zodasiran (ARO-ANG3) / Arrowhead - LARVOL DELTA

Dosed the first subject in the YOSEMITE Phase 3 clinical trial of zodasiran, the company’s investigational RNAi therapeutic being developed as a potential treatment for homozygous familial hypercholesterolemia (HoFH) (Businesswire)

Trial status • Homozygous Familial Hypercholesterolemia

CT.MDP.24: Closing the LDL Gap: Innovations, Access, and Adherence in Lipid-Lowering Therapy (AHA 2025) - "Discover the real-world impact of evolocumab, cost and utilization trends in under-treated populations, and access inequities driven by socioeconomic deprivation. With new evidence on emerging agents like bempedoic acid, obicetrapib, and zodasiran, this session brings together cutting-edge science and pragmatic solutions to confront one of cardiology's most persistent challenges: getting LDL down and keeping it there. This is not a CE accredited session."

Adherence • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders

Future of angiopoietin-like protein 3 inhibitors as a therapeutic agent. (PubMed, Curr Opin Lipidol) - "ANGPTL3 inhibition offers an LDL receptor-independent means to lower atherogenic particles spanning from TRLs to LDL, complementing traditional lipid-lowering therapies. Evinacumab is practice-changing in HoFH, and RNA agents may soon broaden applicability to patients with mixed dyslipidemia and residual cardiovascular risk, pending cardiovascular outcomes trials."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Mixed Hyperlipidemia • ANGPTL3

RNA INTERFERENCE OF ANGPTL3 VIA ZODASIRAN: A NEXT-GENERATION APPROACH FOR TREATING ATHEROGENIC DYSLIPIDEMIA (AHA 2025) - "RNAi-mediated ANGPTL3 inhibition via zodasiran is a promising strategy for managing atherogenic dyslipidemia and cardiovascular risk. Its hepatocyte-specific action, prolonged dosing, and safety profile offer benefits over current treatments, especially for familial hypercholesterolemia and statin-intolerant patients. Long-term outcome trials are needed to confirm clinical benefit."

Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders • Mixed Hyperlipidemia • ANGPTL3 • APOB

YOSEMITE Rationale and Design: Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Zodasiran Efficacy and Safety in Adolescents and Adults with Homozygous Familial Hypercholesterolemia (AHA 2025) - "Secondary endpoints include percent change from baseline in fasting ApoB, non-HDL-C, TGs, ANGPTL3, total cholesterol, Lp(a) and HDL-C; change from baseline and AUC in fasting LDL-C to 1-year. Safety and tolerability will be assessed.ConclusionsYOSEMITE is designed to determine whether quarterly-dosed zodasiran safely reduces LDL-C levels in patients with HoFH."

Clinical • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • ANGPTL3 • APOB • LDLR

Gateway: Study of ARO-ANG3 in Participants With Homozygous Familial Hypercholesterolemia (HOFH) (clinicaltrials.gov) - P2 | N=18 | Active, not recruiting | Sponsor: Arrowhead Pharmaceuticals | Trial completion date: May 2025 ➔ Nov 2025

Trial completion date • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • APOB

A VSA003 Phase 1 Study in Chinese Adult Healthy Volunteers (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Visirna Therapeutics HK Limited | Not yet recruiting ➔ Completed

Trial completion • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Hypertriglyceridemia • Metabolic Disorders

Safety and efficacy of zodasiran, a hepatic sirna targeting angptl3, in mixed hyperlipidemia patients: 2 year open label extension (OLE) results from ARCHES-2 (ESC-WCC 2025) - "Zodasiran delivered substantial and sustained reductions in ANGPTL3, TG, and atherogenic lipoproteins in patients with mixed hyperlipidemia, with a favorable safety profile, consistent with observations from the blinded portion of the study. The cardiovascular effects remain to be determined."

Clinical • Cardiovascular • Dyslipidemia • ANGPTL3 • APOB • LPL

Efficacy of siRNA in lowering lipoprotein(a) and LDL-cholesterol: a meta-analysis of randomized controlled trials (ESC-WCC 2025) - "The doses are: Lepodisiran (Q1: 4mg-12mg-32mg; Q2: 96mg; Q3: 304mg; Q4: 608mg), Olpasiran (Q1: 10mg; Q2: 75mg; Q3: 225mg), Zerlasiran (Q1: 30mg; Q2: 100mg; Q3: 200mg-300mg; Q4: 450mg-600mg), and Zodasiran (Q1: 50mg; Q2: 100mg; Q3: 200 mg). The findings of this meta-analysis demonstrate that siRNA treatment significantly reduces Lp(a) levels in a dose-dependent manner, with higher doses achieving greater efficacy. Additionally, siRNA also lowers LDL-C levels, regardless of dose escalation. However, phase III clinical trials are needed to confirm the safety and efficacy of this therapeutic approach and to establish its correlation with reduced cardiovascular risk."

Retrospective data • Atherosclerosis • Cardiovascular • Dyslipidemia

Arrowhead Pharmaceuticals to Participate in Upcoming September 2025 Conferences (Businesswire)

Clinical data • Familial Chylomicronemia Syndrome • Mixed Hyperlipidemia

A Phase 3 Study of Zodasiran in Adolescent and Adult Subjects With Homozygous Familial Hypercholesterolemia (YOSEMITE) (clinicaltrials.gov) - P3 | N=60 | Recruiting | Sponsor: Arrowhead Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • APOB

Targeting Triglycerides: The Rise of Apolipoprotein C3 and Angiopoietin-Like Protein 3 Inhibitors. (PubMed, Am J Cardiovasc Drugs) - "Several novel agents utilizing these pathways, including olezarsen, plozasiran, and zodasiran, are currently under development for the management of elevated TG, with olezarsen approved in 2024 for the management of familial chylomicronemia syndrome. This comprehensive review provides updated insights into the development of novel hypertriglyceridemia treatments."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Chylomicronemia Syndrome • Hypertriglyceridemia • ANGPTL3

Arrowhead Pharmaceuticals Initiates Phase 3 YOSEMITE Study of Investigational Zodasiran for the Treatment of Homozygous Familial Hypercholesterolemia (Businesswire) - "Arrowhead Pharmaceuticals...announced that it has dosed the first subject in the YOSEMITE Phase 3 clinical trial of zodasiran, the company’s investigational RNA interference (RNAi) therapeutic being developed as a potential treatment for homozygous familial hypercholesterolemia (HoFH), a rare genetic condition that leads to severely elevated LDL-cholesterol and early onset cardiovascular disease. Zodasiran is the fourth investigational RNAi-based candidate developed by Arrowhead to reach late-stage pivotal studies, after investigational drugs plozasiran, fazirsiran (licensed to Takeda) and olpasiran (licensed to Amgen)....YOSEMITE (NCT07037771) is a Phase 3 multicenter, randomized, placebo-controlled study to evaluate the efficacy and safety of zodasiran in adolescent and adult patients with genetically or clinically diagnosed homozygous familial hypercholesterolemia (HoFH) on maximally tolerated lipid lowering therapy."

Trial status • Homozygous Familial Hypercholesterolemia

RNA Interference-Mediated ANGPTL3 Inhibition: The Emerging Therapeutic Potential of Zodasiran in Lipid Management. (PubMed, Cardiol Rev) - "Future research should focus on large-scale trials to evaluate clinical endpoints, optimize patient selection, and explore cost-effective strategies for broader access. Zodasiran exemplifies a promising new class of RNAi-based lipid-lowering agents with the potential to transform the treatment landscape for dyslipidemia and ASCVD prevention."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Mixed Hyperlipidemia • ANGPTL3 • APOB

A PHASE 3 STUDY OF ZODASIRAN IN ADOLESCENT AND ADULT SUBJECTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (clinicaltrials.gov) - P3 | N=60 | Not yet recruiting | Sponsor: Arrowhead Pharmaceuticals

New P3 trial • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • APOB

ANGPTL3: A Breakthrough Target in Treatment for Dyslipidemia and Atherosclerosis. (PubMed, J Atheroscler Thromb) - "Despite conventional treatment with statins, ezetimibe, or PCSK9 inhibitors, there are cases of familial hypercholesterolemia (FH) in which LDL-C levels cannot be sufficiently lowered to the target level, resulting in failure to prevent CVD...In fact, evinacumab, an anti-ANGPTL3 monoclonal antibody, has been shown to substantially reduce LDL-C and TG levels, even in FH patients with LDL receptor gene mutations who are resistant to the conventional treatments described above. Clinical trials have also shown that siRNA therapeutics, such as zodasiran and solbinsiran, improve lipid profiles in patients with dyslipidemia. Recently, we have begun developing a peptide-based anti-ANGPTL3 vaccine and confirmed in a preclinical FH mouse model that it significantly decreases LDL-C and TG levels, reduces atherosclerotic lesions and maintains long-term efficacy without adverse effects. In this review, we discuss the promising advances in ANGPTL3-targeted therapeutics that may..."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Hypertriglyceridemia • Metabolic Disorders • ANGPTL3 • LPL

Small Interfering RNA (siRNA) in Dyslipidemia: A Systematic Review on Safety and Efficacy of siRNA. (PubMed, J Exp Pharmacol) - "Inclisiran led to a notable 44.09% reduction in LDL and 37.5% in apolipoprotein levels among individuals with hypercholesterolemia. In hyperlipoproteinemia(a), therapies like Lepodisiran and Olpasiran achieved a 75.69% drop in apolipoproteins and 16.25% in LDL. For hypertriglyceridemia, agents such as ARO-APOC3 and Plozasiran showed over 50% reductions in both VLDL and triglycerides...In conclusion, the benefits of siRNA therapy in dyslipidemia management appear to outweigh its potential drawbacks, demonstrating promising efficacy and safety profiles. However, further research is necessary to fully understand its long-term effects and optimize its therapeutic potential."

Journal • Review • Back Pain • Cardiovascular • Diabetes • Dyslipidemia • Hypertension • Hypertriglyceridemia • Infectious Disease • Metabolic Disorders • Mixed Hyperlipidemia • Musculoskeletal Pain • Pain

Novel Therapeutics for Familial Chylomicronemia Syndrome. (PubMed, Curr Atheroscler Rep) - "Volanesorsen, an ASO targeting APOC3, has shown effectiveness in managing FCS, multifactorial chylomicronemia, and familial partial lipodystrophy, but its use is limited by thrombocytopenia. Emerging therapies, Olezarsen (ASO anti-APOC3) and Plozasiran (siRNA anti-APOC3), both conjugated with GalNAc, show promise in reducing acute pancreatitis risk without platelet concerns. ANGPTL3 inhibition requires residual lipoprotein lipase (LPL) activity, with only siRNA-based therapies-zodasiran and solbinsiran-under investigation. Suppressing APOC3 expression and targeting ANGPTL3 via siRNA offer significant potential, but long-term studies are needed to confirm their efficacy and safety. Future research may explore gene-editing strategies using lipid nanoparticle-based CRISPR-Cas9 delivery for more durable treatment outcomes."

Journal • Review • Familial Chylomicronemia Syndrome • Hematological Disorders • Lipodystrophy • Metabolic Disorders • Pancreatitis • Rare Diseases • Thrombocytopenia • ANGPTL3 • APOC3 • LPL

Comprehensive evaluation of siRNA therapeutics on Lp(a): A network meta-analysis. (PubMed, Diabetes Obes Metab) - "Lp(a)-targeted siRNA agents have shown robust effectiveness in substantially reducing Lp(a) levels, including both percentage and absolute reductions, with moderate improvements in LDL-C and apo(B) concentrations. Non-Lp(a)-targeted siRNA agents also demonstrate modest reductions in Lp(a) levels. The safety profile is generally favourable, but zerlasiran and inclisiran may increase the incidence of injection-site reactions."

Journal • Retrospective data • Dyslipidemia • APOB

Current and Emerging Treatment Options for Hypertriglyceridemia: State-of-the-Art Review. (PubMed, Pharmaceuticals (Basel)) - "Among apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran appear to be safer alternatives for volanesorsen regarding the risk of drug-induced thrombocytopenia in patients with FCS or severe HTG. After the failure of vupanorsen, a new angiopoietin-like protein 3 (ANGPTL3) inhibitor, zodasiran, demonstrated the potential to decrease TG levels in patients with moderate HTG. Meanwhile, the fibroblast growth factor 21 (FGF21) analog, pegozafermin, became another candidate for the treatment of severe HTG. This comprehensive review outlines pharmacological targets in TG-rich lipoprotein metabolism, discusses international guidelines, and summarizes the latest evidence from clinical trials to provide insight into the current and emerging treatment options for primary HTG."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Chylomicronemia Syndrome • Hematological Disorders • Hypertriglyceridemia • Metabolic Disorders • Pancreatitis • Severe Hypertriglyceridemia • Thrombocytopenia • ANGPTL3 • FGF21

RNA therapeutics in cardiovascular medicine. (PubMed, Curr Opin Cardiol) - "Because of limitless sequence choice; speed of design; and relative ease of synthesis, RNA drugs will be rapidly developed, will have broad applications, and will be generated at lower cost than other drug types. This review aims to highlight RNA therapies for cardiovascular diseases that are approved, and those that are under clinical evaluation."

Journal • Cardiovascular • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • ANGPTL3

Novel RNA-Based Therapies in the Management of Dyslipidemias. (PubMed, Int J Mol Sci) - "This article discusses the latest data from completed and ongoing trials on RNA therapies for dyslipidemia, including inclisiran, pelacarsen, olpasiran, zerlasiran, lepodisiran, volanesorsen, olezarsen, plozasiran, zodasiran, and solbinsiran. Each therapy targets specific molecules while also significantly impacting other lipid parameters. The promising results of these trials indicate potential improvements in lipid therapy and cardiovascular risk reduction, with ongoing studies expected to further refine the role of the novel RNA-based agents in effective lipid management."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • ANGPTL3

Exploring emerging pharmacotherapies for type 2 diabetes patients with hypertriglyceridemia. (PubMed, Expert Opin Pharmacother) - "These were identified by a PubMed search and mainly focus on pemafibrate and the drugs targeting apolipoprotein C3 (apoC3) and angiopoietin-like 3 (ANGPTL3)...Inhibitors of apoC3 are effective in reducing triglycerides even in familial chylomicronaemia syndrome and olezarsen and plozasiran in this group are being studied in patients with combined hyperlipidemia. The ANGPTL3 inhibitor evinacumab has been approved for homozygous familial hypercholesterolemia and other ANGPTL3 inhibitors may prove be useful to reduce triglycerides in T2D."

Journal • Review • Cardiovascular • Diabetes • Dyslipidemia • Familial Chylomicronemia Syndrome • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Hypertriglyceridemia • Metabolic Disorders • Type 2 Diabetes Mellitus • ANGPTL3

Visirna Completes Dosing of First Patient in Phase III Clinical Trial of VSA003 Targeting ANGPTL3 for Homozygous Familial Hypercholesterolemia in China [Google translation] (163.com) - "On December 18, Visirna Biotech...recently announced that its Class 1 new drug VSA003 injection (hereinafter referred to as VSA003) successfully completed the first patient dosing in the Phase III clinical trial at the Peking Union Medical College Hospital, Chinese Academy of Medical Sciences. This trial is a randomized, double-blind, placebo-controlled, multicenter Phase III clinical trial designed to evaluate the efficacy and safety of VSA003 injection in Chinese adolescents and adults with homozygous familial hypercholesterolemia (HoFH) (CTR20244397)."

Trial status • Homozygous Familial Hypercholesterolemia

An up-to-date review of emerging biologic therapies for hypercholesterolemia. (PubMed, Expert Opin Biol Ther) - "In addition to the currently available monoclonal antibodies (mAbs) and small interfering RNA (siRNA), new mAbs and the adenectin lerodalcibep are promising therapies. The antisense oligonucleotide (ASO) and siRNA inhibitors of apoC3 and ANGPTL3 are effective in severe hypertriglyceridemia and homozygous familial hypercholesterolemia, respectively, and may prove to have wider applications. ASO and siRNA inhibitors of Lp(a) are currently in cardiovascular outcome studies."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Hypertriglyceridemia • Metabolic Disorders • Severe Hypertriglyceridemia • ANGPTL3