lepodisiran (LY3819469) / Eli Lilly, Novo Nordisk - LARVOL DELTA

Targeting Lipoprotein(a): A New Era in Cardiovascular Disease Prevention. (PubMed, Methodist Debakey Cardiovasc J) - "Novel unapproved therapies, including an antisense oligonucleotide (pelacarsen), small interfering RNAs (olpasiran, lepodisiran), and an oral small molecule (muvalaplin), have demonstrated Lp(a) reductions of up to 99% and are being tested in ongoing phase 3 cardiovascular outcomes trials to determine whether pharmacologic Lp(a) lowering translates into reduced cardiovascular events. We discuss current knowledge on genetics, biology, epidemiology, and measurement of Lp(a), examine its causal association with cardiovascular disease, and discuss emerging therapeutic strategies that may usher in a new era of cardiovascular disease prevention."

Biomarker • Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia

Effect on Oxidized Phospholipids of Lepodisiran, an Extended Duration siRNA Targeting Lipoprotein(a) (ESC 2026) - No abstract available

Late-breaking abstract • Cardiovascular

Elevated lipoprotein(a) and cardiovascular prognosis in established coronary artery disease: a systematic review and meta-analysis of 129 studies (ESC 2026) - "With novel Lp(a)-lowering therapies (pelacarsen, olpasiran, lepodisiran) now in Phase 3 cardiovascular outcomes trials, robust observational data are urgently needed to contextualise expected therapeutic benefits. In the largest meta-analysis of Lp(a) and cardiovascular prognosis in secondary prevention, elevated Lp(a) was associated with 53% increased MACE, 26% increased all-cause mortality, and 56% increased cardiovascular mortality. Unlike prior meta-analyses, we demonstrate statistically significant mortality associations, confirming Lp(a) as a prognostic marker for both recurrent events and death. The interaction with inflammatory status suggests Lp(a) may be particularly informative in patients with residual inflammatory risk."

Retrospective data • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Myocardial Infarction • CRP

Lipoprotein(a): Cardiovascular Risk and Emerging Targeted Therapies. (PubMed, Am J Cardiovasc Drugs) - "PCSK9 inhibitors and inclisiran produce modest (approximately 20-30%) Lp(a) reductions, and lipoprotein apheresis may be useful in highly selected patients, but none represents a broadly applicable Lp(a)-specific therapy...Antisense oligonucleotides, small interfering RNA therapies and oral small-molecule inhibitors have demonstrated profound and durable Lp(a) reductions, frequently exceeding 80-100% with small interfering RNA (siRNA)-based agents (olpasiran, zerlasiran, lepodisiran), up to 80% with the antisense oligonucleotide pelacarsen, and up to 85% with the oral small-molecule muvalaplin, in phase 1 and phase 2 clinical trials...Current evidence supports strong biological efficacy, but definitive proof of clinical benefit awaits ongoing randomized cardiovascular outcomes trials, including Lp(a)HORIZON (pelacarsen), OCEAN(a)-Outcomes (olpasiran) and ACCLAIM-Lp(a) (lepodisiran). This narrative review summarizes the biology and epidemiological relevance of Lp(a),..."

Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Heart Failure • Ischemic stroke • Myocardial Infarction • Peripheral Arterial Disease

Effect on Lipoprotein(a) Oxidized Phospholipids of Lepodisiran, an Extended-Duration siRNA Targeting Lipoprotein(a). (PubMed, J Am Coll Cardiol) - P2 | "Lepodisiran produced sustained reductions in OxPL-apoB and OxPL-apo(a) levels that correlated with Lp(a) lowering. These findings provide additional biological rationale for the ongoing lepodisiran phase 3 cardiovascular outcomes trial, but do not establish clinical benefit. (A Study of LY3819469 in Participants With Elevated Lipoprotein(a) [Lp(a)]; NCT05565742)."

Journal • Atherosclerosis • Cardiovascular • Inflammation • APOB • CRP

Taking the Sting Out of Lipoprotein(a): Oxidized Phospholipid Lowering With Lepodisiran. (PubMed, J Am Coll Cardiol) - No abstract available

Journal

A Study of Lepodisiran (LY3819469) in Participants With Normal, Mild, Moderate, or Severe Liver Function (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Liver Failure

Novel Lipoprotein (a) Therapies: A Comprehensive Review. (PubMed, Curr Atheroscler Rep) - "Pelacarsen, a GalNAc-conjugated antisense oligonucleotide (ASO), reduces Lp(a) by about 80% via hepatic apo(a) mRNA reduction and is the subject of the phase 3 Lp(a) HORIZON trial, with results due in late 2026. Three small interfering RNA (siRNA) drugs, olpasiran (> 95% reduction, OCEAN(a)-Outcomes), lepodisiran (93.9% reduction lasting over 12 months after one dose, ACCLAIM-Lp(a)), and zerlasiran (96.4% reduction), allow quarterly or possibly yearly dosing. Muvalaplin, the first oral small-molecule Lp(a) inhibitor, interferes with apo(a)-ApoB particle formation and reduces intact Lp(a) by up to 85.8% in phase 2 KRAKEN trials; its phase 3 CVOT (MOVE-Lp(a)) is underway. Additionally, CRISPR/Cas9-based liver gene editing targeting the LPA gene (CTX320) has entered phase 1 studies...Positive outcomes from these CVOTs could lead to regulatory approvals and guideline updates affecting hundreds of millions of high-risk patients globally. Recent guidelines now recommend..."

Journal • Review • Atherosclerosis • Cardiovascular • APOB

ACCLAIM-CTA: A Study to See if Lepodisiran Can Reduce Plaque in Coronary Arteries of Adults With Elevated Lp(a) Who Have Had Heart Events or Are at High Risk (clinicaltrials.gov) - P3 | N=252 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Apr 2029 ➔ Dec 2029 | Trial primary completion date: Apr 2029 ➔ Dec 2029

Trial completion date • Trial primary completion date • Atherosclerosis • Cardiovascular

Emerging Therapies Targeting Lipoprotein(a): A Clinical Trial Landscape Review of Investigational Lp(a)-Lowering Therapies. (PubMed, J Clin Med) - "Available non-head-to-head published evidence showed substantial Lp(a) reductions across several investigational agents, including siRNA-based therapies, pelacarsen, and muvalaplin, although differences between studies preclude direct comparison between therapeutic platforms. The Lp(a) therapeutic landscape has rapidly evolved, with RNA-based therapies demonstrating unprecedented reductions in circulating Lp(a) concentrations. Ongoing cardiovascular outcomes trials will determine whether these reductions translate into meaningful cardiovascular benefits, establish Lp(a) as a therapeutic target in cardiovascular prevention and clarify the long-term safety and risk-benefit profile of Lp(a)-targeted therapies."

Journal • Review • Atherosclerosis • Cardiovascular

Lipoprotein(a) and Cardiovascular Risk: Emerging Therapeutic Perspectives with Implications for Chronic Kidney Disease. (PubMed, Cardiorenal Med) - "However, the causal role of Lp(a) in CKD-related cardiovascular disease remains incompletely defined. Novel RNA-based and small-molecule therapies, including pelacarsen, olpasiran, lepodisiran, zerlasiran, and muvalaplin, have shown marked Lp(a)-lowering effects, but definitive cardiovascular outcome data are still missing."

Journal • Review • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • APOB

Lipoprotein apheresis: From familial hypercholesterolemia and elevated lipoprotein(a) to emerging roles in peripheral arterial and renal disease. (PubMed, Transfus Apher Sci) - "The introduction of PCSK9 inhibitors and inclisiran has progressively reduced apheresis utilization for LDL-centric management, while potent RNA-based Lp(a)-lowering agents (pelacarsen, olpasiran, lepodisiran) in late-stage development may further reshape the field. Beyond traditional cardiovascular indications, accumulating observational evidence supports LA in peripheral arterial disease through pleiotropic rheologic and anti-inflammatory mechanisms, and in steroid-resistant focal segmental glomerulosclerosis through oxidized LDL clearance and podocyte rescue. This review synthesizes current evidence across cardiovascular, peripheral vascular, and renal indications, compares apheresis modalities, examines integration with emerging pharmacotherapies, and proposes a three-part trajectory for LA: progressive contraction in LDL-centric use, a persisting role in Lp(a)-driven disease until RNA-based agents demonstrate outcome benefit, and a mechanistically grounded but..."

Journal • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Focal Segmental Glomerulosclerosis • Genetic Disorders • Glomerulonephritis • Heterozygous Familial Hypercholesterolemia • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Nephrology • Peripheral Arterial Disease • Renal Disease • APOB

ACCLAIM-CTA: A Study to See if Lepodisiran Can Reduce Plaque in Coronary Arteries of Adults With Elevated Lp(a) Who Have Had Heart Events or Are at High Risk (clinicaltrials.gov) - P3 | N=252 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Atherosclerosis • Cardiovascular

A Study of Lepodisiran (LY3819469) in Participants With Normal, Mild, Moderate, or Severe Liver Function (clinicaltrials.gov) - P1 | N=33 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Liver Failure

Comparative Effects of Emerging Lp(a)-Lowering Agents and PCSK9-Directed Therapies on Lipoprotein(a): A Network Meta-Analysis of Randomised Clinical Trials. (PubMed, Diabetes Obes Metab) - "Lp(a)-targeted therapies were associated with larger Lp(a) reductions than PCSK9-directed therapies, while PCSK9-directed therapies had greater LDL-C lowering. Given high heterogeneity, funnel plot asymmetry and low certainty for several estimates, these findings should be interpreted cautiously pending cardiovascular outcome trials."

Journal • Retrospective data • Cardiovascular • Dyslipidemia

Old and New Lines of Therapy Targeting Lipoprotein(a). (PubMed, Curr Atheroscler Rep) - "Randomized clinical trials are now underway for several promising therapeutics targeting LPA gene translation, including antisense oligonucleotides (pelacarsen) and small interfering RNAs (olpasiran, lepodisiran, zerlasiran), with the earliest of these expected to read out in 2026. An oral small-molecule inhibitor (muvalaplin) has also demonstrated substantial Lp(a) lowering by disrupting apo(a)-apoB assembly...A robust pipeline of Lp(a)-lowering therapies - spanning injectable gene-silencing therapeutics, oral small molecules, and next-generation gene-editing technologies - has the potential to fundamentally alter our current risk prevention paradigm. The results of these ongoing clinical trials will be crucial in determining whether targeted Lp(a) reduction can meaningfully reduce residual cardiovascular risk and establish Lp(a) as a modifiable risk factor in both primary and secondary prevention."

Clinical • Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Gene Therapies • Ischemic stroke • Peripheral Arterial Disease • APOB

ACCLAIM-CTA: A Study to See if Lepodisiran Can Reduce Plaque in Coronary Arteries of Adults With Elevated Lp(a) Who Have Had Heart Events or Are at High Risk (clinicaltrials.gov) - P3 | N=252 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Atherosclerosis • Cardiovascular

Lowering of Lipoprotein(a) with Olpasiran. (PubMed, Cardiovasc Hematol Disord Drug Targets) - "Ezetimibe, which inhibits cholesterol absorption and can reduce LDL-C, does not significantly affect Lp(a) levels, even when used in combination with statins. In this review article, we delve further into lowering of Lp(a) with Olpasiran by detailing its pharmacological properties, its efficacy based on data from clinical trials, and ongoing research. The study also contextualizes it within the broader therapeutic landscape alongside other agents targeting Lp(a), such as Pelacarsen and Lepodisiran."

Journal • Atherosclerosis • Cardiovascular • Myocardial Infarction

Efficacy and safety of lipoprotein(a)-targeted therapeutics: a systematic review and network meta-analysis. (PubMed, Front Cardiovasc Med) - "In between-drug comparisons, Olpasiran was superior to Pelacarsen...Zerlasiran, Lepodisiran, and Pelacarsen were found to increase the risk of injection-site reactions...The majority of Lp(a)-targeted therapies demonstrate generally favorable safety profiles; However, injection-site reactions, particularly with Zerlasiran, warrant careful consideration. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251069288, PROSPERO CRD420251069288."

Journal • Retrospective data • Review • Dyslipidemia • APOB

A Study of Lepodisiran (LY3819469) in Participants With Normal, Mild, Moderate, or Severe Liver Function (clinicaltrials.gov) - P1 | N=33 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Jan 2026 ➔ Jun 2026 | Trial primary completion date: Jan 2026 ➔ Jun 2026

Trial completion date • Trial initiation date • Trial primary completion date • Hepatology • Liver Failure

COMPARATIVE EFFICACY AND SAFETY OF NOVEL LIPOPROTEIN(A)-TARGETED THERAPIES: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS OF RNA-BASED INTERVENTIONS (ACC 2026) - " Systematic searches of MEDLINE, EMBASE, Cochrane Library, & clinicaltrials.gov through July 2025 identified RCT ≥12 weeks comparing siRNAs (olpasiran, lepodisiran, zerlasiran), ASOs (pelacarsen), or small molecule inhibitors (muvalaplin) versus placebo or active comparators. siRNA-based Lp(a) therapies demonstrate superior efficacy compared with ASOs or conventional treatments, with olpasiran demonstrating the most favourable efficacy-safety profile. Lepodisiran offers unique dosing advantages with extended durability. While marked Lp(a) reductions (70-98%) are achieved with favorable safety, definitive cardiovascular outcome benefits await Phase 3 trials."

Retrospective data • Review • Cardiovascular • APOB • CRP

Therapeutic innovations in secondary prevention of cardiovascular risk (PubMed, Rev Prat) - "New lipid-lowering therapies (injectable and oral PCSK9 inhibitors, inclisiran, bempedoic acid) allow more intensive LDL-C reduction, including in statin-intolerant patients.Lipoprotein(a) is emerging as a specific target, with ASO/siRNA agents (pelacarsen, olpasiran, lepodisiran) achieving marked reductions while outcome data are pending.Antithrombotic strategies are now tailored to ischemic and bleeding risks, using shortened dual antiplatelet therapy (DAPT), P2Y12 monotherapy and de-escalation approaches. On the inflammatory side, low-dose colchicine offers a simple, low-cost option for selected coronary patients, though recent results are mixed.Remote monitoring, hybrid cardiac rehabilitation and personalized care pathways help to further reduce residual cardiovascular risk."

Journal • Review • Cardiovascular

RNA interference for lipid disorders: is this the future? (PubMed, Curr Opin Lipidol) - "RNAi is a naturally occurring gene-silencing mechanism that can be harnessed therapeutically through siRNA molecules. In lipidology, siRNA-based therapies represent a disruptive technology with the potential to transform both prevention and treatment of atherosclerotic cardiovascular disease. If ongoing trials confirm cardiovascular benefit and safety, RNAi agents could become foundational in personalized lipid management, moving the field toward long-acting, target-specific, and potentially combination-based regimens. The coming years will determine whether RNAi fulfills its promise as the future standard of care in lipid disorders."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders

Lepodisiran: An Updated Review on a Novel and Emerging Lipoprotein (a) Lowering Agent. (PubMed, Cardiol Rev) - "A phase 3 RCT, ACCLAIM-Lp(a), is currently ongoing with the main purpose of assessing the effect on major cardiovascular events in patients with established ASCVD or at high cardiovascular risk. Herein, we present an updated review on this lipoprotein (a) lowering agent, including the results of the published clinical trials and the design of the ongoing phase 3 clinical trial."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

From physiopathology to treatment of familial hypercholesterolemia: Existing and emerging pharmacotherapies. (PubMed, Pharmacol Rev) - "This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin...Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders • APOB