--- title: "Zilebesiran | PepTracker Pro" url: https://peptrackerpro.com/peptides/zilebesiran description: "An investigational subcutaneous GalNAc-conjugated small interfering RNA (siRNA) from Alnylam Pharmaceuticals and Roche/Genentech that lowers blood pressure by silencing angiotensinogen (AGT), the single upstream precursor of the renin-angiotensin-aldosterone system (RAAS). Designed for dosing as infrequently as once or twice a year, it is the first RNА interference (RNAi) therapeutic developed for hypertension. In Phase 2 KARDIA-1 and KARDIA-2 trials it produced durable, clinically meaningful reductions in systolic blood pressure sustained for up to 6 months from a single dose, and in 2025 it advanced into the large Phase 3 ZENITH cardiovascular outcomes trial." lang: en --- Skip to main content **Educational information only.** This site does not provide medical advice. Read full disclaimer (https://peptrackerpro.com/disclaimer) **Research-only content.** This page is for educational purposes and does not constitute medical advice. Read full disclaimer → (https://peptrackerpro.com/research-disclaimer) # Zilebesiran Medium Evidence An investigational subcutaneous GalNAc-conjugated small interfering RNA (siRNA) from Alnylam Pharmaceuticals and Roche/Genentech that lowers blood pressure by silencing angiotensinogen (AGT), the single upstream precursor of the renin-angiotensin-aldosterone system (RAAS). Designed for dosing as infrequently as once or twice a year, it is the first RNА interference (RNAi) therapeutic developed for hypertension. In Phase 2 KARDIA-1 and KARDIA-2 trials it produced durable, clinically meaningful reductions in systolic blood pressure sustained for up to 6 months from a single dose, and in 2025 it advanced into the large Phase 3 ZENITH cardiovascular outcomes trial. Aliases ALN-AGT +4 more Evidence Medium Evidence Last Updated 2026-08-14 Reading Time 5 min ## What It Is Zilebesiran (development codes ALN-AGT / ALN-AGT01) is a GalNAc-conjugated small interfering RNA (siRNA) that targets the messenger RNA for angiotensinogen (AGT) in the liver. Angiotensinogen is the sole precursor protein from which the entire renin-angiotensin-aldosterone system (RAAS) is built - it is cleaved to angiotensin I and then to angiotensin II, the hormone that constricts blood vessels and drives sodium retention and high blood pressure. Most blood-pressure drugs (ACE inhibitors, ARBs, renin inhibitors) block steps downstream in this cascade and must be taken every day. Zilebesiran instead switches off production of the precursor itself: by using RNA interference to degrade AGT messenger RNA before the protein is made, it lowers circulating angiotensinogen by more than 90% and produces deep, durable suppression of the whole pathway. Because the siRNA is conjugated to GalNAc (N-acetylgalactosamine), a sugar tag that binds a receptor found almost exclusively on liver cells, the drug concentrates in the liver where angiotensinogen is made, allowing a small subcutaneous dose given as rarely as once or twice a year. It is being developed by Alnylam Pharmaceuticals in collaboration with Roche (Genentech in the United States); under the 2018 partnership Alnylam retains U.S. rights while Roche holds rights outside the U.S. Zilebesiran is investigational and not approved for any use. Also known as: ALN-AGT, ALN-AGT01, angiotensinogen siRNA, AGT RNAi, anti-angiotensinogen siRNA ## Regulatory Status Investigational (Phase 3; not approved) Zilebesiran has not been approved by the FDA or any regulator; it remains investigational. After positive Phase 2 KARDIA-1, KARDIA-2 and KARDIA-3 results, Alnylam and Roche announced in August 2025 the decision to advance zilebesiran into ZENITH, a global Phase 3 cardiovascular outcomes trial (CVOT) of roughly 11,000 patients across about 35 countries, testing zilebesiran 300 mg given every 6 months versus placebo in people with uncontrolled hypertension who have established cardiovascular disease or high cardiovascular risk on two or more antihypertensives. The first patient was dosed in ZENITH in 2025. It is developed by Alnylam Pharmaceuticals with Roche/Genentech; Alnylam holds U.S. rights and Roche holds ex-U.S. rights under their 2018 collaboration. ## Why Researchers Study It Hypertension is the world's leading modifiable cause of heart attack, stroke and cardiovascular death, yet most patients never reach their blood-pressure goal - largely because daily pills are easy to miss and adherence erodes over months and years. Zilebesiran is interesting because it attacks that adherence problem at its root: instead of a drug that must be taken every day, it is an injection given as infrequently as once or twice a year that could keep blood pressure controlled continuously between doses. Scientifically it is a landmark because it is the first RNA interference (RNAi) therapeutic aimed at hypertension and the first to silence angiotensinogen - the single upstream protein that feeds the entire renin-angiotensin-aldosterone system (RAAS). By shutting off the precursor rather than blocking a downstream step, it offers unusually deep and durable suppression of the pathway. Researchers are studying whether that translates into not just lower numbers on a cuff but fewer real cardiovascular events, which is the question the Phase 3 ZENITH outcomes trial is designed to answer. It also extends the GalNAc-siRNA platform - already validated in lipid drugs like inclisiran, olpasiran, lepodisiran, zerlasiran and plozasiran - into blood-pressure control. ## Proposed Mechanisms - Small interfering RNA (siRNA) that binds and triggers degradation of the messenger RNA encoding angiotensinogen (AGT) in the liver, reducing production of the protein - Angiotensinogen is the sole precursor of the renin-angiotensin-aldosterone system (RAAS); lowering it reduces downstream angiotensin I and angiotensin II, the vasoconstrictor that raises blood pressure and promotes sodium retention - GalNAc (N-acetylgalactosamine) conjugation targets delivery to liver hepatocytes via the asialoglycoprotein receptor, allowing a small, infrequent subcutaneous dose - Reduces serum angiotensinogen by more than 90%, producing deep and durable suppression of the RAAS pathway from a single dose - Long tissue half-life supports dosing as infrequently as every 3 to 6 months (potentially once or twice yearly), aimed at overcoming the poor adherence of daily antihypertensive pills - Administered subcutaneously; effect on blood pressure is sustained for up to 6 months after a single injection ## Evidence Snapshot Medium Evidence Low Medium High | Study Type | Model | Outcome | Link | | --- | --- | --- | --- | | Phase 2 (KARDIA-1, NEJM 2024) | 377 adults with mild-to-moderate hypertension; single subcutaneous doses of zilebesiran 150, 300 or 600 mg vs placebo, with ambulatory blood-pressure monitoring | Placebo-adjusted reductions in 24-hour mean ambulatory systolic blood pressure at Month 3 of about 14.1 mmHg (150 mg), 16.7 mmHg (300 mg) and 15.7 mmHg (600 mg), all p<0.0001; efficacy durable to 6 months; serum angiotensinogen reduced by more than 90% | Source | | Phase 2 (KARDIA-2, ACC 2024) | Adults with hypertension not controlled on a single agent; single zilebesiran 300 mg added to a background antihypertensive (indapamide, amlodipine or olmesartan) vs placebo add-on | Placebo-adjusted daytime ambulatory systolic blood-pressure reduction of about 8.7 to 12.1 mmHg at Month 3, sustained to Month 6, consistent across the three background-drug arms | Source | | Phase 2 (KARDIA-3, ESC 2025) | Patients at higher cardiovascular risk with blood pressure uncontrolled on 2-4 background antihypertensives; zilebesiran add-on vs placebo | Clinically meaningful office systolic blood-pressure reductions through Month 6; the single-dose 300 mg office systolic difference at Month 3 (about 5 mmHg vs placebo) did not reach statistical significance, informing dose and endpoint choices for Phase 3 | Source | ## Commonly Discussed Benefits Cardiovascular: https://peptrackerpro.com/benefits/cardiovascular Disease Modification: https://peptrackerpro.com/benefits/disease-modification Researching Zilebesiran? Track it, set reminders, and keep notes in the free app. Track in App (https://app.peptrackerpro.com/?add=zilebesiran) ## Safety & Cautions - Zilebesiran is investigational and not approved for any use; all data to date are from Phase 2 trials, and cardiovascular outcome benefit has not yet been established - Because it produces deep, long-lasting (months-long) suppression of the renin-angiotensin system, hypotension (low blood pressure) is a key monitored risk - especially during illness, volume depletion, surgery or when combined with other blood-pressure-lowering drugs; the long duration means the effect cannot be quickly reversed - Blunting of the RAAS raises theoretical concerns about blood pressure control in states of low blood volume and about renal perfusion; kidney function and potassium warrant monitoring, as with other RAAS-acting agents - As a RAAS-blocking therapy it would be expected to be contraindicated in pregnancy given the known fetal risks of the drug class; contraception and pregnancy status are relevant in trials - Injection-site reactions are the most common adverse effect reported with the GalNAc-siRNA class - It is an injectable investigational biologic used only under medical supervision in clinical trials; it is not a supplement or research chemical, and any 'zilebesiran' or 'ALN-AGT' offered by a vendor is unverified and unsafe ## Comparisons See how Zilebesiran compares to related peptides: Zilebesiran vs Eplontersen: https://peptrackerpro.com/compare/zilebesiran-vs-eplontersen Zilebesiran vs Inclisiran: https://peptrackerpro.com/compare/zilebesiran-vs-inclisiran Zilebesiran vs Lepodisiran: https://peptrackerpro.com/compare/zilebesiran-vs-lepodisiran Zilebesiran vs Olezarsen: https://peptrackerpro.com/compare/zilebesiran-vs-olezarsen Zilebesiran vs Olpasiran: https://peptrackerpro.com/compare/zilebesiran-vs-olpasiran Zilebesiran vs Pelacarsen: https://peptrackerpro.com/compare/zilebesiran-vs-pelacarsen Zilebesiran vs Plozasiran: https://peptrackerpro.com/compare/zilebesiran-vs-plozasiran Zilebesiran vs Solbinsiran: https://peptrackerpro.com/compare/zilebesiran-vs-solbinsiran Zilebesiran vs Volenrelaxin: https://peptrackerpro.com/compare/zilebesiran-vs-volenrelaxin Zilebesiran vs Vutrisiran: https://peptrackerpro.com/compare/zilebesiran-vs-vutrisiran Zilebesiran vs Zerlasiran: https://peptrackerpro.com/compare/zilebesiran-vs-zerlasiran Zilebesiran vs Zodasiran: https://peptrackerpro.com/compare/zilebesiran-vs-zodasiran Zilebesiran vs Fitusiran: https://peptrackerpro.com/compare/zilebesiran-vs-fitusiran Zilebesiran vs Nucresiran: https://peptrackerpro.com/compare/zilebesiran-vs-nucresiran Zilebesiran vs Abelacimab: https://peptrackerpro.com/compare/zilebesiran-vs-abelacimab ## Calculator Tools Use our research tools to explore dosing and reconstitution data: Reconstitution Calculator: https://peptrackerpro.com/calculators ## Citations 1. [1] Desai AS, et al. - Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension (KARDIA-1, Phase 2), New England Journal of Medicine (2024) PubMed (https://www.nejm.org/doi/full/10.1056/NEJMoa2208391) 2. [2] Roche - Positive topline results from the Phase II KARDIA-2 study of zilebesiran (March 5, 2024) PubMed (https://www.roche.com/media/releases/med-cor-2024-03-05) 3. [3] European Society of Cardiology - KARDIA-3 trial of zilebesiran in hypertensive patients at high cardiovascular risk (ESC Congress 2025) PubMed (https://www.escardio.org/news/press/press-releases/KARDIA-3-trial-examines-blood-pressure-lowering-effects-of-zilebesiran-in-hypertensive-patients-at-high-cardiovascular-risk/) 4. [4] Roche and Alnylam - Advancing zilebesiran into global Phase III cardiovascular outcomes trial (ZENITH) for uncontrolled hypertension (August 30, 2025) PubMed (https://www.roche.com/media/releases/med-cor-2025-08-30) 5. [5] Alnylam Pharmaceuticals - To Advance Zilebesiran into Global Phase 3 Cardiovascular Outcomes Trial PubMed (https://investors.alnylam.com/press-release?id=29246) ### Keep researching in the app - Log Zilebesiran to your private tracker - Set a dosing reminder - Compare it side-by-side with your stack Open PepTracker Pro Free: https://app.peptrackerpro.com/?add=zilebesiran Browse more peptides: https://peptrackerpro.com/peptides ## Related Peptides ### Eplontersen High Evidence An approved, once-monthly, self-administered subcutaneous GalNAc-conjugated antisense oligonucleotide (ASO) from Ionis and AstraZeneca that treats transthyretin-mediated (ATTR) amyloidosis by lowering the liver's production of transthyretin (TTR). Transthyretin is a liver-made transport protein that can misfold and deposit as amyloid in nerves and the heart; eplontersen is a short synthetic strand of chemically modified DNA/RNA that binds TTR messenger RNA and directs its enzymatic (RNase H1) degradation before the protein is made, cutting circulating TTR by roughly 80%. A triantennary N-acetylgalactosamine (GalNAc) tag delivers it to liver cells, allowing a low-dose 45 mg injection just once a month via autoinjector or pre-filled syringe. Marketed as Wainua (US) and Wainzua (EU), it was FDA-approved in December 2023 for the polyneuropathy of hereditary ATTR amyloidosis (ATTRv-PN) on the strength of the NEURO-TTRansform trial, and is now approved in more than 20 countries. 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By switching off PCSK9 production inside hepatocytes, inclisiran leaves more LDL receptors on the liver surface to pull LDL cholesterol out of the blood - achieving roughly a 50% LDL reduction with an injection given only twice a year after a loading dose. Marketed as Leqvio, it was the first siRNA medicine approved for a chronic cardiovascular condition: the EU cleared it in December 2020 and the FDA in December 2021, and in July 2025 the FDA expanded the U.S. label to first-line monotherapy, dropping the requirement that it be added on top of a statin. Its Phase 3 ORION-9, ORION-10 and ORION-11 trials established the LDL benefit; a large cardiovascular outcomes program (VICTORION-2-PREVENT and others) is still running to test whether that LDL lowering prevents heart attacks and strokes. Inclisiran is the approved, real-world proof-of-concept for the GalNAc-siRNA cardiometabolic platform that newer investigational agents like zodasiran, solbinsiran, olpasiran and plozasiran build on. 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Marketed as Amvuttra, it was first FDA-approved in June 2022 for the polyneuropathy of hereditary ATTR amyloidosis (HELIOS-A), and in March 2025 the FDA expanded the label to ATTR cardiomyopathy (ATTR-CM) of wild-type or hereditary disease - making vutrisiran the first RNAi therapeutic shown to reduce cardiovascular death and cardiovascular events, on the strength of the HELIOS-B outcomes trial. It shares the exact GalNAc-siRNA delivery platform that underlies the cardiometabolic RNAi medicine inclisiran and the investigational agents olpasiran, lepodisiran, zerlasiran, zilebesiran, zodasiran, solbinsiran and plozasiran, and it is the direct successor to Alnylam's earlier intravenous TTR siRNA patisiran (Onpattro). Cardiovascular: https://peptrackerpro.com/benefits/cardiovascular Neuroprotection: https://peptrackerpro.com/benefits/neuroprotection Disease Modification: https://peptrackerpro.com/benefits/disease-modification Rare Disease Treatment: https://peptrackerpro.com/benefits/rare-disease-treatment View Details: https://peptrackerpro.com/peptides/vutrisiran \+ Compare: https://peptrackerpro.com/compare?select=vutrisiran Track in App: https://app.peptrackerpro.com/?add=vutrisiran ### Zerlasiran Medium Evidence An investigational, long-acting injectable small interfering RNA (siRNA) from Silence Therapeutics that lowers lipoprotein(a) [Lp(a)] by more than 80% by silencing the LPA gene in the liver. Dosed only every 16–24 weeks, it produced durable ~90% reductions in its Phase 2 ALPACAR-360 trial (published in JAMA, 2024); as of 2026 the company is seeking a partner before starting its Phase 3 cardiovascular outcomes study. View Details: https://peptrackerpro.com/peptides/zerlasiran \+ Compare: https://peptrackerpro.com/compare?select=zerlasiran Track in App: https://app.peptrackerpro.com/?add=zerlasiran ### Zodasiran Medium Evidence An investigational subcutaneous GalNAc-conjugated small interfering RNA (siRNA) from Arrowhead Pharmaceuticals that lowers atherogenic lipids by silencing ANGPTL3 (angiopoietin-like protein 3), a liver-made regulator of fat metabolism. By switching off ANGPTL3 production, zodasiran deeply reduces triglycerides, remnant cholesterol and LDL cholesterol through a pathway that does not depend on the LDL receptor - making it especially relevant for people, such as those with homozygous familial hypercholesterolemia (HoFH), whose LDL receptors barely work. In the Phase 2b ARCHES-2 trial (NEJM 2024) it produced durable, dose-dependent reductions in triglycerides, remnant cholesterol and ANGPTL3, and in the Phase 2 GATEWAY study it lowered LDL cholesterol by about 40% in HoFH. It is now in the Phase 3 YOSEMITE trial in HoFH, which completed enrollment in July 2026. View Details: https://peptrackerpro.com/peptides/zodasiran \+ Compare: https://peptrackerpro.com/compare?select=zodasiran Track in App: https://app.peptrackerpro.com/?add=zodasiran ### Fitusiran High Evidence An FDA-approved RNA-interference (RNAi) therapy for hemophilia that works by lowering a natural blood-thinning protein rather than replacing a missing clotting factor. Fitusiran (brand name Qfitlia) is a GalNAc-conjugated small interfering RNA (siRNA) that is taken up by liver cells and silences the gene for antithrombin, the body's main brake on clotting. By reducing antithrombin, fitusiran 'rebalances' hemostasis so that people with hemophilia A or B can generate enough thrombin to form stable clots and bleed less often. It was approved by the U.S. FDA on March 28, 2025 - the first siRNA (RNAi) therapy for hemophilia and the first medicine that treats hemophilia by lowering antithrombin - for routine prophylaxis in adults and children aged 12 and older with hemophilia A or B, with or without factor VIII or IX inhibitors. A key practical advantage is that it is given as an infrequent subcutaneous injection (starting once every two months, as few as about six injections per year) and works regardless of hemophilia type or inhibitor status. In the pivotal Phase 3 ATLAS trials, fitusiran reduced the annualized bleeding rate by about 90% versus on-demand treatment. Because lowering antithrombin shifts the clotting balance, fitusiran carries a boxed warning for thrombotic (clotting) events and gallbladder disease, and it is now dosed to a target antithrombin level (15-35%) to reduce clot risk. Fitusiran is a prescription biologic administered under medical supervision - not a supplement or research chemical. Hematology: https://peptrackerpro.com/benefits/hematology Rare Disease Treatment: https://peptrackerpro.com/benefits/rare-disease-treatment View Details: https://peptrackerpro.com/peptides/fitusiran \+ Compare: https://peptrackerpro.com/compare?select=fitusiran Track in App: https://app.peptrackerpro.com/?add=fitusiran ### Nucresiran Medium Evidence An investigational next-generation RNA interference (RNAi) therapeutic from Alnylam Pharmaceuticals designed to silence the transthyretin (TTR) gene and treat transthyretin amyloidosis (ATTR) - the same disease targeted by Alnylam's approved drugs patisiran and vutrisiran (Amvuttra) and by Ionis/AstraZeneca's eplontersen (Wainua/Wainzua). Nucresiran (formerly ALN-TTRsc04) is a subcutaneous GalNAc-conjugated small interfering RNA (siRNA) built on Alnylam's newer IKARIA platform, engineered for deeper, more durable knockdown of both mutant and wild-type TTR with the potential for once- or twice-yearly dosing - a substantial step beyond the current quarterly (vutrisiran) or monthly (eplontersen) schedules. In an interim Phase 1 single-ascending-dose study in 48 healthy volunteers (presented at AHA 2024), a single dose of 300 mg or higher rapidly lowered serum TTR by more than 90% by Day 15 and by more than 96% at peak (Day 29), with more than 70% reduction still present at one year after a single 300 mg dose and low patient-to-patient variability; all doses were well tolerated with no injection-site reactions and no liver safety signals. Alnylam has moved nucresiran into a Phase 3 TRITON program: TRITON-PN (NCT07223203) in hereditary ATTR with polyneuropathy, an open-label study using vutrisiran as an active comparator, and TRITON-CM (NCT07052903), a large event-driven cardiovascular outcomes trial in ATTR cardiomyopathy dosing nucresiran 300 mg subcutaneously once every six months. Nucresiran is investigational and not approved by the FDA, EMA or any regulator; it is studied only in clinical trials and is not a supplement or research chemical. View Details: https://peptrackerpro.com/peptides/nucresiran \+ Compare: https://peptrackerpro.com/compare?select=nucresiran Track in App: https://app.peptrackerpro.com/?add=nucresiran ### Abelacimab Medium Evidence Abelacimab (development code MAA868) is an investigational fully human monoclonal antibody being developed as a new kind of blood thinner (anticoagulant). It works by targeting Factor XI, a clotting protein that sits high in the coagulation 'cascade.' Abelacimab is described as a dual inhibitor: it binds the catalytic domain of Factor XI and locks the protein in its inactive (zymogen) shape, so it blocks both Factor XI itself and its activated form, Factor XIa, preventing the enzyme from being switched on by upstream triggers such as Factor XIIa or thrombin. The appeal of the Factor XI target is a long-standing observation in human biology: Factor XI contributes strongly to pathological clot formation (thrombosis) but only modestly to normal wound-sealing (hemostasis), so blocking it may prevent strokes and clots while causing much less bleeding than standard anticoagulants. Abelacimab is given as a once-monthly subcutaneous injection (with an intravenous loading option in some settings) and has a long duration of action. Its lead uses are stroke prevention in atrial fibrillation and the treatment and prevention of cancer-associated blood clots (venous thromboembolism, VTE). In the Phase 2b AZALEA-TIMI 71 trial, abelacimab reduced bleeding dramatically compared with the direct oral anticoagulant rivaroxaban - so much so that the study was stopped early - and it is now in Phase 3 development. Abelacimab was developed by Anthos Therapeutics, which Novartis originally helped launch and then reacquired in 2025. It is an investigational prescription biologic administered under medical supervision; it is not approved, and it is not a supplement, nootropic or research chemical. Cardiovascular: https://peptrackerpro.com/benefits/cardiovascular Hematology: https://peptrackerpro.com/benefits/hematology Disease Modification: https://peptrackerpro.com/benefits/disease-modification View Details: https://peptrackerpro.com/peptides/abelacimab \+ Compare: https://peptrackerpro.com/compare?select=abelacimab Track in App: https://app.peptrackerpro.com/?add=abelacimab ## Structured data ```json [ { "@context": "https://schema.org", "@type": "Organization", "name": "PepTracker Pro", "url": "https://peptrackerpro.com", "logo": "https://peptrackerpro.com/favicon.png", "description": "Evidence-based educational resource dedicated to improving peptide research literacy.", "contactPoint": { "@type": "ContactPoint", "email": "hello@peptrackerpro.com", "contactType": "customer support" }, "sameAs": [] }, { "@context": "https://schema.org", "@type": "MedicalWebPage", "name": "Zilebesiran", "description": "An investigational subcutaneous GalNAc-conjugated small interfering RNA (siRNA) from Alnylam Pharmaceuticals and Roche/Genentech that lowers blood pressure by silencing angiotensinogen (AGT), the single upstream precursor of the renin-angiotensin-aldosterone system (RAAS). 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