--- title: "Zodasiran: The ANGPTL3-Silencing RNAi Injection That Lowers Triglycerides, Remnant Cholesterol and LDL - ARCHES-2, GATEWAY and the Phase 3 YOSEMITE Trial in Homozygous FH (August 15, 2026) | PepTracker Pro Blog" url: https://peptrackerpro.com/blog/zodasiran-arrowhead-aro-ang3-angptl3-galnac-sirna-rnai-triglycerides-remnant-cholesterol-ldl-homozygous-familial-hypercholesterolemia-hofh-arches-2-gateway-yosemite-august-15-2026 description: "Most cholesterol drugs work through the LDL receptor - but some patients barely have one. Zodasiran, Arrowhead's investigational GalNAc-siRNA, silences the liver protein ANGPTL3 to cut triglycerides, remnant cholesterol and LDL through an LDL-receptor-independent route. Here is what the Phase 2b ARCHES-2 trial and the Phase 2 GATEWAY study in homozygous familial hypercholesterolemia showed, and what the pivotal Phase 3 YOSEMITE trial - enrollment completed in July 2026 - is testing." lang: en --- Skip to main content **Educational information only.** This site does not provide medical advice. Read full disclaimer (https://peptrackerpro.com/disclaimer) Research & Compounds Research & Compounds # Zodasiran: The ANGPTL3-Silencing RNAi Injection That Lowers Triglycerides, Remnant Cholesterol and LDL - ARCHES-2, GATEWAY and the Phase 3 YOSEMITE Trial in Homozygous FH (August 15, 2026) PepTracker Pro Research Team August 15, 2026 8 min read ## Table of Contents - A different way to lower cholesterol and triglycerides - What ANGPTL3 does, and why silencing it helps - How zodasiran is built: GalNAc-siRNA - ARCHES-2: deep triglyceride and remnant-cholesterol reductions - Liver fat and metabolic signals - GATEWAY: the case for homozygous FH - YOSEMITE: the pivotal Phase 3 in HoFH - How zodasiran compares - What to keep in mind ## A different way to lower cholesterol and triglycerides Most cholesterol drugs work by revving up the LDL receptor - the cell-surface catcher that pulls LDL cholesterol out of the blood. Statins, ezetimibe and PCSK9 inhibitors all lean on that pathway. But some people cannot use it. In homozygous familial hypercholesterolemia (HoFH), a rare inherited disease, both copies of the LDL-receptor machinery are severely broken, so those drugs barely move the needle and LDL cholesterol can sit at life-threatening levels from childhood. Zodasiran (development code ARO-ANG3), an investigational RNA interference therapeutic from Arrowhead Pharmaceuticals, takes a different route. It silences a liver protein called ANGPTL3, lowering triglycerides, remnant cholesterol and LDL cholesterol through a mechanism that does not depend on the LDL receptor at all. ## What ANGPTL3 does, and why silencing it helps ANGPTL3 (angiopoietin-like protein 3) is made by the liver and acts as a brake on two fat-clearing enzymes - lipoprotein lipase and endothelial lipase. When those enzymes are held back, triglyceride-rich particles and their cholesterol-laden remnants linger in the blood. Turn ANGPTL3 down and the brakes come off: the body clears triglycerides and remnant cholesterol faster, and LDL cholesterol falls too. The target has strong human genetic backing. People born with loss-of-function ANGPTL3 variants naturally run low triglycerides and low LDL cholesterol and appear to be protected against coronary artery disease - a natural experiment that zodasiran is designed to imitate with an occasional injection. ## How zodasiran is built: GalNAc-siRNA Zodasiran is a small interfering RNA (siRNA) conjugated to GalNAc (N-acetylgalactosamine), a sugar tag that binds a receptor found almost exclusively on liver cells. That tag delivers the siRNA straight to hepatocytes, where it latches onto the messenger RNA for ANGPTL3 and marks it for destruction before the protein can be made. Because the delivery is so targeted and the silencing so durable, zodasiran can be given as a small subcutaneous injection once every few months rather than as a daily pill. It belongs to the same GalNAc-siRNA family now being aimed at other cardiometabolic targets - Lp(a) with olpasiran, lepodisiran and zerlasiran, apoC-III with plozasiran, and angiotensinogen with zilebesiran. ## ARCHES-2: deep triglyceride and remnant-cholesterol reductions The Phase 2b ARCHES-2 trial, published in the New England Journal of Medicine in 2024 and presented at the European Atherosclerosis Society congress, enrolled 204 adults with mixed hyperlipidemia (triglycerides 150-499 mg/dL plus elevated LDL or non-HDL cholesterol) who were already on maximally tolerated statins. They received subcutaneous zodasiran 50, 100 or 200 mg, or placebo, on day 1 and again at week 12. At week 24, the placebo-adjusted reductions were striking: roughly 54% to 74% for ANGPTL3, 51% to 63% for triglycerides, and 73% to 82% for remnant cholesterol, along with significant drops in non-HDL cholesterol (up to about 36%), LDL cholesterol (up to about 20%) and apolipoprotein B (up to about 22%). The effects were durable, remaining significant at week 36 - a full 24 weeks after the last dose. ## Liver fat and metabolic signals ARCHES-2 also looked at the liver. In a subgroup of patients with meaningful baseline liver fat, MRI-based measurement (MRI-PDFF) showed liver fat falling by about 28% with the 200 mg dose versus essentially no change on placebo - an intriguing signal given how often high triglycerides travel with fatty liver. Changes in HbA1c, a marker of blood sugar, were modest. Because ANGPTL3 sits at a crossroads of fat and glucose handling, trials continue to watch metabolic measures closely, and the long-term picture is still being filled in. ## GATEWAY: the case for homozygous FH The open-label Phase 2 GATEWAY study, published in The Lancet Diabetes & Endocrinology in 2025, tested zodasiran where it may matter most: homozygous familial hypercholesterolemia. Patients received 200 or 300 mg on day 1 and at month 3. Zodasiran lowered LDL cholesterol by approximately 40% - notable because these patients have so little working LDL-receptor function that receptor-dependent drugs underperform. The study reported no drug discontinuations, no drug-related serious adverse events and no deaths. That LDL-receptor-independent action is the core scientific rationale for pursuing HoFH. ## YOSEMITE: the pivotal Phase 3 in HoFH Arrowhead has concentrated late-stage development of zodasiran on HoFH through the global Phase 3 YOSEMITE trial. It is a randomized, double-blind, placebo-controlled study in patients aged 12 and older, who are assigned 2:1 to zodasiran 200 mg or placebo given subcutaneously once every three months for four doses. Originally planned for 60 participants, YOSEMITE expanded to 70 on strong global interest from HoFH patients and physicians, and Arrowhead announced on July 27, 2026 that enrollment was complete. The trial is expected to finish in mid-2027; pending successful results, Arrowhead has said it intends to seek regulatory approval in multiple regions. ## How zodasiran compares Zodasiran is not the only way to hit ANGPTL3. Evinacumab, an approved monoclonal antibody for HoFH, blocks the ANGPTL3 protein directly but must be given by intravenous infusion; zodasiran instead shuts off production of the protein upstream and is dosed as an infrequent subcutaneous injection. Among the newer RNA-based cardiometabolic drugs, zodasiran is distinguished by its target - most siRNA and antisense programs in this space aim at Lp(a) (olpasiran, lepodisiran, zerlasiran, pelacarsen) or apoC-III (plozasiran, olezarsen), while zilebesiran targets blood pressure via angiotensinogen. ANGPTL3 gives zodasiran a broad footprint across triglycerides, remnant cholesterol and LDL at once. ## What to keep in mind Zodasiran is investigational and not approved for any use. Its efficacy and safety data come from Phase 2 and 2b trials, and it has not yet been shown to reduce heart attacks or strokes - that kind of cardiovascular outcome evidence is a separate, longer question. Because RNA interference produces deep, months-long silencing, the effect of a dose cannot be quickly reversed, and metabolic measures such as blood sugar and liver fat warrant ongoing monitoring. It is an injectable biologic used only under medical supervision in clinical trials - not a supplement or research chemical - and any product marketed as 'zodasiran' or 'ARO-ANG3' outside a trial is unverified and unsafe. This article is educational and not medical advice. Ready to track your peptide research? Open PepTracker Pro (https://app.peptrackerpro.com/) PepTracker Pro Research Team The PepTracker Pro Research Team is an editorial group of science writers, pharmacologists, and clinical researchers dedicated to making peptide science accessible. Every article is reviewed for accuracy against peer-reviewed sources and updated as new evidence emerges. ## Citations 1. [1] Rosenson RS, et al. - Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia (ARCHES-2, Phase 2b), New England Journal of Medicine (2024) Source (https://www.nejm.org/doi/full/10.1056/NEJMoa2404147) 2. [2] Arrowhead Pharmaceuticals - Presents New Phase 2 (ARCHES-2) Data of Zodasiran in Patients with Mixed Hyperlipidemia (EAS 2024) Source (https://arrowheadpharma.com/en-us/newsroom/arrowhead-pharmaceuticals-presents-new-phase-2) 3. [3] Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY), Lancet Diabetes & Endocrinology (2025) Source (https://www.thelancet.com/journals/landia/article/PIIS2213-8587(25)00290-6/abstract) 4. [4] Arrowhead Pharmaceuticals - Completes Enrollment in Global Phase 3 YOSEMITE Study of Zodasiran for HoFH (July 27, 2026) Source (https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-completes-enrollment-global-phase-3) 5. [5] Arrowhead concludes enrolment for Phase III zodasiran trial in HoFH - Clinical Trials Arena Source (https://www.clinicaltrialsarena.com/news/arrowhead-concludes-enrolment-zodasiran-trial/) **Disclaimer:** This article is for educational purposes only and does not constitute medical advice. Always consult a licensed healthcare provider. 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