zerlasiran (SLN360) / Silence Therap - LARVOL DELTA

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

Lipoprotein(a) in Japan: An Expert Consensus Statement. (PubMed, J Atheroscler Thromb) - "Emerging Lp(a)-specific therapies, including pelacarsen, olpasiran, muvalaplin, and SLN360, demonstrate up to 80-95% reductions in Lp(a) and may redefine care once outcome trial data (e.g., HORIZON) become available.Finally, we outline the implementation priorities for Japan, emphasizing improved measurement access, laboratory harmonization, public and professional education, and the integration of Lp(a) into existing clinical pathways and research infrastructures. This consensus statement is intended to support clinicians, researchers, and policymakers in reducing the residual ASCVD risk attributable to Lp(a) in Japan."

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

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

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

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

Zerlasiran for Lipoprotein(a) Reduction: Mechanisms, Evidence, and Future Directions. (PubMed, Cardiovasc Hematol Disord Drug Targets) - "Zerlasiran represents a novel and highly targeted approach to managing elevated Lp(a), with the potential to shift future ASCVD prevention strategies. Pending Phase 3 trial results will be critical in establishing its role in clinical practice."

Journal • Atherosclerosis • Cardiovascular • APOB

A Phase 1 Study Evaluating the Pharmacokinetics, Pharmacodynamics, and Safety of Zerlasiran in Japanese Participants. (PubMed, J Atheroscler Thromb) - "Zerlasiran was well tolerated with no significant safety findings observed at any dose level. A typical pharmacokinetic profile expected of an N-acetylgalactosamine-conjugated small interfering RNA, coupled with a potent and sustained reduction in lipoprotein(a), was observed in Japanese participants. No adverse effects on either the liver or kidney function were observed."

Journal • P1 data • PK/PD data • Atherosclerosis • Cardiovascular

Comparative Efficacy and Safety of Novel Lp(a)-Lowering Therapies for ASCVD Prevention: A Network Meta-Analysis. (PubMed, Pharmacol Res) - "SiRNA therapies achieved the greatest Lp(a) reductions (olpasiran: mean difference [MD] -92.1%, 95% CI -100.1 to -84.0%; zerlasiran: -80.6%, 95% CI -87.7 to -73.5%), followed by muvalaplin (-76.8%, 95% CI -90.3 to -63.2%) and ASO therapy (pelacarsen: -54.2%, 95% CI -72.2 to -36.2%; all P < 0.001). All therapies were well tolerated, with injection-site reactions most frequent for injectables, while muvalaplin was well tolerated. These findings indicate that targeted Lp(a)-lowering therapies substantially reduce circulating Lp(a), with siRNA showing the greatest potency and muvalaplin offering a convenient oral alternative for personalized ASCVD risk reduction."

Journal • Retrospective data • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • APOB

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

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

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

Chest Pain and Hidden Genetic Risk: A Case Report on the Role of Elevated Lipoprotein(a) in Early Cardiovascular Disease. (PubMed, Cureus) - "While lifestyle interventions play a critical role in cardiovascular health, targeted therapies such as PCSK9 inhibitors and emerging nucleic acid-based treatments, including Zerlasiran, offer promising options for significantly lowering Lp(a) levels. Recognizing and addressing elevated Lp(a) is vital for identifying patients at high cardiovascular risk and for informing tailored management strategies aimed at improving patient outcomes."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Pain

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

Structure-guided dissection of the genetic variations within human LPA locus and its role in the development of cardiovascular diseases. (PubMed, Prog Lipid Res) - "While conventional lipid-lowering therapies exert little influence on Lp(a), antisense oligonucleotides (pelacarsen) and small interfering RNA agents (olpasiran, SLN360) achieve robust Lp(a) reductions. Integrating genetic insights with structural modeling provides a framework to disentangle functional from proxy associations within LPA and neutralize the cardiovascular hazard conferred by elevated levels of Lp(a)."

Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease

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

Assessing the clinical development of zerlasiran, a small-interfering rna for elevated lipoprotein(a). (PubMed, Expert Opin Investig Drugs) - "However, long-term studies are needed to assess its impact on major adverse cardiovascular events and safety in diverse patient populations, and across different clinical settings. The phase III cardiovascular outcome study is eagerly anticipated."

Journal • Review • Atherosclerosis • Cardiovascular • Developmental Disorders • APOB

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

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