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

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

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

Therapeutic advances in the Lp(a) battle: what do we know and what are the most awaited novelties in the field ? (PubMed, Curr Opin Lipidol) - "The RNA-based agents pelacarsen, olpasiran, and lepodisiran represent the most advanced developments in this field. Ongoing Phase 3 trials, expected to be finalized between 2025 and 2029, will be crucial in determining their efficacy in improving cardiovascular outcomes and their safety profiles."

Journal • Cardiovascular • Myocardial Infarction

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

A Study of LY3819469 in Participants With Elevated Lipoprotein(a) [Lp(a)] (clinicaltrials.gov) - P2 | N=320 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed | N=216 ➔ 320

Enrollment change • Trial completion

Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin. (PubMed, J Lipid Res) - "Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor, and there is considerable interest in developing Lp(a)-lowering therapeutics for cardiovascular prevention. In contrast, the Lp(a)-lowering effect of lepodisiran was clinically comparable between the intact Lp(a) assay and commercial assay. This novel intact Lp(a) assay provides a more accurate approach for the assessment of Lp(a)-lowering agents and study of Lp(a)-associated risk compared with currently available assays."

Journal • Cardiovascular

Lp(a): A Rapidly Evolving Therapeutic Landscape. (PubMed, Curr Atheroscler Rep) - "Pelacarsen and olpasiran are two novel RNA-based injectable therapies which are being studied in ongoing phase 3 clinical trials, with the earliest of these to be concluded in 2025...Other candidate drugs, such as Lepodisiran, Zerlasiran, and Muvalaplin, are also in early-stage development. While there are presently no Lp(a)-lowering drugs available for routine clinical use, several promising candidates are currently under investigation. If these prove to be effective in randomized clinical trials, they will expand the cardiovascular care armamentarium and will allow clinicians to treat a presently unmitigated cardiovascular risk factor."

Clinical • Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia

Expanding therapeutic options: overview of novel pharmacotherapies for dyslipidemia. (PubMed, Expert Opin Pharmacother) - "Optimizing the use of available first- and second-line lipid-lowering drugs allows us to adequately control low-density lipoprotein cholesterol (LDL-C) levels, even in statin-intolerant individuals and in patients at high and very high risk of developing cardiovascular diseases who must reach more aggressive LDL-C targets. The drugs under development will further improve our ability to manage the overall lipid-related cardiovascular disease risk and target other dyslipidemia biomarkers."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders

The Risk Of Arteriosclerosis And Its Complications Are Increased By LDL Cholesterol (LDL-C) Levels, Elevated Lp(a) And Inflammation: What Are The Best Medical Strategies To Decrease These Parameters: Statins, Adjunctive LDL-C Lowering Drugs Inclisiran, Bempedoic Acid, Ezetimibe, PCSK-9 Inhibitors, Lepodisiran, Colchicine, Olezarsen, Etc.) And Anti-Inflammatories: How They Should Be Administered (VEITH 2024) - No abstract available

Atherosclerosis • Cardiovascular • Inflammation

RNA interference therapy in cardiology: will new targets improve therapeutic goals? (PubMed, Drugs Context) - "Patisiran, the first FDA-approved siRNA medication, targets hereditary transthyretin amyloidosis with polyneuropathy. Givosiran, lumasiran and nedosiran further expand siRNA applications in treating rare genetic diseases, demonstrating positive outcomes. In cardiology, inclisiran, approved for hypercholesterolaemia, showcases sustained reductions in LDL cholesterol levels...Lipoprotein(a), an independent risk factor for atherosclerotic cardiovascular disease, has become a focus of siRNA therapies, precipitating the development of specific siRNA drugs like olpasiran, zerlasiran and lepodisiran, with promising reductions in lipoprotein(a) levels...Zodasiran and plozasiran address potential risk factors for cardiovascular diseases, targeting triglyceride-rich lipoproteins. Zilebesiran, which targets hepatic angiotensinogen mRNA, has demonstrated a dose-related reduction in serum angiotensinogen levels, thereby lowering blood pressure in patients with systemic arterial..."

Journal • Review • Amyloidosis • Atherosclerosis • Cardiac Amyloidosis • Cardiovascular • Dyslipidemia • Genetic Disorders • Hypertension • Pain • Pulmonary Arterial Hypertension

Lipoprotein (a) and lipid-lowering treatment from the perspective of a cardiac surgeon. An impact on the prognosis in patients with aortic valve replacement and after heart transplantation. (PubMed, Int J Cardiol Cardiovasc Risk Prev) - "There is still no targeted therapy for Lp(a), however, drugs such as pelacarsen, olpasiran, zerlasiran, lepodisiran and muvalaplin are in clinical trials and have been shown to be effective in significantly reducing Lp(a) levels. Therefore, the assessment of Lp(a) concentration in these patients will allow for a more accurate stratification of their cardiovascular risk, and the possibility of lowering Lp(a) will allow for the optimization of this risk. In this article, we summarized the most important information regarding the role of Lp(a) and lipid-lowering treatment in patients after AVR and HTx."

Journal • Cardiovascular • Transplantation

Therapeutic Potential of Lipoprotein(a) Inhibitors. (PubMed, Drugs) - "Early studies of antisense oligonucleotides (e.g., mipomersen, pelacarsen), RNA interference (e.g., olpasiran, zerlasiran, lepodisiran) and small molecule inhibitors (e.g., muvalaplin) have demonstrated effective Lp(a) lowering and good tolerability. These agents are moving forward in clinical development, in order to determine whether Lp(a) lowering reduces cardiovascular risk. The results of these studies have the potential to transform our approach to the prevention of cardiovascular disease."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

New insights into the therapeutic options to lower lipoprotein(a). (PubMed, Eur J Clin Invest) - "If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

Lepodisiran, an siRNA targeting lipoprotein(a) for the potential future treatment of cardiovascular disease. (PubMed, Expert Opin Investig Drugs) - No abstract available

Journal • Cardiovascular