several key approaches, including antisense oligonucleotides (IONIS-AGT-LRx), small interfering RNA (siRNAs; zilebesiran), and adeno-associated viruses carrying short hairpin RNAs. They offer long-term BP control with fewer doses, potentially improving patient adherence and outcome. Although these therapies address several limitations of current antihypertensive treatments, further studies are required to confirm their long-term safety and efficacy."

Journal • Review • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension

Zilebesiran as Add-on Therapy in Patients With High Cardiovascular Risk and Hypertension Not Adequately Controlled by Standard of Care Antihypertensive Medications (KARDIA-3) (clinicaltrials.gov) - P2 | N=375 | Active, not recruiting | Sponsor: Alnylam Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Hypertension

Small Interfering RNA Therapy for the Management and Prevention of Hypertension. (PubMed, Curr Hypertens Rep) - "One subcutaneous injection of angiotensinogen siRNA lowers blood pressure for 6 months without severe side effects. The decrease in angiotensinogen and blood pressure can be reversed with a drug called REVERSIR if needed."

Journal • Review • Cardiovascular • Hypertension

Zilebesiran and Hypertension: A Systematic Review and Meta-analysis. (PubMed, J Saudi Heart Assoc) - "Optimal dosing appears between 250 and 500 mg. Further research should explore patient-specific responses to enhance therapeutic efficacy and minimize side effects."

Journal • Retrospective data • Review • Cardiovascular • Hypertension • Hypotension

KARDIA-1: A Study to Evaluate Efficacy and Safety of ALN-AGT01 in Patients With Mild To-Moderate Hypertension (clinicaltrials.gov) - P2 | N=394 | Completed | Sponsor: Alnylam Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Hypertension

Novel pharmacologic approaches in resistant hypertension. (PubMed, Wiad Lek) - "Recently, valsartan/sacubitrol and flozins have been increasingly used in resistant hypertension, which have been introduced for the treatment of diseases other than hypertension but can be a supplement to previously used drugs in resistant hypertension...The results to date allow for the consideration of aprocitentan (a drug that inhibits endothelin receptors) or baxdrostat or another new aldosterone synthesis inhibitor in the treatment of resistant hypertension that does not respond to 4 drugs, including spironolactone. Further studies are needed to confirm the efficacy and safety of these new drugs in the treatment of resistant hypertension."

Journal • Review • Cardiovascular • Hypertension

Transforming Hypertension Treatment: Zilebesiran's Possible Impact. (PubMed, Cardiovasc Drugs Ther) - No abstract available

Journal • Cardiovascular • Hypertension

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

Enrollment open

KARDIA-3 Study Design: Zilebesiran as Add-On Therapy in Patients with High Cardiovascular Risk and Hypertension Inadequately Controlled by Standard of Care Antihypertensives (CVCT USA 2024) - No abstract available

Clinical • Cardiovascular • Hypertension

Zilebesiran An Investigational Ribonucleic Acid Interference Therapeutic for Subcutaneous Treatment of Hypertension (ASHP 2024) - No abstract available

Cardiovascular • Hypertension

A Study to Evaluate ALN-AGT01 RVR in Adult Healthy Volunteers (clinicaltrials.gov) - P1 | N=78 | Not yet recruiting | Sponsor: Alnylam Pharmaceuticals

New P1 trial

Will zilebesiran, an RNA interference therapy, be effective, safe, and improve the treatment of hypertension? (PubMed, Expert Opin Biol Ther) - "It was also difficult to reliably interpret the results of KARDIA-1 as blood pressure went up significantly in the placebo group. KARDIA-1 did not answer previous concerns about zilebesiran; (i) what happens during volume depletion, sepsis, and pregnancy when angiotensinogen is inhibited long-term or (ii) will it be effective in a high sodium diet."

Journal • Review • Cardiovascular • Hypertension • Infectious Disease • Renal Disease • Septic Shock

Home Blood Pressure Reductions With Zilebesiran In Patients With Mild-To-Moderate Hypertension Are Consistent With Ambulatory And Office Blood Pressure Reductions In The KARDIA-1 Study (AHA 2024) - P2 | "Clinically significant time-adjusted reductions observed with self-assessed home BP following treatment with zilebesiran were consistent with ambulatory and office BP reductions, indicating that self-monitoring of BP control with zilebesiran is viable outside of the clinical visit setting. Weekly home BP measurements demonstrated consistent reductions in SBP, highlighting the potential of zilebesiran for providing sustained BP control."

Clinical • Cardiovascular • Hypertension

Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (KARDIA-2) (clinicaltrials.gov) - P2 | N=672 | Completed | Sponsor: Alnylam Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Hypertension