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

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

A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a) - ACCLAIM-Lp(a) (clinicaltrials.gov) - P3 | N=17300 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Adverse events • Enrollment closed • Atherosclerosis • Cardiovascular

Dyslipidemia Management in Stroke Prevention: An individualized approach. (PubMed, Int J Stroke) - "For statin intolerance or suboptimal response, ezetimibe and PCSK9 inhibitors provide potent, bleeding-neutral LDL-C lowering. Inclisiran and bempedoic acid broaden therapeutic options, although stroke-specific efficacy data are still pending. Lp(a)-lowering agents, including pelacarsen, olpasiran and lepodisiran, are under active evaluation and may address residual cardiovascular risk. For triglyceride lowering, recent randomized evidence supports icosapent ethyl for reducing IS risk...This review synthesizes current evidence and proposes a phenotype-guided, individualized framework for dyslipidemia management across stroke subtypes. Moving beyond uniform targets toward etiologic and genetically informed lipid modulation may improve post-stroke outcomes and refine individualized stroke prevention."

Journal • Review • Cardiovascular • Cerebral Hemorrhage • Dyslipidemia • Hematological Disorders • Ischemic stroke • Metabolic Disorders • APOB

Emerging therapies targeting lipoprotein(a): the next frontier in cardiovascular risk reduction. (PubMed, Front Med (Lausanne)) - "Antisense oligonucleotides (e.g., pelacarsen), small-interfering RNAs (e.g., olpasiran, lepodisiran, and zerlasiran), and oral small-molecule Lp(a) inhibitors (e.g., muvalaplin) have demonstrated profound reductions in circulating Lp(a) concentrations, typically achieving decreases of 80-90%. As these agents progress toward clinical use, routine Lp(a) measurement and risk stratification will become increasingly essential for personalized cardiovascular prevention. This review summarizes the molecular biology of Lp(a), highlights the limitations of current therapies, and discusses emerging RNA-based and small-molecule approaches with the potential to redefine the management of residual cardiovascular risk."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • APOB

Lepodisiran: An Investigational Long-Duration Small Interfering Ribonucleic Acid for Reduction of Lipoprotein(a) (ASHP 2025) - No abstract available

Clinical Response to Elevated Lipoprotein(a): Practical Approach for Risk Management in the Absence of Targeted Therapies. (PubMed, Semin Thromb Hemost) - "Statins, ezetimibe, bempedoic acid and lifestyle interventions have little or no effect on Lp(a). Statins may modestly raise levels, niacin is now contraindicated as it has not been shown to reduce cardiovascular or all-cause mortality, while PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors and inclisiran reduce Lp(a) concentrations by ~20-30%, though this effect remains secondary to their LDL-C lowering effect...Future promise lies in RNA-based therapies, including antisense oligonucleotides (pelacarsen) and small-interfering RNAs (olpasiran, lepodisiran, SLN360), which achieve 80-95% sustained Lp(a) reductions...High or extreme elevations, especially with ASCVD, mandate aggressive LDL-C lowering, optimization of modifiable risk factors, family cascade screening, and apheresis or referral to RNA-therapy trials in select cases. Thus, while therapeutic options remain limited, systematic measurement and risk stratification are ethically justified to prepare..."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

The Emerging Lipid Risk: Lipoprotein(a). (PubMed, Korean Circ J) - "Trials on new therapeutics targeting Lp(a) RNA, including antisense oligonucleotide (e.g., pelacarsen), siRNAs (e.g., olpasiran, lepodisiran, and zerlasiran), and small molecules (e.g., muvalaplin), are under way. Depending on the study or dose, these agents lowered Lp(a) levels by 80-100% compared with the control; however, results of clinical outcomes have yet to be reported."

Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Preventive care

Lipoprotein(a) - treatments in development. (PubMed, Expert Opin Pharmacother) - "The N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO) pelacarsen and the small-interfering RNA (siRNA) agents olpasiran, lepodisiran and zerlasiran have all been shown to be safe and effective in lowering Lp(a) levels between 80% and almost 100%...Muvalaplin is a small molecule given orally once daily and reduces Lp(a) by up to 65%. It is also being assessed in a cardiovascular outcome study. It will be essential to identify what baseline level of Lp(a) is needed and what degree of Lp(a) lowering is required to produce a cardiovascular benefit and whether aggressive lowering of Lp(a) has any adverse effects."

Journal • Review • Cardiovascular

Lipoprotein(a) in Cardiovascular Diseases and Emerging Therapeutic Strategies. (PubMed, Cardiovasc Drugs Ther) - "As novel therapies advance and clinical guidelines evolve, Lp(a) is emerging as a central determinant in personalized cardiovascular care. The increasing emphasis on Lp(a) testing underscores its importance in risk stratification and future therapeutic decisionmaking."

Journal • Review • Atherosclerosis • Cardiovascular • Peripheral Arterial Disease

LPA-Targeted siRNAs Lower Lp(a) by Over 90%: A Meta-Analysis of Olpasiran, Lepodisiran, and Zerlasiran (AHA 2025) - "siRNA therapeutics targeting LPA mRNA demonstrate substantial efficacy, lowering Lp(a) levels by over 90% with concurrent reductions in ApoB and LDL-C. Ongoing phase 3 trials will be pivotal in further characterizing their safety profile and determining the extent to which these promising lipid changes translate into cardiovascular risk reduction."

Retrospective data • Atherosclerosis • Cardiovascular • Dyslipidemia • APOB

Olpasiran Outperforms Other Subcutaneous Lipoprotein(a)-Lowering Agents in Efficacy and Safety: A Network Meta-Analysis of Randomized Controlled Trials (AHA 2025) - "Compared to placebo, olpasiran showed the largest reduction in Lp(a) (MD: –87.72%; 95% CI: –113.78 to –61.66), followed by zerlasiran (–66.68%), lepodisiran (–54.61%), and pelacarsen (–54.15%). Among Lp(a)-targeted therapies, olpasiran showed the largest Lp(a), LDL-C, ApoB, and ACM lowering effects, ranking better than other drugs. Olpasiran and lepodisiran ranked better for reducing safety outcomes than other drugs."

Retrospective data • APOB

The new generation of small interfering RNAs directed against apoprotein(a): focus on the safety and efficacy of zerlasiran and lepodisiran. (PubMed, Cardiovasc Res) - No abstract available

Journal • Cardiovascular

Lepodisiran: Effects on Lipoprotein(a) and Cardiovascular Outcomes in Adults with Elevated Lp(a). (PubMed, Cardiovasc Hematol Disord Drug Targets) - "Lepodisiran demonstrates potent and sustained reductions in Lp(a) levels with a favorable safety profile, making it a promising therapeutic candidate for Lp(a)-mediated cardiovascular risk. Ongoing long-term outcome studies are essential to confirm its clinical benefit."

Journal • Atherosclerosis • Cardiovascular • APOB

Lepodisiran: From genetic targeting to cardiovascular promise: A detailed narrative review of the literature. (PubMed, World J Cardiol) - "Compared to other therapies, lepodisiran offers longer duration, high efficacy, and minimal side effects. Ongoing phase 3 studies aim to determine its impact on cardiovascular outcomes, potentially establishing a new standard in precise ASCVD risk management."

Journal • Review • Atherosclerosis • Cardiovascular

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

Lipoprotein (a): A new target for pharmacological research and an option for treatment. (PubMed, Eur J Intern Med) - "Novel RNA-based therapies, including antisense oligonucleotides (pelacarsen) and small interfering RNAs (olpasiran, lepodisiran, zerlasiran)-have shown the potential to reduce Lp(a) levels by >80 %. The small oral molecule muvalaplin also shows promise in inhibiting Lp(a) formation...As new therapeutic options are developed that specifically target Lp(a), the inclusion of Lp(a) in cardiovascular risk assessment could improve stratification and lead to targeted interventions, particularly in high-risk populations. The growing body of genetic, epidemiological and clinical evidence makes Lp(a) a critical target in cardiovascular research and therapy."

Journal • Review • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Dyslipidemia • Familial Hypercholesterolemia • Heart Failure • Peripheral Arterial Disease

Emerging pharmacological strategies in lipoprotein(a) reduction. (PubMed, Proc (Bayl Univ Med Cent)) - P3 | "The three large, multicenter phase 3 outcome trials evaluating clinical cardiovascular disease endpoints of major adverse cardiac event (MACE) are Lp(a)HORIZON (NCT04023552), OCEAN(a) (NCT05581303), and ACCLAIM-Lpa(a) (NCT06292013), which investigate pelacarsen, olpasiran, and lepodisiran, respectively. Other phase 2 and phase 3 trials are also under way. Results from upcoming trials will inform us whether Lp(a) reductions translate to improved cardiovascular clinical outcomes."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

Advances in RNA-Based Therapies Targeted at Lipoprotein(a): Olpasiran in the Management of Atherosclerotic Cardiovascular Disease. (PubMed, Cardiol Rev) - "Olpasiran also has the potential to be a cost-effective treatment due to the infrequent dosing needed to achieve a high degree of Lp(a) reduction. Other similar nucleic acid therapeutic agents, such as pelacarsen, zerlasiran, and lepodisiran, have also shown efficacy in reducing Lp(a) levels in early trials, creating an exciting avenue for cardiovascular prevention in the coming decade."

Journal • Atherosclerosis • Cardiovascular