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

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

Pelacarsen reduces the need for lipoprotein apheresis in patients with elevated lipoprotein(a) and cardiovascular disease: The Phase 3 Lp(a)FRONTIERS APHERESIS trial (ESC-WCC 2025) - No abstract available

Clinical • P3 data • Cardiovascular

Lp(a) Lowering Study of Pelacarsen (TQJ230) in US Black/African American and Hispanic Participants With Elevated Lp(a) and Established ASCVD (clinicaltrials.gov) - P3 | N=400 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2027 ➔ Mar 2026 | Trial primary completion date: Mar 2027 ➔ Mar 2026

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

Pelacarsen Roll-over Extension Program (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Atherosclerosis • Cardiovascular

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

Lp(a) Lowering Study of Pelacarsen (TQJ230) in US Black/African American and Hispanic Participants With Elevated Lp(a) and Established ASCVD (clinicaltrials.gov) - P3 | N=423 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Atherosclerosis • Cardiovascular

Pelacarsen: Mechanism of action and Lp(a)-lowering effect. (PubMed, J Clin Lipidol) - "The ongoing phase 3 Lp(a)HORIZON study is evaluating whether the Lp(a)-lowering effects of pelacarsen translate into reductions in the incidence of major cardiovascular events, also in patients with established ASCVD. Herein, we review the mechanism of action of pelacarsen and evidence for its Lp(a)-lowering effects."

Journal • Review • Atherosclerosis • Cardiovascular • APOB

Lp(a) in daily clinical routine: risk-factor for both cardiovascular events and heart-failure? A retrospective analysis of the Luebeck Lp(a) heart-failure (HF) registry in patients after myocardial infarction. (PubMed, Atheroscler Plus) - "Despite ESC recommendation, routine Lp(a) measurement is only rarely performed even in a high-risk patient collective. In patients with MI, we could retrospectively not observe a correlation between Lp(a) levels and heart failure, as assessed by surrogate markers as EF and NTproBNP."

Journal • Retrospective data • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hypertension • Metabolic Disorders • Myocardial Infarction • Obesity

Cardiovascular risk management beyond statins: review of new therapies available in Italy. (PubMed, Egypt Heart J) - "This review underscores the evolving landscape of lipid-lowering therapies, with emphasis on agents acting through novel mechanisms beyond statin pathways. Bempedoic acid, by inhibiting ACLY and increasing LDL receptor expression, represents a safe and effective option for reducing LDL-C, especially in statin-intolerant individuals. PCSK9 inhibitors further expand therapeutic options by augmenting LDL receptor recycling and clearance. The integration of these agents into clinical practice may help mitigate residual cardiovascular risk and personalize treatment strategies in dyslipidemia management."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOA1