muvalaplin (LY3473329) / Eli Lilly - 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

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

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

Assessing the clinical progress of Muvalaplin for lowering lipoprotein(a). (PubMed, Expert Opin Investig Drugs) - "In terms of patient convenience and adherence, the oral dosing of Muvalaplin may confer practical advantages over injectable Lp(a)-lowering therapies. The results of the MOVE-Lp(a) phase III trial, which is evaluating the effect of Muvalaplin on cardiovascular outcomes in high-risk patients with elevated Lp(a), are eagerly awaited."

Journal • Review • Atherosclerosis • Cardiovascular • Developmental Disorders

MOVE-Lp(a): Assessing the Impact of Muvalaplin on Major Cardiovascular Events in Adults With Elevated Lipoprotein(a) (clinicaltrials.gov) - P3 | N=10450 | Recruiting | Sponsor: Eli Lilly and Company

Adverse events • New P3 trial • 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

Lp(a)-Lowering Agents in Development: A New Era in Tackling the Burden of Cardiovascular Risk? (PubMed, Pharmaceuticals (Basel)) - "Such drugs include pelacarsen (an injectable ASO) and olpasiran, zerlasiran, and lepodisiran (injectable siRNA agents). Muvalaplin represents another therapeutic option to lower Lp(a) levels, since it is an oral selective small molecule inhibitor of Lp(a) formation, thus potentially exerting certain advantages in terms of its clinical use...The phase 3 CV trial outcomes are ongoing for some of these agents (i.e., pelacarsen, olpasiran, and lepodisiran) and are briefly mentioned. Overall, there is an urgent need for evidence-based guidelines on Lp(a) reduction in daily clinical practice, following the results of the phase 3 CV trials, as well as for establishing the ideal Lp(a) quantification method (i.e., using an apo(a) isoform-independent assay with appropriate calibrators, reporting the Lp(a) level in molar units)."

Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Heart Failure

Promising results with the daily oral small molecule lipoprotein(a) inhibitor, muvalaplin, in high-risk cardiovascular patients with elevated lipoprotein(a) levels. (PubMed, Ann Transl Med) - No abstract available

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2024 American Heart Association Scientific Sessions. (PubMed, Curr Atheroscler Rep) - "Included studies assessed effects of intensive blood pressure control in patients with type 2 diabetes (BPROAD); decision support system for physicians to optimize early lipid lowering therapies after acute coronary syndrome (ZODIAC); efficacy and safety of zerlasiran, a short interfering RNA targeting lipoprotein(a) (ALPACAR); efficacy and safety of muvalaplin an oral disrupter of the assembly of lipoprotein(a) particles (KRAKEN); safety and efficacy of obicetrapib in patients with heterozygous familial hypercholesterolemia (BROOKLYN); efficacy and safety of lerodalcibep, a third generation PCSK9 inhibitor in heterozygous familial hypercholesterolemia subjects (LIBerate-HeFH_OLE); personalized app-based coaching to improve physical activity in patients with HFpEF compared to standard care (MyoMobile); semaglutide to improve cardiovascular outcomes in patients with a history of coronary artery bypass surgery and overweight or obesity (the SELECT trial); efficacy and..."

Journal • Review • Acute Coronary Syndrome • Cardiovascular • Diabetes • Dyslipidemia • Familial Chylomicronemia Syndrome • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Metabolic Disorders • Obesity • Pancreatitis • Type 2 Diabetes Mellitus

Promises of an oral inhibitor: Muvalaplin. (CVCT USA 2024) - No abstract available

Atherosclerosis • Cardiovascular

Measuring Lp(a) particles with a novel isoform-insensitive immunoassay illustrates efficacy of muvalaplin. (PubMed, J Lipid Res) - "Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor, and there is considerable interest in developing Lp(a)-lowering therapeutics for cardiovascular prevention. In contrast, the Lp(a)-lowering effect of lepodisiran was clinically comparable between the intact Lp(a) assay and commercial assay. This novel intact Lp(a) assay provides a more accurate approach for the assessment of Lp(a)-lowering agents and study of Lp(a)-associated risk compared with currently available assays."

Journal • Cardiovascular

Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial. (PubMed, JAMA) - P2 | "The effect of muvalaplin on cardiovascular events requires further investigation. ClinicalTrials.gov Identifier: NCT05563246."

Clinical • Journal • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders • APOB • CRP

A Randomized Phase 2 Trial of Muvalaplin: An Oral Disrupter of the Assembly of Lipoprotein(a) Particles (AHA 2024) - "These findings will inform future large-scale trials of muvalaplin to determine whether it will be a clinically effective therapy for patients with elevated Lp(a) levels at high risk for CV events."

Clinical • Late-breaking abstract • P2 data • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Diabetes • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders • Peripheral Arterial Disease • Type 2 Diabetes Mellitus • APOB • CRP

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

Oral agents for lowering lipoprotein(a). (PubMed, Curr Opin Lipidol) - "Muvalaplin is the first oral agent, developed to lower Lp(a) levels. The ability of muvalaplin to reduce cardiovascular risk remains to be investigated, in order to determine whether it will be a useful agent for the prevention of cardiovascular disease."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • APOB

A Study of LY3473329 in Participants With Impaired and Normal Renal Function (clinicaltrials.gov) - P1 | N=47 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Nephrology • Renal Disease

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

A Study of LY3473329 in Participants With Impaired and Normal Renal Function (clinicaltrials.gov) - P1 | N=48 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Nephrology • Renal Disease

Emerging Lp(a)-Lowering therapies: Is muvalaplin a potential breakthrough? (PubMed, Int J Cardiol Cardiovasc Risk Prev) - No abstract available

Journal

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

A Study of Carbon-14-Labelled [14C] LY3473329 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion