muvalaplin (LY3473329) / Eli Lilly - LARVOL DELTA

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

Discovery of potent small-molecule inhibitors of lipoprotein(a) formation. (PubMed, Nature) - "Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a)."

Journal • Cardiovascular • Dyslipidemia • APOB

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

Enrollment closed

A Study of Carbon-14-Labelled [14C] LY3473329 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Eli Lilly and Company

New P1 trial

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand? (PubMed, Int J Mol Sci) - "In particular, we discuss novel agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that are currently being developed and target Lp(a). The promising role of muvalaplin, an oral inhibitor of Lp(a) formation, is then further analyzed."

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

KRAKEN: A Study of LY3473329 in Adult Participants With Elevated Lipoprotein(a) at High Risk for Cardiovascular Events (clinicaltrials.gov) - P2 | N=233 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Familial Hypercholesterolemia

KRAKEN: A Study of LY3473329 in Adult Participants With Elevated Lipoprotein(a) at High Risk for Cardiovascular Events (clinicaltrials.gov) - P2 | N=233 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Familial Hypercholesterolemia

A Study of LY3473329 in Participants With Impaired and Normal Renal Function (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Dec 2023 ➔ Oct 2024 | Trial primary completion date: Dec 2023 ➔ Oct 2024

Trial completion date • Trial primary completion date • Nephrology • Renal Disease

Potential of muvalaplin as a lipoprotein(a) inhibitor. (PubMed, Expert Opin Investig Drugs) - No abstract available

Journal

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2023 European Society of Cardiology Congress. (PubMed, Curr Atheroscler Rep) - "Safety and efficacy data of inclisiran, a PCSK9-interfering mRNA (PCSK9i) administered subcutaneously twice annually, were presented. Data on two new PCSK9is were presented, recaticimab, an oral drug, and lerodalcibep, a subcutaneous drug with a slightly different architecture than currently available PSCK9is. A phase 1 trial on muvalaplin, an oral lipoprotein (a) inhibitor, was presented...Long-term follow-up of patients enrolled in the CLEAR outcomes trial showed sustained and more significant ASCVD risk reduction with bempedoic acid in high-risk patients. The late-breaking clinical science at the 2023 congress of the ESC extends the known safety and efficacy data of a PCSK9i with the introduction of new drugs in this class. Using cumulative exposure to LDL-C rather than a single value will help clinicians tailor the LDL-C reduction strategy to individual risk and is an important step towards personalized medicine."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia

Muvalaplin, a Potent Small Molecule Inhibitor of Lipoprotein(a) (ESC 2023) - No abstract available

Late-breaking abstract • Cardiovascular