plozasiran (ARO-APOC3) / Arrowhead - LARVOL DELTA

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

Glycerol Kinase Gene Variant as a Cause of Pseudohypertriglyceridemia and Apparent Poor Response to Plozasiran. (PubMed, JCEM Case Rep) - "This case report suggests that in the absence of response to APOC3 inhibition, measuring free glycerol could be clinically relevant. It also highlights that APOC3 inhibition has no effect on free glycerol concentration."

Journal • Cardiovascular • Dyslipidemia • Genetic Disorders • Hypertriglyceridemia • Pancreatitis • Severe Hypertriglyceridemia • GK

A randomized, placebo-controlled phase 3 study of plozasiran in patients with familial chylomicronemia syndrome: PALISADE - 1 year open label extension (ESC-WCC 2025) - No abstract available

Clinical • P3 data • Cardiovascular

MUIR-3: Phase 3 Study of Plozasiran in Adults With Hypertriglyceridemia (clinicaltrials.gov) - P3 | N=1456 | Active, not recruiting | Sponsor: Arrowhead Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Dyslipidemia • Hypertriglyceridemia

Arrowhead Pharmaceuticals Completes Enrollment in SHASTA-3, SHASTA-4, and MUIR-3 Phase 3 Studies of Plozasiran (Businesswire) - "Study completion anticipated in mid-2026 with subsequent data readout and regulatory submissions for treatment of severe hypertriglyceridemia...The company previously submitted a New Drug Application (NDA) for plozasiran based on positive Phase 3 PALISADE study results in patients with familial chylomicronemia syndrome, which the U.S. FDA has accepted with a Prescription Drug User Fee Act (PDUFA) action date set for November 18, 2025."

PDUFA • Trial status • Familial Chylomicronemia Syndrome • Severe Hypertriglyceridemia

Population Pharmacokinetic Modeling of Subcutaneous Plozasiran in Healthy Volunteers and Patients with Familial Chylomicronemia Syndrome, Severe Hypertriglyceridemia, and Mixed Hyperlipidemia. (PubMed, J Clin Pharmacol) - "As plozasiran PK were not differentiated by patient population, a substantially reduced schedule of PK sampling was justified for the ongoing Phase 3 studies to confirm the safety and efficacy of plozasiran in patients with SHTG. Model-based extrapolation of plozasiran concentrations in plasma and liver suggests that the plozasiran dosing regimen of 25 mg every 3 months recommended for adult patients is likely safe and effective in adolescent patients aged 12 to 17 years old."

Journal • PK/PD data • Dyslipidemia • Familial Chylomicronemia Syndrome • Hepatology • Hypertriglyceridemia • Mixed Hyperlipidemia • Renal Disease • Severe Hypertriglyceridemia

SHASTA-5 rationale and design: Randomized, double-blind, placebo-controlled study to evaluate plozasiran efficacy and safety in sHTG at risk for AP (NLA 2025) - "Secondary endpoints include percent change in fasting TG from baseline to month-12 with plozasiran; proportion of patients who achieve fasting TG of < 880 mg/dL; achievement of fasting TG of < 500 mg/dL; time to first major abdominal pain event occurring; and change from baseline in patient-reported productivity and activity impairment (WPAI-SHP score) and health status (EQ-5D-5L score). Conclusions SHASTA-5 is designed to determine whether the quarterly-dosed APOC3 siRNA plozasiran safely reduces the rate of AP in patients with sHTG."

Clinical • Dyslipidemia • Hypertriglyceridemia • Pain • Pancreatitis • Severe Hypertriglyceridemia • LPL

Plozasiran decreases the risk of acute pancreatitis and may improve quality of life in familial chylomicronemia syndrome (NLA 2025) - "Clinically meaningful improvements were shown for appetite loss, insomnia, cognitive functioning, emotional functioning, and role functioning in the plozasiran treated subjects compared to placebo (nominal p-values of < 0.05). Conclusions Plozasiran significantly reduced TG and AP while improving QoL in the PALISADE trial."

HEOR • Anorexia • CNS Disorders • Familial Chylomicronemia Syndrome • Insomnia • Pain • Pancreatitis • Sleep Disorder • LPL

† Effect of plozasiran targeting APOC3 on lipoprotein particle number and size measured by NMR in patients with hypertriglyceridemia (NLA 2025) - "While high-potency TRL-lowering therapies can sometimes lead to an overall LDL-C increase, LDL-P is not increased and plozasiran shifts the LDL particle size distribution from sdLDL towards larger sizes. The 50% reduction in TRL-P coupled with potential benefits of qualitative changes in LDL without any increase in LDL-P, suggests a promising potential to lower ASCVD risk, which will be evaluated in a prospective outcomes trial."

Clinical • Dyslipidemia • Hypertriglyceridemia • Mixed Hyperlipidemia • Severe Hypertriglyceridemia • APOB

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

Plozasiran: Completion of enrollment of P3 MUIR-3 trial (NCT06347133) for hypertriglyceridemia in Q3 2025 (Arrowhead) - Corporate Presentation

Enrollment status • Hypertriglyceridemia • Metabolic Disorders

Plozasiran: Completion of enrollment of P3 SHASTA-3 trial (NCT06347003) for severe hypertriglyceridemia in Q3 2025 (Arrowhead) - Corporate Presentation: Completion of enrollment of P3 SHASTA-4 trial (NCT06347016) for severe hypertriglyceridemia in Q3 2025

Enrollment status • Hypertriglyceridemia • Metabolic Disorders

Arrowhead Pharmaceuticals Reports Fiscal 2025 Second Quarter Results (Businesswire) - "...'We are on schedule to launch plozasiran this year, pending regulatory approval, with what we think is a best-in-class profile with meaningful differentiation from currently available therapies in FCS.'"

Launch US • Familial Chylomicronemia Syndrome

Plozasiran and Apolipoprotein C-III Inhibition: Lipoprotein Particle Insights and Cardiovascular Implications. (PubMed, J Am Coll Cardiol) - No abstract available

Journal • Cardiovascular

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

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Pancreatitis

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. (PubMed, N Engl J Med) - No abstract available

Journal • Pancreatitis

EFFECT OF PLOZASIRAN TARGETING APOC3 ON LIPOPROTEIN PARTICLE NUMBER AND SIZE MEASURED BY NMR IN PATIENTS WITH HYPERTRIGLYCERIDEMIA (HTG) - Christie M. Ballantyne (ACC 2025) - "PZN induces APOC3 decreases and favorable quantitative and qualitative changes in lipoproteins as assessed by NMR in HTG patients. PZN reduces TRL-P by ~50%, shifts LDL to larger particles, and increases HDL-P concentration. While high-potency TRL-lowering therapies can sometimes lead to an overall LDL-C increase, PZN does not increase LDL-P but does shift LDL particle size distribution from sdLDL towards larger sizes."

Clinical • Dyslipidemia • Hypertriglyceridemia • Mixed Hyperlipidemia • Severe Hypertriglyceridemia

Plozasiran: "Plozasiran demonstrated potent and durable reductions of atherogenic lipoproteins in HTG populations"; Hypertriglyceridemia (Arrowhead) - Effect of Plozasiran Targeting APOC3 on Lipoprotein Particle Number and Size Measured by NMR in Patients with Hypertriglyceridemia

P2 data • Hypertriglyceridemia • Metabolic Disorders

Safety and efficacy of antisense oligonucleotides on triglyceride, apolipoprotein C-III, and other lipid parameters levels in hypertriglyceridemia; a network meta-analysis of randomized controlled trials. (PubMed, Lipids Health Dis) - "APOC3 antisense oligonucleotide inhibitors effectively reduced triglyceride and APOC3 levels in hypertriglyceridemia with an acceptable safety profile. However, the results should be interpreted cautiously due to the small sample size. Further research is needed to confirm the beneficial effects of APOC3 inhibitors and show strong evidence of the impact of each regimen."

Clinical • Journal • Retrospective data • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • APOC3

Apolipoprotein C-III inhibitors for the treatment of hypertriglyceridemia: A meta-analysis of randomized controlled trials. (PubMed, Metabolism) - "APOC-III inhibitors improve TG levels and other lipid panel parameters, as well as reduce episodes of acute pancreatitis in patients with primary and secondary hypertriglyceridemia."

Journal • Retrospective data • Atherosclerosis • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Pancreatitis • Severe Hypertriglyceridemia

Familial chylomicronemia syndrome and treatments to target hepatic APOC3 mRNA. (PubMed, Atherosclerosis) - "Reduced TG, lower rates of acute pancreatitis events, and similar proportions of adverse events in placebo and treated patients were recently demonstrated in placebo-controlled phase 3 trials of patients with FCS treated with olezarsen in Balance and with plozasiran in PALISADE. This review discusses causes and consequences of FCS and the rationale and progress made in developing APOC3 RNA-targeted therapeutics for the treatment of FCS."

Journal • Review • Dyslipidemia • Familial Chylomicronemia Syndrome • Hypertriglyceridemia • Pancreatitis • APOC3 • LPL

Study of VSA001 Injection in Chinese Healthy Adult Volunteers (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: Visirna Therapeutics HK Limited | Not yet recruiting ➔ Completed

Trial completion

Effect of Targeting apoC-III with Plozasiran on Lipoprotein Particle Size and Number in Hypertriglyceridemia. (PubMed, J Am Coll Cardiol) - "Plozasiran induced reductions in apoC-III and showed potentially favorable quantitative and qualitative changes in lipoproteins as assessed by NMR in patients with hypertriglyceridemia and mixed hyperlipidemia. Plozasiran reduced TRL-P by ∼50%, shifted LDL to larger particles, and modestly increased HDL-P concentration. While high-potency TRL-lowering therapies can lead to an overall LDL-C increase, plozasiran did not increase LDL-P or apoB but shifted LDL particle size distribution from small dense LDL towards larger sizes. The ∼50% reduction in TRL-P with no increase in apoB and possibly beneficial qualitative changes in LDL suggests the potential of plozasiran to lower cardiovascular risk, which may be evaluated in a prospective outcomes trial."

Journal • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Mixed Hyperlipidemia • Severe Hypertriglyceridemia • APOB

The first-of-its-kind APOC3 siRNA was successfully tested in China in Phase III, requiring only one dose every three months [Google translation] (vbdata.cn) - P3 | N=30 | NCT05902598 | Sponsor: Visirna Therapeutics HK Limited | "Viagene announced that VSA001 injection (Pleslan sodium) has obtained positive top-line data in the Phase III clinical trial (CTR20231418/NCT05902598) of patients with familial chylomicronemia syndrome (FCS) in China, successfully reaching the primary efficacy endpoint and all key secondary endpoints....A total of 37 FCS patients were randomly assigned to receive subcutaneous injections of VSA001 25 mg, 50 mg or placebo every 3 months for 12 months, aiming to evaluate the efficacy and safety of VSA001 in adult patients with FCS in China. The primary endpoint of the study was the median percentage change in fasting serum triglyceride levels from baseline at month 10 compared with the placebo group."

P3 data: top line • Familial Chylomicronemia Syndrome