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

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

Lepodisiran - A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). Reply. (PubMed, N Engl J Med) - No abstract available

Journal

Lepodisiran - A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). (PubMed, N Engl J Med) - No abstract available

Journal

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2025 American College of Cardiology Conference. (PubMed, Curr Atheroscler Rep) - No abstract available

Journal • Review • Cardiovascular

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=16700 | Recruiting | Sponsor: Eli Lilly and Company | N=12500 ➔ 16700

Adverse events • Enrollment change • Atherosclerosis • Cardiovascular

Lp(a)-Lowering Agents in Development: A New Era in Tackling the Burden of Cardiovascular Risk? (PubMed, Pharmaceuticals (Basel)) - "Such drugs include pelacarsen (an injectable ASO) and olpasiran, zerlasiran, and lepodisiran (injectable siRNA agents). Muvalaplin represents another therapeutic option to lower Lp(a) levels, since it is an oral selective small molecule inhibitor of Lp(a) formation, thus potentially exerting certain advantages in terms of its clinical use...The phase 3 CV trial outcomes are ongoing for some of these agents (i.e., pelacarsen, olpasiran, and lepodisiran) and are briefly mentioned. Overall, there is an urgent need for evidence-based guidelines on Lp(a) reduction in daily clinical practice, following the results of the phase 3 CV trials, as well as for establishing the ideal Lp(a) quantification method (i.e., using an apo(a) isoform-independent assay with appropriate calibrators, reporting the Lp(a) level in molar units)."

Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Heart Failure

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

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 | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology • Liver Failure

Development of A Population Pharmacokinetic/Pharmacodynamic Model of Lepodisiran, A Small Interfering RNA Targeting Lipoprotein (A), in Healthy Adults (DDG 2025) - P2 | "A Pop-PK/PD Model Was Developed Using Phase 1 Data from Healthy Adults With Elevated LP (a) which Robustly Explained the Time Course of Lepodisiran Plasma Concentrations and LP (a) Levels. The Inclusion of the Liver Com Party Based on the Mechanistic Understanding of Galnac-Sirnas Enabled Characterization of the Temporal Difference Between Short-Lived Plasma Exposure and Prolonged Effect On LP (a) Lowering. Lepodisiran Demonstrated Durable and Significant LP (A) KD at Doses Greater Than 96 Mg."

Clinical • PK/PD data • Diabetes

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

New P1 trial • Hepatology • Liver Failure

An Extended Duration Small-interfering RNA Targeting Lipoprotein(a): The Alpaca Phase 2 Trial Of Lepodisiran With 540 Day Follow Up - Steven E. Nissen (ACC 2025) - No abstract available

Late-breaking abstract • P2 data

Lepodisiran - A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). (PubMed, N Engl J Med) - P2 | "Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration. (Funded by Eli Lilly; ALPACA ClinicalTrials.gov number, NCT05565742.)."

Journal • Atherosclerosis • Cardiovascular

Lilly's lepodisiran reduced levels of genetically inherited heart disease risk factor, lipoprotein(a), by nearly 94% from baseline at the highest tested dose in adults with elevated levels (PRNewswire) - P2 | N=320 | ALPACA (NCT05565742) | Sponsor: Eli Lilly and Company | "Eli Lilly and Company...announced positive Phase 2 results for lepodisiran...In the Phase 2 ALPACA study, lepodisiran significantly reduced Lp(a) levels by an average of 93.9% over the 60 to 180-day period after treatment with the highest tested dose (400 mg), meeting the primary endpoint....Results from additional secondary endpoints showed: Participants who received 400 mg of lepodisiran at both baseline and day 180 experienced a 94.8% reduction in average Lp(a) levels over the day 30 to 360 period, which remained 91.0% below baseline at day 360 (~1 year) and 74.2% below baseline at day 540 (~1.5 years); Lepodisiran also reduced apolipoprotein B (apoB) levels, a separate cholesterol biomarker. The highest dose (400 mg) of lepodisiran showed 14.1% and 13.7% ApoB reductions from baseline at day 60 and 180, respectively. A second 400 mg lepodisiran dose at day 180 sustained these apoB reductions through day 540."

P2 data • Metabolic Disorders