Zilebesiran: An Sirna-Based Therapeutic Approach For Hypertension Management. Review
Abstract
Highlights
• Zilebesiran uses siRNA to stop liver angiotensinogen and lower blood pressure.
• One dose can work for 24 weeks.
• Side effects are mostly just skin redness at the injection site.
• Dosing twice a year may help patients stick to their treatment.
Keywords
Full Text:
PDFReferences
- Carey, Robert M., Andrew E. Moran, and Paul K. Whelton. "Treatment of hypertension: a review." Jama 328.18 (2022): 1849-1861.
- Strilchuk, Larysa, et al. "Dietary interventions in blood pressure lowering: current evidence in 2020." Polish Heart Journal (Kardiologia Polska) 78.7-8 (2020): 659-666.
- Taddei, Stefano, Lorenzo Ghiadoni, and Antonio Salvetti. "Current treatment of patients with hypertension: therapeutic implications of INSIGHT." Drugs 63.14 (2003): 1435-1444.
- Olowofela, Abimbola O., and Ambrose O. Isah. "A profile of adverse effects of antihypertensive medicines in a tertiary care clinic in Nigeria." Annals of African medicine 16.3 (2017): 114-119.
- Dézsi, Csaba András. "Differences in the clinical effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a critical review of the evidence." American Journal of Cardiovascular Drugs 14.3 (2014): 167-173.
- Mooser, V., et al. "Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition." Journal of cardiovascular pharmacology 15.2 (1990): 276-282.
- Cruz-López, Edwyn O., et al. "Angiotensinogen suppression: a new tool to treat cardiovascular and renal disease." Hypertension 79.10 (2022): 2115-2126.
- Ren, Liwei, et al. "Targeting angiotensinogen with RNA-based therapeutics." Current opinion in nephrology and hypertension 29.2 (2020): 180-189.
- Padda, Inderbir S., Arun U. Mahtani, and Mayur Parmar. "Small interfering RNA (siRNA) based therapy." (2022)
- Poulter, Neil R., et al. "Medication adherence in hypertension." Journal of hypertension 38.4 (2020): 579-587.
- da Silva, Vandermi João, et al. "Commercial devices-based system designed to improve the treatment adherence of hypertensive patients." Sensors (Basel, Switzerland) 19.20 (2019): 4539.
- Parati, Gianfranco, et al. "Current challenges for hypertension management: From better hypertension diagnosis to improved patients' adherence and blood pressure control." International journal of cardiology 331 (2021): 262-269.
- Hoppe, Bernd, et al. "Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria." Kidney international 101.3 (2022): 626-634.
- Garrelfs, Sander F., et al. "Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1." New England journal of medicine 384.13 (2021): 1216-1226.
- Balwani, Manisha, et al. "Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria." New England journal of medicine 382.24 (2020): 2289-2301.
- Syed, Yahiya Y. "Anlotinib: first global approval." Drugs 78.10 (2018): 1057.
- Adams, David, et al. "Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis." New england journal of medicine 379.1 (2018): 11-21.
- Ray, Kausik K., et al. "Inclisiran and cardiovascular events: a patient-level analysis of phase III trials." European heart journal 44.2 (2023): 129-138.
- Zhang, M. May, et al. "The growth of siRNA-based therapeutics: Updated clinical studies." Biochemical pharmacology 189 (2021): 114432.
- Desai, Akshay S., et al. "Zilebesiran, an RNA interference therapeutic agent for hypertension." New England Journal of Medicine 389.3 (2023): 228-238.
- Cruz-López, Edwyn O., et al. "Angiotensinogen suppression: a new tool to treat cardiovascular and renal disease." Hypertension 79.10 (2022): 2115-2126.
- Sealey, Jean E., and John H. Laragh. "Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness." American journal of hypertension 20.5 (2007): 587-597.
- Balcarek, Joanna, et al. "Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition." Hypertension 63.5 (2014): 942-950.
- Uijl, Estrellita, et al. "Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen." Hypertension 73.6 (2019): 1249-1257.
- Uijl, Estrellita, et al. "Conventional Vasopressor and Vasopressor‐Sparing Strategies to Counteract the Blood Pressure–Lowering Effect of Small Interfering RNA Targeting Angiotensinogen." Journal of the American Heart Association 11.15 (2022): e026426.
- Cruz-López, Edwyn O., Estrellita Uijl, and AH Jan Danser. "Perivascular adipose tissue in vascular function: does locally synthesized angiotensinogen play a role?." Journal of Cardiovascular Pharmacology 78 (2021): S53-S62.
- Uijl, Estrellita, et al. "No evidence for brain renin–angiotensin system activation during DOCA-salt hypertension." Clinical Science 135.2 (2021): 259-274.
- van Thiel, Bibi S., et al. "Brain renin–angiotensin system: does It exist?." Hypertension 69.6 (2017): 1136-1144.
- Ren, Liwei, Xifeng Lu, and AH Jan Danser. "Revisiting the brain renin-angiotensin system—focus on novel therapies." Current hypertension reports 21.4 (2019): 28.
- Crick, Francis. "Central dogma of molecular biology." Nature 227.5258 (1970): 561-563.
- Ren, Liwei, et al. "Targeting angiotensinogen with RNA-based therapeutics." Current opinion in nephrology and hypertension 29.2 (2020): 180-189.
- Liang, Xue-Hai, et al. "RNase H1-dependent antisense oligonucleotides are robustly active in directing RNA cleavage in both the cytoplasm and the nucleus." Molecular therapy 25.9 (2017): 2075-2092.
- Liang, Xue-Hai, et al. "RNase H1-dependent antisense oligonucleotides are robustly active in directing RNA cleavage in both the cytoplasm and the nucleus." Molecular therapy 25.9 (2017): 2075-2092.
- Morris, Kevin V., et al. "Small interfering RNA-induced transcriptional gene silencing in human cells." Science 305.5688 (2004): 1289-1292.
- Daga, Pawan, et al. "Emerging RNAi therapies to treat hypertension." Molecular Diagnosis & Therapy 29.1 (2025): 25-41.
- Hutvagner, Gyorgy, and Martin J. Simard. "Argonaute proteins: key players in RNA silencing." Nature reviews Molecular cell biology 9.1 (2008): 22-32.
- Addison, Melisande L., Priyanga Ranasinghe, and David J. Webb. "Emerging insights and future prospects for therapeutic application of siRNA targeting angiotensinogen in hypertension." Expert Review of Clinical Pharmacology 16.11 (2023): 1025-1033.
- Addison, Melisande L., Priyanga Ranasinghe, and David J. Webb. "Novel pharmacological approaches in the treatment of hypertension: a focus on RNA-based therapeutics." Hypertension 80.11 (2023): 2243-2254.
- Nair, Jayaprakash K., et al. "Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing." Journal of the American Chemical Society 136.49 (2014): 16958-16961.
- Spiess, Martin. "The asialoglycoprotein receptor: a model for endocytic transport receptors." Biochemistry 29.43 (1990): 10009-10018.
- Prakash, Thazha P., et al. "Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice." Nucleic acids research 42.13 (2014): 8796-8807.
- Uijl, Estrellita, et al. "Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen." Hypertension 73.6 (2019): 1249-1257.
- Brown, Christopher R., et al. "Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates." Nucleic acids research 48.21 (2020): 11827-11844.
- Ranasinghe, Priyanga, et al. "Small interfering RNA: Discovery, pharmacology and clinical development—An introductory review." British Journal of Pharmacology 180.21 (2023): 2697-2720.
- Morgan, Erin S., et al. "Antisense inhibition of angiotensinogen with IONIS-AGT-LRx: results of phase 1 and phase 2 studies." Basic to Translational Science 6.6 (2021): 485-496.
- Bovée, Dominique M., et al. "Renoprotective effects of small interfering RNA targeting liver angiotensinogen in experimental chronic kidney disease." Hypertension 77.5 (2021): 1600-1612.
- Clahsen-van Groningen, Marian C., et al. "Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes." (2022).
- Ye, Dien, et al. "Counteracting angiotensinogen small-interfering RNA-mediated antihypertensive effects with REVERSIR." Hypertension 81.7 (2024): 1491-1499.
- Bakris, George L., et al. "RNA interference with zilebesiran for mild to moderate hypertension: the KARDIA-1 randomized clinical trial." Jama 331.9 (2024): 740-749.
- Saxena, Manish, et al. "Zilebesiran as add-on therapy in patients with hypertension inadequately controlled with a standard antihypertensive medication: efficacy and safety results from the kardia-2 study." Journal of Hypertension 42.Suppl 1 (2024): e115.
- Havasi, Andrea, et al. "KARDIA-3 study design: zilebesiran as add-on therapy in patients with high cardiovascular risk and hypertension inadequately controlled by standard of care antihypertensives." J Hypertens 42.Suppl 1 (2024): e120.
- Ray, Kausik K., et al. "Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol." New England journal of medicine 382.16 (2020): 1507-1519.
- Leiter, Lawrence A., et al. "Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION‐9, ORION‐10 and ORION‐11 Phase 3 randomized trials." Diabetes, Obesity and Metabolism 26.8 (2024): 3223-3237.
- Danser, AH Jan, and Anton H. Van Den Meiracker. "New data do not SUPPORT triple RAAS blockade." Nature Reviews Nephrology 11.5 (2015): 260-262.
- Cruz‐López, Edwyn O., et al. "Kidney Arteriolar Responses to Liver‐Targeted Small Interference RNA Targeting Angiotensinogen in Diabetic Rats: Comparison With Other Renin‐Angiotensin System Blockers." Journal of the American Heart Association 14.2 (2025): e038326.
- Webb, David J. "Zilebesiran, a ribonucleic acid interference agent targeting angiotensinogen, proves a promising approach in hypertension." (2024): e41-e43.
- Zlatev, Ivan, et al. "Reversal of siRNA-mediated gene silencing in vivo." Nature biotechnology 36.6 (2018): 509-511.
- Pushparaj, Peter N., and Alirio J. Melendez. "SHORT INTEFERING RNA (siRNA) AS A NOVEL THERAPEUTIC." Clinical & Experimental Pharmacology & Physiology 33 (2006).
- Thadani, Udho, and Thomas Wittig. "A randomized, double-blind, placebo-controlled, crossover, dose-ranging multicenter study to determine the effect of sublingual nitroglycerin spray on exercise capacity in patients with chronic stable angina." Clinical Medicine Insights: Cardiology 6 (2012): CMC-S9132.
- Levin, Arthur A. "Targeting therapeutic oligonucleotides." New England Journal of Medicine 376.1 (2017): 86-88.
- Uijl, Estrellita, et al. "Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen." Hypertension 73.6 (2019): 1249-1257.
- Traber, Gavin M., and Ai-Ming Yu. "RNAi-based therapeutics and novel RNA bioengineering technologies." The Journal of pharmacology and experimental therapeutics 384.1 (2023): 133-154.
- Alshaer, Walhan, et al. "siRNA: Mechanism of action, challenges, and therapeutic approaches." European journal of pharmacology 905 (2021): 174178.
- Nair, Jayaprakash K., et al. "Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing." Journal of the American Chemical Society 136.49 (2014): 16958-16961.
- Foster, Donald J., et al. "Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates." Molecular Therapy 26.3 (2018): 708-717.
- Benigni, Ariela, Paola Cassis, and Giuseppe Remuzzi. "Angiotensin II revisited: new roles in inflammation, immunology and aging." EMBO molecular medicine 2.7 (2010): 247-257.
- Touyz, Rhian M. "Silencing angiotensinogen in hypertension." New England Journal of Medicine 389.3 (2023): 278-281.
- Ye, Dien, et al. "Targeting angiotensinogen with N-acetylgalactosamine–conjugated small interfering RNA to reduce blood pressure." Arteriosclerosis, thrombosis, and vascular biology 43.12 (2023): 2256-2264.
- Springer, Aaron D., and Steven F. Dowdy. "GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics." Nucleic acid therapeutics 28.3 (2018): 109-118.
- Zimmermann, Tracy S., et al. "Clinical proof of concept for a novel hepatocyte-targeting GalNAc-siRNA conjugate." Molecular therapy 25.1 (2017): 71-78.
- Brown, Christopher R., et al. "Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates." Nucleic acids research 48.21 (2020): 11827-11844.
- Radauceanu, Anca, et al. "Differential time effect profiles of amlodipine, as compared to valsartan, revealed by ambulatory blood pressure monitoring, self-blood pressure measurements and dose omission protocol." Fundamental & clinical pharmacology 18.4 (2004): 483-491.
- Scheen, A. J., C. Wallemacq, and P. Lancellotti. "Inclisiran (Leqvio®), a potent cholesterol-lowering agent by inhibiting PCSK9 using small interfering RNA-based innovative therapy." Revue Medicale de Liege 77.12 (2022): 745-751.
- Bakris, George L., et al. "RNA interference with zilebesiran for mild to moderate hypertension: the KARDIA-1 randomized clinical trial." Jama 331.9 (2024): 740-749.
- Uijl, Estrellita, et al. "Conventional Vasopressor and Vasopressor‐Sparing Strategies to Counteract the Blood Pressure–Lowering Effect of Small Interfering RNA Targeting Angiotensinogen." Journal of the American Heart Association 11.15 (2022): e026426.
- Morosan, Petruta A., et al. "Zilebesiran as an Innovative siRNA-Based Therapeutic Approach for Hypertension: Emerging Perspectives in Cardiovascular Medicine." International Journal of Molecular Sciences 26.21 (2025): 10717.
- Poli, Antoine, et al. "Givosiran in acute intermittent porphyria: a personalized medicine approach." Molecular Genetics and Metabolism 135.3 (2022): 206-214.
- Adams, David, et al. "Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study." The Lancet Neurology 20.1 (2021): 49-59.
- Poli, Antoine, et al. "Givosiran in acute intermittent porphyria: a personalized medicine approach." Molecular Genetics and Metabolism 135.3 (2022): 206-214.
- Lin, Yen-Chung, et al. "Effects of calcium channel blockers comparing to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension and chronic kidney disease stage 3 to 5 and dialysis: A systematic review and meta-analysis." PloS one 12.12 (2017): e0188975.
- Ssentongo, Anna E., et al. "Renin–angiotensin–aldosterone system inhibitors and the risk of mortality in patients with hypertension hospitalised for COVID-19: systematic review and meta-analysis." Open heart 7.2 (2020).
- García-Prieto, A. M., et al. "Renin–angiotensin–aldosterone system blockers effect in chronic kidney disease progression in hypertensive elderly patients without proteinuria: PROERCAN trial." Hipertensión y riesgo vascular 41.2 (2024): 95-103.
- García-Prieto, A. M., et al. "Renin–angiotensin–aldosterone system blockers effect in chronic kidney disease progression in hypertensive elderly patients without proteinuria: PROERCAN trial." Hipertensión y riesgo vascular 41.2 (2024): 95-103.
- Haase, Nadine, et al. "RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models." The Journal of clinical investigation 130.6 (2020): 2928-2942.
DOI: http://dx.doi.org/10.52155/ijpsat.v58.2.8521
Refbacks
- There are currently no refbacks.
Copyright (c) 2026 Maged Naser

This work is licensed under a Creative Commons Attribution 4.0 International License.

















