pelacarsen (AKCEA-APO(a)-LRx) / Ionis, Novartis, Royalty - 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

RNA-Based Therapies for Hypercholesterolemia and Coronary Artery Disease. (PubMed, Cureus) - "Pelacarsen and other emerging antisense therapies show promise for reducing lipoprotein(a), an independent cardiovascular risk factor, while siRNAs targeting ANGPTL3 offer prolonged lipid-lowering effects beyond those achieved with monoclonal antibodies...Hepatic safety concerns have halted the development of some agents, such as vupanorsen, and long-term cardiovascular outcome data for several therapies, including inclisiran, are still in development. Cost and accessibility also limit broad adoption, emphasizing the need for cost-effective strategies and long-term surveillance. Nevertheless, current evidence supports the integration of RNA-based therapies into modern lipid-lowering algorithms, particularly for high-risk patients, while ongoing research continues to refine delivery systems, enhance safety, and expand therapeutic indications."

Journal • Review • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Metabolic Disorders • ANGPTL3 • 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

ADD-VANTAGE: Lp(a) Lowering Study of Pelacarsen (TQJ230) With Background Inclisiran in Participants With Elevated Lp(a) and Established ASCVD (clinicaltrials.gov) - P3 | N=340 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2027 ➔ Feb 2028 | Trial primary completion date: Nov 2027 ➔ Feb 2028

Trial completion date • Trial primary completion date • Atherosclerosis • Cardiovascular

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

Lp(a)HORIZON: Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD (clinicaltrials.gov) - P3 | N=8323 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Feb 2026 ➔ Jun 2026 | Trial primary completion date: Feb 2026 ➔ Jun 2026

Trial completion date • Trial primary completion date • Cardiovascular

Pelacarsen Roll-over Extension Program (clinicaltrials.gov) - P3 | N=599 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jan 2028 ➔ Dec 2030 | Trial primary completion date: Dec 2027 ➔ Dec 2030

Trial completion date • Trial primary completion date • Atherosclerosis • Cardiovascular

CTQJ230A12304: Lp(a) lowering study of pelacarsen (TQJ230) with background inclisiran in participants with elevated Lp(a) and established ASCVD (clinicaltrialsregister.eu) - P2/3 | N=188 | Recruiting | Sponsor: Novartis Pharma AG | Not yet recruiting ➔ Recruiting

Enrollment open • Atherosclerosis • Cardiovascular

Pelacarsen and lipoprotein(a) apheresis in secondary prevention: the Lp(a)FRONTIERS APHERESIS trial. (PubMed, Eur Heart J) - P3 | "Pelacarsen is a highly effective and well-tolerated Lp(a)-targeted therapy that substantially reduces the need for LA in patients with elevated Lp(a) and established CVD."

Journal • Cardiovascular • Dermatology

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

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

Lipoprotein(a) knowledge, awareness, and clinical practice among physicians in the Arabian Gulf region. (PubMed, J Clin Lipidol) - "Physicians in the Arabian Gulf region report limited basic and clinical knowledge of Lp(a), which could result in underestimation of cardiovascular risk. These findings, in the largest such study to date, are a call to action to increase awareness about Lp(a) and accessibility to testing."

Journal • 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

Overcoming Barriers For Research Participation In Minority Patients In Lp(a)FRONTIERS EXPANSION: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Evaluate Efficacy And Safety Of Pelacarsen In U.S. Black And Hispanic Patients with Elevated Lp(a) And Established ASCVD (AHA 2025) - "The Lp(a)FRONTIERS EXPANSION trial successfully demonstrated that deliberate, culturally tailored strategies can improve participation of minority populations, underrepresented in cardiovascular clinical trials. These results highlight the importance of inclusive trial design and operational efforts to achieve equitable representation in clinical research, ensuring generalizability of trial results."

Clinical • Atherosclerosis • Cardiovascular

Precision Management of Dyslipidemia in Atherosclerosis: Mechanisms, Therapeutic Strategies, and Future Directions. (PubMed, J Vis Exp) - "Emerging targeted therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, small interfering RNA (siRNA)-based treatments, and Lp(a)-lowering agents like pelacarsen, represent promising strategies for more precise lipid modulation...The integration of the 2023 Chinese Guidelines for Lipid Management, imaging, and AI-assisted decision-making will promote data-driven, precision medicine. Personalized drug selection, efficacy monitoring, and long-term follow-up will optimize clinical outcomes and enhance prevention strategies for high-risk patients."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • Metabolic Disorders

Lipoprotein(a) Lowering with Pelacarsen (TQJ230). (PubMed, Cardiovasc Hematol Disord Drug Targets) - "Pelacarsen (TQJ230) is a potent Lp(a)-lowering agent with promising efficacy and a favorable safety profile. However, its definitive role in reducing atherosclerotic cardiovascular events remains to be established. Ongoing Phase 3 trials will be critical in determining whether its lipid-lowering effects translate into meaningful long-term cardiovascular outcomes."

Journal • Atherosclerosis • Cardiovascular

Pharmacokinetics and Safety of Pelacarsen, a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Apo(a), in Participants With Mild Hepatic Impairment. (PubMed, Clin Transl Sci) - P1 | "Overall, pelacarsen was well tolerated, and mild HI had no significant effect on Cmax. The increase in AUC, likely due to slower early-phase disposition, was within the exposure range tested in the first-in-human study and considered safe."

Journal • PK/PD data • Hepatology