omecamtiv mecarbil (AMG 423) / Royalty, Amgen, Servier, Cytokinetics - LARVOL DELTA

Phenotype specific nuclear lamina remodeling in hiPSC derived cardiomyocytes bearing TNNT2 sarcomeric variants. (PubMed, iScience) - "These changes in stiffness were rescued by treatment with myosin modulators Mavacamten or Omecamtiv Mecarbil. This study shows that nuclear mechanics is influenced by the interaction between the sarcomere and the cytoskeletal network. Exploring the relationship between contractile dysfunction and nuclear lamina remodeling may reveal new therapeutic targets for cardiomyopathies."

Journal • Cardiomyopathy • LMNA

Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Omecamtiv Mecarbil in Healthy Chinese Subjects. (PubMed, Drugs R D) - "Omecamtiv mecarbil was well tolerated at the dose levels of 25-50 mg in healthy Chinese participants according to a pharmacokinetic-based titration scheme. Exposure of omecamtiv mecarbil was dose proportional, and no dose-related trends were observed in treatment-emergent adverse events."

Journal • PK/PD data • Cardiovascular

Cryo-EM Reveals How Cardiomyopathy Therapeutic Drugs Modulate the Myosin Motors of the Heart. (PubMed, bioRxiv) - "Mavacamten and omecamtiv mecarbil are therapeutic, myosin-targeted drugs designed to treat these myopathies, but their mechanism of action has remained unclear. This remodeling elucidates previously unclear allosteric mechanisms through which these drugs either inhibit or enhance myosin activity, countering the deleterious impacts of disease. These findings reveal how drugs modulate myosin structure to control cardiac contractility."

Journal • Cardiomyopathy • Cardiovascular • Myositis

Lactate dehydrogenase and clinical outcomes in patients with heart failure and reduced ejection fraction: Insights from the GALACTIC-HF trial (AHA 2025) - "However, whether LDH levels are also prognostically important in heart failure (HF) is unknown.Hypothesis:LDH concentration is associated with fatal and non-fatal outcomes in patients with HF and reduced ejection fraction (HFrEF).GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a randomized, double-blind, multicenter, event-driven trial that evaluated the efficacy and safety of the cardiac myosin activator, omecamtiv mecarbil (OM) versus placebo in 8,232 patients with HFrEF...In GALACTIC-HF, higher LDH levels were independently associated with increased risk of fatal and non-fatal outcomes in patients with HFrEF."

Clinical • Clinical data • Cardiovascular • Congestive Heart Failure • Heart Failure

A dual in silico framework for cardiac drug evaluation to assess electrophysiological and mechanical responses. (PubMed, J Physiol) - No abstract available

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Continued conduct of COMET-HF (Confirmation of Omecamtiv Mecarbil Efficacy Trial in Heart Failure), a confirmatory Phase 3 clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction. (The Manila Times) - "We expect to continue patient enrollment through 2026."

Enrollment status • Heart Failure

Semiquantitative urine dipstick protein assessments predict clinical outcomes in patients with heart failure and reduced ejection fraction: Insights from the GALACTIC-HF trial (AHA 2025) - "Given the renewed emphasis on CV-metabolic-kidney overlap in medicine, we have examined the prognostic value of semiquantitative urine dipstick protein (DP) assessments in patients with heart failure and reduced ejection fraction (HFrEF).Hypothesis:DP predicts clinical outcomes and enables risk stratification in HFrEF.GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a randomized, double-blind, multicenter, event-driven trial that evaluated the efficacy and safety of the cardiac myosin activator omecamtiv mecarbil (OM) versus placebo in 8,232 patients with HFrEF...DP is a simple inexpensive test with prognostic value in HFrEF."

Clinical • Clinical data • Cardiovascular • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Heart Failure • Metabolic Disorders • Nephrology • Renal Disease

Efficacy of cardiac myosin activators compared to placebo in patients with heart failure and reduced ejection fraction: A systematic review and meta-analysis of randomized controlled trials. (PubMed, Heart Lung) - "CMAs, particularly omecamtiv mecarbil, did not significantly impact all-cause mortality, cardiovascular death, or HF recurrence in patients with HFrEF. However, modest reductions were observed in composite outcomes and stroke. These findings should be interpreted cautiously, and further trials are needed to validate their clinical role."

Journal • Retrospective data • Review • Cardiovascular • Congestive Heart Failure • Heart Failure

Efficacy and Safety of Omecamtiv Mecarbil in Heart Failure With Reduced Ejection Fraction According to Age: The GALACTIC-HF Trial. (PubMed, JACC Heart Fail) - P3 | "In GALACTIC-HF, older individuals were well-represented and faced higher risks of CV events. Treatment with omecamtiv mecarbil was safe irrespective of age and reduced the risk of CV death or first HF event across the age spectrum, especially in those with severe HF. (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure [GALACTIC-HF]; NCT02929329.)."

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Confirmation of Omecamtiv Mecarbil Efficacy Trial in Heart Failure (COMET-HF): A Phase 3, Randomized, Placebo-Controlled Clinical Trial (HFSA 2025) - "In this multicenter, randomized, placebo-controlled clinical trial, patients will be randomized 1:1 between omecamtiv mecarbil and placebo. The primary composite endpoint is time to a first heart failure event, cardiovascular death, left ventricular assist device implantation, heart transplantation, or stroke."

Clinical • P3 data • Cardiovascular • Congestive Heart Failure • Heart Failure

Breaking new ground in heart failure management: novel therapies and future frontiers. (PubMed, Front Cardiovasc Med) - "Emerging pharmacological therapies in heart failure management include SGLT-2 inhibitors, ARNI, Vericiguat, and Omecamtiv. Other novel therapies that are changing the scope of HF management include IV Iron therapy and new antifibrotic agents, such as pirfenidone and pamrevlumab...Additionally, the limitations and challenges associated with the emerging therapies will be discussed. Overall, this literature review aims to provide a comprehensive understanding of how these therapies are transforming the management of HF and related cardiomyopathies."

Journal • Review • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Gene Therapies • Heart Failure

Serum magnesium and outcomes in patients with heart failure and reduced ejection fraction: insights from the GALACTIC-HF trial (ESC-WCC 2025) - " GALACTIC-HF was a randomised, double-blind, multicentre, event-driven trial that investigated the efficacy and safety of the cardiac myosin activator omecamtiv mecarbil (OM) compared to placebo in patients with HF and a left ventricular ejection fraction (LVEF) ≤35%... In GALACTIC-HF, 10.7% of patients with HFrEF had hypermagnesemia, which was associated with a higher risk of the primary outcome than in people with normal magnesium levels. However, incidence rates of sudden death were similar across all magnesium levels. The effect of OM on clinical outcomes was unaffected by magnesium levels."

Clinical • Cardiovascular • Congestive Heart Failure • Heart Failure

Omecamtiv mecarbil and red cell distribution width in patients with heart failure and reduced ejection fraction: results from the GALACTIC-HF trial (ESC-WCC 2025) - "RDW, a routinely available and inexpensive biomarker, independently predicts the risk of HF hospitalisation or CV death in HFrEF. In GALACTIC-HF, the benefit of omecamtiv mecarbil was consistent across the range of RDW examined.Figure: Red cell distribution width (RDW) in heart failure. The upper panel illustrates the distribution of RDW, and the lower panel shows the association between RDW and the composite of HF hospitalisation and CV death."

Clinical • Cardiovascular • Congestive Heart Failure • Heart Failure

Serum magnesium and outcomes in heart failure with reduced ejection fraction: the GALACTIC-HF trial. (PubMed, Eur Heart J) - "In GALACTIC-HF, 10.7% of outpatients with HFrEF had hypermagnesaemia, which was associated with a higher risk of the primary outcome compared to normal magnesium concentrations. Abnormal magnesium levels were not associated with a higher risk of sudden death or ventricular tachyarrhythmias. These findings do not support routine correction of hypomagnesaemia."

Clinical • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Ventricular Tachycardia

Danicamtiv reduces myosin's working stroke but activates the thin filament by accelerating actomyosin attachment. (PubMed, Proc Natl Acad Sci U S A) - "We demonstrate important mechanistic differences with another cardiac myosin binding myotrope, omecamtiv mecarbil. Finally, we computationally model how the observed changes in mechanics and kinetics at the level of single crossbridges can contribute to increased cardiac contraction. Taken together, our results have important implications for the design of sarcomeric-targeting compounds for heart failure."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Transplantation

Lack of Effect of Omecamtiv Mecarbil on Smooth Muscle Myosin Phosphatase Target Subunit-1 (MYPT1) Phosphorylation and Hemodynamics in Rats. (PubMed, Cureus) - "Intravenous omecamtiv mecarbil (10-5 mol/L) did not change either mean arterial pressure or heart rate under general anesthesia. Conclusion At clinical and supra-clinical doses, omecamtiv mecarbil did not alter phenylephrine-induced vascular smooth muscle contraction via MYPT1 phosphorylation or hemodynamic parameters under anesthesia in rats. These findings suggest that omecamtiv mecarbil, even at high doses, does not appear to influence vascular smooth muscle function, supporting its preclinical evidence of vascular safety as a cardiac myosin direct activator."

Journal • Preclinical • Anesthesia

Insights from electromechanical simulations to assess omecamtiv mecarbil efficacy in heart failure. (PubMed, J Physiol) - "Undesirable effects on diastolic function and contraction duration override the positive effects. Fast heart rates and elevated omecamtiv mecarbil doses aggravate cardiac dysfunction."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Omecamtiv mecarbil, a cardiac myosin activator with potential efficacy in heart failure. (PubMed, Arch Med Sci Atheroscler Dis) - "The first major trial investigating omecamtiv mecarbil use in HFrEF demonstrated a statistically significant decrease in the composite endpoint of the first HF event or death from cardiovascular causes. A post hoc analysis demonstrated that omecamtiv mecarbil produced a statistically significant reduction in the composite endpoint of time to the first HF event or cardiovascular death among patients with severe HFrEF."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Excessive autophagic degradation of MYLK3 causes sunitinib-induced cardiotoxicity. (PubMed, Autophagy) - "Sunitinib is a receptor tyrosine kinase inhibitor used for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors...Moreover, pharmacological intervention of the cardiac myosin activator omecamtiv mecarbil (OM) or overexpression of MYLK3 significantly restored the expression of MYLK3 and reversed pathogenic phenotypes in sunitinib-treated iPSC-CMs. Nanoparticle delivery of OM effectively prevented sunitinib-induced cardiac dysfunction in mice. Our findings suggest that sunitinib-induced MYLK3 degradation causes the inhibition of the CAMK2-PLN-ATP2A2a signaling pathway and leads to sunitinib-induced arrhythmogenesis, and that MYLK3 can act as a novel cardioprotective target for sunitinib-induced cardiotoxicity."

Journal • Cardiovascular • Congestive Heart Failure • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Genito-urinary Cancer • Heart Failure • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • MYLK • SQSTM1

Comparative mechanistic analysis of danicamtiv and omecamtiv mecarbil's in vivo cardiac effects. (PubMed, J Gen Physiol) - "These similarities between danicamtiv and OM in the whole heart were surprising given recent evidence showing significant differences in the drugs' molecular effects on myosin mechanics. We therefore conclude that danicamtiv likely has a wider therapeutic window than OM, but may be limited by the same trade-off between systolic and diastolic performance, driven by similar underlying mechanisms."

Clinical • Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure

The effect of omecamtiv mecarbil on outcomes analysed using the win ratio: an exploratory analysis of GALACTIC-HF (HEART FAILURE 2025) - No abstract available

Late-breaking abstract • Cardiovascular

Omecamtiv mecarbil (HEART FAILURE 2025) - "Joint session with the Canadian Heart Failure Society"

Cardiovascular • Congestive Heart Failure • Heart Failure

Mitral regurgitation in patients with heart failure and reduced ejection fraction and clinical outcomes: Insights from GALACTIC-HF (HEART FAILURE 2025) - " GALACTIC-HF was a randomized, double-blind, multicenter, event-driven trial that investigated the efficacy and safety of the cardiac myosin activator omecamtiv mecarbil (OM) compared to placebo in patients with HF and a left ventricular ejection fraction ≤35%... In GALACTIC-HF, 15.6% of patients with HFrEF had moderate/severe MR and this was associated with a higher risk of the primary outcome and first HF hospitalization (but not cardiovascular death or all-cause death). There was no significant association between mild MR and any outcome. The effect of OM on clinical outcomes was not modified by MR severity."

Clinical • Clinical data • Cardiovascular • Congestive Heart Failure • Heart Failure

Omecamtiv Mecarbil in Systolic Heart Failure: Clinical Efficacy and Future Directions of a Novel Myosin-Activating Inotropic Agent. (PubMed, Cureus) - "This narrative review discusses OM's pharmacologic profile, clinical trial data, and its potential as an adjunct therapy in advanced HFrEF. While not yet guideline-recommended, OM may benefit patients who remain symptomatic despite optimal treatment."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure

Mechanistic insights into effects of the cardiac myosin activator omecamtiv mecarbil from mechanokinetic modelling. (PubMed, Front Physiol) - "These encompass a reduced difference in binding free energy between the pre- and post-power-stroke states and greatly increased activation energy for the lever arm swing during the power-stroke. Better quantitative agreement, e.g., isometric force minimally changed from the control value by OM is achieved by additional changes in model parameter values previously suggested by studies of isolated proteins."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure