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

Lipoprotein(a) After HORIZON: Causal Culprit, Risk Marker, or Unfulfilled Therapeutic Promise? (PubMed, J Cardiovasc Pharmacol Ther) - No abstract available

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders

Targeting Lipoprotein(a): A New Era in Cardiovascular Disease Prevention. (PubMed, Methodist Debakey Cardiovasc J) - "Novel unapproved therapies, including an antisense oligonucleotide (pelacarsen), small interfering RNAs (olpasiran, lepodisiran), and an oral small molecule (muvalaplin), have demonstrated Lp(a) reductions of up to 99% and are being tested in ongoing phase 3 cardiovascular outcomes trials to determine whether pharmacologic Lp(a) lowering translates into reduced cardiovascular events. We discuss current knowledge on genetics, biology, epidemiology, and measurement of Lp(a), examine its causal association with cardiovascular disease, and discuss emerging therapeutic strategies that may usher in a new era of cardiovascular disease prevention."

Biomarker • Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia

Elevated lipoprotein(a) and cardiovascular prognosis in established coronary artery disease: a systematic review and meta-analysis of 129 studies (ESC 2026) - "With novel Lp(a)-lowering therapies (pelacarsen, olpasiran, lepodisiran) now in Phase 3 cardiovascular outcomes trials, robust observational data are urgently needed to contextualise expected therapeutic benefits. In the largest meta-analysis of Lp(a) and cardiovascular prognosis in secondary prevention, elevated Lp(a) was associated with 53% increased MACE, 26% increased all-cause mortality, and 56% increased cardiovascular mortality. Unlike prior meta-analyses, we demonstrate statistically significant mortality associations, confirming Lp(a) as a prognostic marker for both recurrent events and death. The interaction with inflammatory status suggests Lp(a) may be particularly informative in patients with residual inflammatory risk."

Retrospective data • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Myocardial Infarction • CRP

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

Efficacy and Safety of Pelacarsen in Black/African American and Hispanic Patients with Elevated Lipoprotein(a) and Established Atherosclerotic Cardiovascular Disease: The Lp(a)FRONTIERS EXPANSION Study (AHA 2026) - "Abstract is embargoed at this time."

Clinical • Atherosclerosis • Cardiovascular

Novartis today announced that the pelacarsen phase III Lp(a)HORIZON trial…did not meet its primary endpoint of reducing the risk of cardiovascular events, a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization, compared to placebo (GlobeNewswire) - "Lower lipoprotein (a), Lp(a), levels were achieved with pelacarsen in this study population, which was receiving guideline-directed treatments, including lipid lowering and antihypertensive therapies. The findings provide important new evidence on the relationship between Lp(a) lowering and cardiovascular outcomes. Elevated Lp(a) is an inherited cardiovascular risk factor affecting approximately one in five people worldwide with no approved targeted treatment....The Lp(a)HORIZON trial data will be presented at an upcoming medical congress."

P3 data: top line • 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 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular

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

Lipoprotein apheresis: From familial hypercholesterolemia and elevated lipoprotein(a) to emerging roles in peripheral arterial and renal disease. (PubMed, Transfus Apher Sci) - "The introduction of PCSK9 inhibitors and inclisiran has progressively reduced apheresis utilization for LDL-centric management, while potent RNA-based Lp(a)-lowering agents (pelacarsen, olpasiran, lepodisiran) in late-stage development may further reshape the field. Beyond traditional cardiovascular indications, accumulating observational evidence supports LA in peripheral arterial disease through pleiotropic rheologic and anti-inflammatory mechanisms, and in steroid-resistant focal segmental glomerulosclerosis through oxidized LDL clearance and podocyte rescue. This review synthesizes current evidence across cardiovascular, peripheral vascular, and renal indications, compares apheresis modalities, examines integration with emerging pharmacotherapies, and proposes a three-part trajectory for LA: progressive contraction in LDL-centric use, a persisting role in Lp(a)-driven disease until RNA-based agents demonstrate outcome benefit, and a mechanistically grounded but..."

Journal • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Focal Segmental Glomerulosclerosis • Genetic Disorders • Glomerulonephritis • Heterozygous Familial Hypercholesterolemia • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Nephrology • Peripheral Arterial Disease • Renal Disease • APOB

Enhancing representation in cardiovascular trials: Lessons from Lp(a)FRONTIERS EXPANSION in United States Black and Hispanic patients with elevated lipoprotein(a) and established atherosclerotic cardiovascular disease. (PubMed, Am J Prev Cardiol) - P3 | "The Lp(a)FRONTIERS EXPANSION trial suggests that deliberate, culturally tailored design and operational strategies may improve cardiovascular trial participation by US minority populations. Results from Lp(a)FRONTIERS EXPANSION will provide critical insights into the efficacy and safety profile of pelacarsen in treating elevated Lp(a)."

Clinical • Journal • Atherosclerosis • Cardiovascular

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

Lp(a) Lowering Study of Pelacarsen (TQJ230) in Patients in the US With Elevated Lp(a) and Recent ACS (STEMI/NSTEMI) - Lp(a)FRONTIERS PEARL (clinicaltrials.gov) - P3 | N=240 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P3 trial • Acute Coronary Syndrome • Cardiovascular

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

Tushla said Ionis…highlighted anticipated data for pelacarsen in the second half of the year (TradingView)

Clinical data • Cardiovascular

An Open Label Extension (OLE) Study (Following Completion of CTQJ230A12301) to Evaluate Long-term Safety and Tolerability of Pelacarsen (TQJ230) (clinicaltrials.gov) - P3 | N=5700 | Recruiting | Sponsor: Novartis Pharmaceuticals

Trial initiation date • Cardiovascular

Early Health Technology Assessment (HTA) of Olpasiran and Pelacarsen for Secondary Prevention of Coronary Heart Disease (CHD). (PubMed, Clinicoecon Outcomes Res) - P3 | "Pelacarsen was highly cost-effective at the annual price of 6105.99 BGN. The threshold applied is that of gross domestic product (GDP) per capita as indicated by the National Council on prices and reimbursement of medicinal products in Bulgaria."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heart Failure • Metabolic Disorders • Myocardial Infarction • Peripheral Arterial Disease

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=422 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Atherosclerosis • Cardiovascular

An Open Label Extension (OLE) Study (Following Completion of CTQJ230A12301) to Evaluate Long-term Safety and Tolerability of Pelacarsen (TQJ230) (clinicaltrials.gov) - P3 | N=5700 | Recruiting | Sponsor: Novartis Pharmaceuticals

New P3 trial • 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

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