solbinsiran (LY3561774) / Eli Lilly, Novo Nordisk - LARVOL DELTA

SOLARIS-1: A Study of Solbinsiran (LY3561774) in Participants With Severe Hypertriglyceridemia (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P2 trial • Dyslipidemia • Hypertriglyceridemia • Severe Hypertriglyceridemia

SOLARIS-1: A Study of Solbinsiran (LY3561774) in Participants With Severe Hypertriglyceridemia (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Dyslipidemia • Hypertriglyceridemia • Severe Hypertriglyceridemia

Promise of ANGPTL3 as a therapeutic target for controlling cholesterol levels. (PubMed, Expert Opin Ther Targets) - "These observations rapidly catalyzed the development of pharmacologic strategies to inhibit ANGPTL3 using monoclonal antibodies (e.g. evinacumab), antisense oligonucleotides (e.g. vupanorsen), small interfering ribonucleic acid (e.g. zodasiran and solbinsiran), and most recently genome-editing approaches (e.g. VERVE-201 and CTX310). The degree of hypertriglyceridemia in the patient's baseline lipid profile appears to be an important determinant of drug response. Drawing on genetic, mechanistic, and clinical trial data, the promise and limitations of ANGPTL3 inhibition are considered and its potential place in future lipid-lowering strategies is outlined."

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

Effect of angiopoietin-like protein 3 inhibitors on lipid profile and other biomarkers: a meta-analysis of randomized controlled trials. (PubMed, Eur J Prev Cardiol) - "ANGPTL3 inhibition offers broad lipid-lowering benefits, with particularly marked reductions in TG-rich lipoproteins."

Biomarker • Journal • Retrospective data • Cardiovascular • Dyslipidemia • ANGPTL3 • APOA1 • APOB • APOE • CRP

Solbinsiran, a durable GalNAc-conjugated siRNA targeting ANGPTL3 in adults with mixed dyslipidaemia (PROLONG-ANG3): lessons from a randomized, placebo-controlled, phase 2 trial. (PubMed, Cardiovasc Res) - No abstract available

Journal • P2 data • Dyslipidemia • Mixed Hyperlipidemia • ANGPTL3

Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis. (PubMed, Front Pharmacol) - "APOC3-targeted treatments primarily reduce triglycerides while increasing HDL-C, whereas ANGPTL3-targeted therapies offer broader lipid modulation, including substantial reductions in LDL-C. Both therapies demonstrate favorable safety profiles."

Journal • Retrospective data • Review • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders • Mixed Hyperlipidemia • ANGPTL3 • APOB

Angiopoietin-like Protein 3 (ANGPTL3) Targeting in the Management of Dyslipidemias. (PubMed, Int J Mol Sci) - "We also discuss Evinacumab, a monoclonal antibody, its structure, mechanism of action, safety, tolerability, pharmacokinetics, and pharmacodynamics, as well as its clinical trial-derived results. The antisense oligonucleotides modify ANGPTL3 mRNA to inhibit protein production, and small interfering RNAs induce mRNA degradation; results from clinical trials were reviewed in detail. Finally, we discuss promising gene editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems."

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

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

Emerging ANGPTL3-directed therapies for hyperlipidemia: insights from two recent phase II trials. (PubMed, Expert Opin Investig Drugs) - No abstract available

Journal • P2 data • Dyslipidemia • Hypertriglyceridemia • ANGPTL3

siRNAs targeting ANGPTL3 for mixed dyslipidemia. (PubMed, Med) - "The PROLONG-ANG3 trial demonstrated that two doses of solbinsiran, an siRNA targeting hepatic ANGPTL3, given 90 days apart, decreased concentrations of apoB, triglycerides, LDL-C, non-HDL-C, ANGPTL3, and hepatic fat content at day 180 in adults with mixed dyslipidemia.1 Long-term studies assessing the safety of solbinsiran and its efficacy in decreasing the risk of atherosclerotic cardiovascular disease are warranted."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • Mixed Hyperlipidemia • ANGPTL3 • 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

Angiopoietin-Like Protein 3 Inhibition: A Key to Silencing Residual Lipid Risk? (PubMed, J Am Coll Cardiol) - No abstract available

Journal • Dyslipidemia • Metabolic Disorders

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

Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial. (PubMed, Lancet) - P2 | "Solbinsiran 400 mg reduced apoB in patients with mixed dyslipidaemia and was generally well tolerated. The impact of solbinsiran on cardiovascular outcomes remains to be investigated."

Journal • P2 data • Atherosclerosis • Cardiovascular • Dyslipidemia • Mixed Hyperlipidemia • ANGPTL3 • APOB

Effect Of Solbinsiran, A Small Interfering RNA Targeting ANGPTL3, On Biomarkers Of Major Adverse Cardiovascular Events In Adults With Mixed Dyslipidemia: A Randomized Phase 2 Trial - Kausik K. Ray (ACC 2025) - No abstract available

Adverse events • Biomarker • Clinical • Late-breaking abstract • P2 data • Cardiovascular • Dyslipidemia • Metabolic Disorders • Mixed Hyperlipidemia • ANGPTL3

Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early Human Studies. (PubMed, J Am Coll Cardiol) - P1 | "Solbinsiran inhibits hepatic ANGPTL3 translation and results in significant reductions in all atherogenic lipoproteins in mixed dyslipidemia. The impact of this approach on cardiovascular outcomes remains to be determined. (A Study of LY3561774 in Participants With Dyslipidemia; NCT04644809)."

Journal • Preclinical • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders • Mixed Hyperlipidemia • ANGPTL3 • APOB

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

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

PROLONG-ANG3: A Study of LY3561774 in Participants With Mixed Dyslipidemia (clinicaltrials.gov) - P2 | N=204 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Dyslipidemia • Metabolic Disorders • APOB

SOLBINSIRAN, A GALNAC-CONJUGATED SIRNA TARGETING ANGPTL3, REDUCES ATHEROGENIC LIPOPROTEINS IN INDIVIDUALS WITH MIXED DYSLIPIDAEMIA IN A DURABLE AND DOSE-DEPENDENT MANNER (ACC 2024) - P1 | "Solbinsiran has potential as a therapeutic option for inhibiting synthesis of ANGPTL3 and reducing TG and atherogenic apoB-containing lipoproteins (NCT04644809)."

Clinical • Dyslipidemia • ANGPTL3 • APOB

Identification and Characterization of Solbinsiran, a GalNAc Conjugated siRNA Targeting Angiopoietin-Like 3 (AHA 2023) - P1 | "These data supported the advancement of solbinsiran to Phase 1 clinical testing in participants with mixed dyslipidemia (ClinicalTrials.gov Identifier: NCT04644809)."

Dyslipidemia • Hepatology • Metabolic Disorders • ANGPTL3 • APOB

PROLONG-ANG3: A Study of LY3561774 in Participants With Mixed Dyslipidemia (clinicaltrials.gov) - P2 | N=175 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Dyslipidemia • Metabolic Disorders • ANGPTL3 • APOB

PROLONG-ANG3: A Study of LY3561774 in Participants With Mixed Dyslipidemia (clinicaltrials.gov) - P2 | N=175 | Recruiting | Sponsor: Eli Lilly and Company | Trial primary completion date: Sep 2023 ➔ Jan 2024

Trial primary completion date • Dyslipidemia • Metabolic Disorders • APOB

PROLONG-ANG3: A Study of LY3561774 in Participants With Mixed Dyslipidemia (clinicaltrials.gov) - P2 | N=175 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2023 ➔ Mar 2024

Trial completion date • Dyslipidemia • Metabolic Disorders • APOB