olpasiran (AMG 890) / Amgen, Arrowhead, Royalty - LARVOL DELTA

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

Muvalaplin: A Novel Oral Therapy for Targeted Reduction of Plasma Lipoprotein(a). (PubMed, Cardiovasc Hematol Disord Drug Targets) - "Notably, unlike other Lp(a)-lowering agents, muvalaplin did not cause skinrelated adverse events at injection sites. Although the initial clinical data are promising, Phase III trials are required to establish long-term safety and determine whether reductions in plasma Lp(a) translate into meaningful reductions in cardiovascular events."

Journal • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure • Hematological Disorders • Inflammation • Thrombosis

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

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

OCEAN(a)-CCTA: Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction - Coronary Computed Tomography Angiography Trial (clinicaltrials.gov) - P3 | N=406 | Not yet recruiting | Sponsor: Amgen

New P3 trial • Atherosclerosis • Cardiovascular

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

Small-Interfering RNA Olpasiran and Apolipoprotein B Particles. (PubMed, JAMA Cardiol) - No abstract available

Journal • APOB

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

Efficacy of Olpasiran by Apolipoprotein(a) Isoform Size: Insights from the OCEAN(a)-DOSE Trial (AHA 2025) - "In patients with ASCVD and elevated Lp(a), olpasiran reduces Lp(a) irrespective of apo(a) isoform size and appears to affect both isoforms equally."

Clinical • Atherosclerosis • Cardiovascular

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

Changes in Lipoprotein(a) and Oxidized Phospholipids Are Associated with Myocardial Inflammation but Not Systemic Inflammatory Markers Following an Acute Myocardial Infarction (AHA 2025) - "In the OCEAN(a) DOSE trial olpasiran reduced Lp(a) and OxPL-apoB but not hs-CRP or IL-6, markers of systemic inflammation...We examined the associations between the changes of Lp(a), OxPL-apoB, hs-CRP, and IL-6, and the changes of local myocardial inflammation from hospitalization to 30 days in patients with an acute myocardial infarction (MI).Research Objective: To determine the association of changes in Lp(a), OxPL-apoB, hsCRP, and IL-6 with the changes in local myocardial inflammation following an MI. Fifty-five patients from the EVACS I and II trials with an acute MI were randomized to evolocumab, a PCSK9 inhibitor known to reduce Lp(a) levels or placebo and underwent 18F-FDG PET imaging during hospitalization and at 30 days... Changes in myocardial inflammation after an acute MI were associated with changes in Lp(a) and OxPL-apoB but not with indices of systemic inflammation. These findings support a pathophysiologic role for Lp(a)-associated OxPLs in myocardial..."

Cardiovascular • Inflammation • Myocardial Infarction • APOB • CRP • IL6

AMGEN'S LANDMARK PHASE 3 REPATHA DATA TO BE PRESENTED AS LATE BREAKER AT THE AMERICAN HEART ASSOCIATION SCIENTIFIC SESSIONS 2025 (Amgen Press Release)

Clinical data • Atherosclerosis • Cardiovascular • Obesity

OCEAN(a)-PreEvent - Olpasiran Trials of Cardiovascular Events And LipoproteiN(a) Reduction to Prevent First Major Cardiovascular Events (clinicaltrials.gov) - P3 | N=11000 | Recruiting | Sponsor: Amgen | Trial completion date: Mar 2031 ➔ Oct 2031 | Trial primary completion date: Mar 2031 ➔ Oct 2031

Trial completion date • Trial primary completion date • Cardiovascular

OCEAN(a)-PreEvent - Olpasiran Trials of Cardiovascular Events And LipoproteiN(a) Reduction to Prevent First Major Cardiovascular Events (clinicaltrials.gov) - P3 | N=11000 | Recruiting | Sponsor: Amgen | Trial completion date: Oct 2031 ➔ Mar 2031 | Trial primary completion date: Oct 2031 ➔ Mar 2031

Trial completion date • Trial primary completion date • 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

OCEAN(a)-PreEvent - Olpasiran Trials of Cardiovascular Events And LipoproteiN(a) Reduction to Prevent First Major Cardiovascular Events (clinicaltrials.gov) - P3 | N=11000 | Recruiting | Sponsor: Amgen

New P3 trial • Cardiovascular

Olpasiran Expanded Access Program (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Amgen

New trial

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

An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Olpasiran in Chinese Participants With Elevated Serum Lipoprotein(a). (PubMed, Clin Ther) - "Olpasiran administration (75 and 225 mg) was safe and well-tolerated in Chinese participants, and olpasiran PK and Lp(a) responses are generally consistent with those observed in East Asian/non-East Asian participants. Dose adjustments of olpasiran based on ethnicity are therefore not warranted, and work investigating the effects of olpasiran treatment on long-term cardiovascular risk in East Asian populations should continue."

Journal • PK/PD data • Cardiovascular