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

Lp(a): A Rapidly Evolving Therapeutic Landscape. (PubMed, Curr Atheroscler Rep) - "Pelacarsen and olpasiran are two novel RNA-based injectable therapies which are being studied in ongoing phase 3 clinical trials, with the earliest of these to be concluded in 2025...Other candidate drugs, such as Lepodisiran, Zerlasiran, and Muvalaplin, are also in early-stage development. While there are presently no Lp(a)-lowering drugs available for routine clinical use, several promising candidates are currently under investigation. If these prove to be effective in randomized clinical trials, they will expand the cardiovascular care armamentarium and will allow clinicians to treat a presently unmitigated cardiovascular risk factor."

Clinical • Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia

Effect of mild hepatic impairment on the pharmacokinetics of pelacarsen (AHA 2024) - P1 | "Pelacarsen Cmax, AUClast, and AUCinf were, on average, 7%, 37%, and 50% higher, respectively, in participants with mild HI versus matched controls. All 90% confidence intervals around the HI versus healthy control geometric mean ratios included 1 (Table). The ranges of all PK parameters and estimated half-lives were similar between groups."

PK/PD data • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • ASGR

Early health technology assessment of gene silencing therapies for lowering lipoprotein(a) in the secondary prevention of coronary heart disease. (PubMed, J Clin Lipidol) - P3 | "This early health technology assessment model used inclusion criteria from clinical trials. Olpasiran and pelacarsen would be cost-effective if annual treatment prices were AU$1867 and AU$984 respectively, from the Australian healthcare perspective."

Journal • Cardiovascular • Coronary Artery Disease • Heart Failure

Expanding therapeutic options: overview of novel pharmacotherapies for dyslipidemia. (PubMed, Expert Opin Pharmacother) - "Optimizing the use of available first- and second-line lipid-lowering drugs allows us to adequately control low-density lipoprotein cholesterol (LDL-C) levels, even in statin-intolerant individuals and in patients at high and very high risk of developing cardiovascular diseases who must reach more aggressive LDL-C targets. The drugs under development will further improve our ability to manage the overall lipid-related cardiovascular disease risk and target other dyslipidemia biomarkers."

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

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 | Not yet recruiting ➔ Recruiting | Trial completion date: Jun 2027 ➔ Mar 2027 | Trial primary completion date: Jun 2027 ➔ Mar 2027

Enrollment open • Trial completion date • Trial primary completion date • Atherosclerosis • Cardiovascular • Dyslipidemia

Lipoprotein (a) and cerebrovascular disease. (PubMed, J Int Med Res) - "Lp(a) seems to play a significant role in the pathogenesis of arterial ischemic stroke in children because environmental thrombotic and atherogenic factors are generally not present.Phase 3 trials of novel Lp(a) targeting agents, such as pelacarsen and olpasiran, are anticipated to demonstrate their efficacy in reducing the incidence of stroke. Given the richness of the literature, new guidelines regarding Lp(a) screening and management in targeted populations are warranted to provide more effective primary and secondary prevention."

Journal • Review • Atherosclerosis • Cardiovascular • CNS Disorders • Dyslipidemia • Ischemic stroke • Pediatrics • Vascular Neurology

A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Rate of Weekly Lipoprotein Apheresis Sessions in Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease in Germany (clinicaltrials.gov) - P3 | N=51 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jun 2025 ➔ Jan 2025 | Trial primary completion date: Jun 2025 ➔ Jan 2025

Trial completion date • Trial primary completion date • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOB

Lipoprotein (a) and lipid-lowering treatment from the perspective of a cardiac surgeon. An impact on the prognosis in patients with aortic valve replacement and after heart transplantation. (PubMed, Int J Cardiol Cardiovasc Risk Prev) - "There is still no targeted therapy for Lp(a), however, drugs such as pelacarsen, olpasiran, zerlasiran, lepodisiran and muvalaplin are in clinical trials and have been shown to be effective in significantly reducing Lp(a) levels. Therefore, the assessment of Lp(a) concentration in these patients will allow for a more accurate stratification of their cardiovascular risk, and the possibility of lowering Lp(a) will allow for the optimization of this risk. In this article, we summarized the most important information regarding the role of Lp(a) and lipid-lowering treatment in patients after AVR and HTx."

Journal • Cardiovascular • Transplantation

Therapeutic Potential of Lipoprotein(a) Inhibitors. (PubMed, Drugs) - "Early studies of antisense oligonucleotides (e.g., mipomersen, pelacarsen), RNA interference (e.g., olpasiran, zerlasiran, lepodisiran) and small molecule inhibitors (e.g., muvalaplin) have demonstrated effective Lp(a) lowering and good tolerability. These agents are moving forward in clinical development, in order to determine whether Lp(a) lowering reduces cardiovascular risk. The results of these studies have the potential to transform our approach to the prevention of cardiovascular disease."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

New insights into the therapeutic options to lower lipoprotein(a). (PubMed, Eur J Clin Invest) - "If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

Elevated Lipoprotein(a) Levels: A Crucial Determinant of Cardiovascular Disease Risk and Target for Emerging Therapies. (PubMed, Curr Probl Cardiol) - "Newly emerging therapies, including pelacarsen, zerlasiran, olpasiran, muvalaplin, and lepodisiran, show promise in significantly lowering Lp(a) levels, potentially transforming the management of cardiovascular disease. However, further research is essential to assess these novel therapies' long-term efficacy and safety, heralding a new era in cardiovascular disease prevention and treatment and providing hope for at-risk patients."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Hematological Disorders • Inflammation • Thrombosis

A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Progression of Calcific Aortic Valve Stenosis (clinicaltrials.gov) - P2 | N=502 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Sep 2028 ➔ Jan 2029

Trial primary completion date

A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Progression of Calcific Aortic Valve Stenosis (clinicaltrials.gov) - P2 | N=502 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open

A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Rate of Weekly Lipoprotein Apheresis Sessions in Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease in Germany (clinicaltrials.gov) - P3 | N=51 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOB

Targeting Lipoprotein(a): Can RNA Therapeutics Provide the Next Step in the Prevention of Cardiovascular Disease? (PubMed, Cardiol Ther) - "Promising treatment approaches targeting apo(a) expression include RNA-based drugs such as pelacarsen, olpasiran, SLN360, and lepodisiran, which are currently in clinical trials. In this comprehensive review, we provide a detailed overview of RNA-based therapeutic approaches and discuss the recent advances and challenges of RNA therapeutics specifically designed to reduce Lp(a) levels and thus the risk of cardiovascular disease."

Journal • Review • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Dyslipidemia • Heart Failure • APOB

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 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P3 trial • Atherosclerosis • Cardiovascular • Dyslipidemia

Diacylglycerols and Lysophosphatidic Acid, Enriched on Lipoprotein(a), Contribute to Monocyte Inflammation. (PubMed, Arterioscler Thromb Vasc Biol) - "Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]). Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is, in part, NLRP3 inflammasome dependent."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • CXCL8 • IL1B • NLRP3

Lipoprotein a - Lp(a). (PubMed, Indian Heart J) - "PCSK9 inhibitors and Inclisiran reduces Lp(a) by 25 %. Pelacarsen is an antisense oligonucleotide and is found to reduce Lp(a) by 80 %. In a recent Indian study of 1021 CAD patients presence of elevated Lp(a) (>50 mg/dL) correlated with severe angiographic disease. 37 % of ACS patients exhibited elevated Lp(a) and it was higher in young CAD patients with FH (43 %)."

Journal • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Dyslipidemia • Endocrine Disorders • Heart Failure • Hematological Disorders • Infectious Disease • Inflammation • Ischemic stroke • Myocardial Infarction • Nephrology • Renal Disease • Septic Shock • Thrombosis

A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Rate of Weekly Lipoprotein Apheresis Sessions in Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease in Germany (clinicaltrials.gov) - P3 | N=60 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Feb 2025 ➔ Jun 2025 | Trial primary completion date: Feb 2025 ➔ Jun 2025

Trial completion date • Trial primary completion date • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOB

Traditional and novel non-statin lipid-lowering drugs. (PubMed, Indian Heart J) - "The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS...Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the..."

Journal • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Hepatology • Heterozygous Familial Hypercholesterolemia • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Pancreatitis • APOB • PCSK9

Lp(a) in the Pathogenesis of Aortic Stenosis and Approach to Therapy with Antisense Oligonucleotides or Short Interfering RNA. (PubMed, Int J Mol Sci) - "Olpasiran and pelacarsen reduce circulating Lp(a) levels by 85-90%. Phase 3 studies are underway to evaluate the effect of these drugs on cardiovascular events (cardiovascular death, non-fatal myocardial injury, and non-fatal stroke) in patients with elevated Lp(a) and CVD (cardiovascular diseases). For instance, if a reduction in Lp(a) levels is associated with aortic stenosis prevention or progression, further prospective clinical trials are warranted to confirm this observation in this high-risk population."

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

An Open Label Extension (OLE) Study to Evaluate Long-term Safety and Tolerability of Pelacarsen (TQJ230) (clinicaltrials.gov) - P3 | N=60 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Dyslipidemia • Metabolic Disorders

A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Rate of Weekly Lipoprotein Apheresis Sessions in Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease in Germany (clinicaltrials.gov) - P3 | N=60 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jul 2024 ➔ Feb 2025 | Trial primary completion date: Jul 2024 ➔ Feb 2025

Trial completion date • Trial primary completion date • Cardiovascular • Dyslipidemia • Metabolic Disorders

Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a). (PubMed, Int J Mol Sci) - "Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results...Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule...The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off."

Journal • Review • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Heart Failure • Metabolic Disorders

Treatment of Lp(a): Is It the Future or Are We Ready Today? (PubMed, Curr Atheroscler Rep) - "These new drugs are the ASO pelacarsen and the siRNAs olpasiran and SLN360. We are not ready today to significantly reduce plasma Lp(a). Emerging therapies potently decrease Lp(a) and ongoing clinical trials will determine their effectiveness in reducing ASCVD risk in subjects with high Lp(a) levels."

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