danicamtiv (MYK-491) / BMS - LARVOL DELTA

Bayesian Estimation of Muscle Mechanisms and Therapeutic Targets Using Variational Autoencoders. (PubMed, Biophys J) - "Given simulated or experimental isometric twitches, this machine learning model is able to then predict the set of rate parameters which are most likely to yield that result. We then predict the set of rate parameters associated with twitches from control mice with the cardiac Troponin C (cTnC) I61Q variant and control twitches treated with the myosin activator Danicamtiv, as well as model parameters that recover the abnormal I61Q cTnC twitches."

Journal • Cardiomyopathy • Cardiovascular

Differential effects of myosin activators on myocardial contractile function in non-failing and failing human hearts. (PubMed, Am J Physiol Heart Circ Physiol) - "The second-generation myosin activator danicamtiv (DN) has shown improved function compared to the first generation myosin activator omecamtiv mecarbil (OM) in non-failing myocardium by enhancing cardiac force generation but attenuating slowed relaxation. Although these effects were less pronounced with DN compared to OM in failing myocardium, DN impaired contractile properties in failing myocardium that were not affected in donor myocardium. Our results indicate that similar to first-generation myosin activators, the DN-induced slowing of cross-bridge kinetics may result in a prolongation of systolic ejection and delayed diastolic relaxation in the heart failure setting."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Danicamtiv reduces myosin's working stroke but enhances contraction by activating the thin filament. (PubMed, bioRxiv) - "Heart failure is a leading cause of death worldwide, and there is a need to develop new treatments that improve outcomes for patients. Recently, the myosin-binding small molecule danicamtiv entered clinical trials for heart failure; however, its mechanism at the level of single myosin crossbridges is not well understood. We determined the molecular mechanism of danicamtiv and showed how drug-induced molecular changes can mechanistically increase heart contraction. Moreover, we demonstrate fundamental differences between danicamtiv and the related myosin-binding small molecule omecamtiv mecarbil that explain the improved diastolic function seen with danicamtiv. Our results have important implications for the design of new therapeutics for heart failure."

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

Titin Cardiomyopathy Associated With Refractory Ventricular Tachycardia: A Case Report. (PubMed, Cureus) - "The course was complicated by multiple ventricular tachycardias (VTs) refractory to medical management, despite treatment with amiodarone, sotalol, dofetilide, mexiletine, and propranolol. Interestingly, endocardial mapping failed to delineate the substrate of tachycardia. This report underscores the importance of genetic testing in DCM and highlights the potential association of titin cardiomyopathy with refractory VTs, possibly of epicardial origin."

Journal • Cardiomyopathy • Cardiovascular • Ventricular Tachycardia • TTN

A Study to Evaluate the Safety, Tolerability, and Drug Levels of Danicamtiv in Healthy Japanese and Caucasian Participants (clinicaltrials.gov) - P1 | N=33 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed

Trial completion

The novel myosin activator, danicamtiv alters both systolic and diastolic functions in vitro and in vivo (HEART FAILURE 2024) - "Danicamtiv improves systolic function without affecting the intracellular Ca2+ transient, however, significantly alters LV diastolic function. Impairment in diastolic function seems to be a class-effect of direct myosin activators. Attention should be paid to the development/worsening of diastolic function in patients treated with danicamtiv."

Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure

Danicamtiv affected isometric force and cross-bridge kinetics similarly in skinned myocardial strips from male and female rats. (PubMed, J Muscle Res Cell Motil) - "These findings imply that danicamtiv increases force production via increasing cross-bridge contributions to activation of contraction, especially at sub-maximal Ca2+-activation. The inclusion of both sexes in animal models during the formative stages of drug development could be helpful for understanding the efficacy or limitation of a drug's therapeutic impact on cardiac function."

Journal • Preclinical • Cardiovascular • Heart Failure

A Study to Assess the Effect of Danicamtiv on the Drug Levels of Midazolam in Participants With Stable Heart Failure (clinicaltrials.gov) - P1 | N=13 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure • Heart Failure

Exploratory Study of Danicamtiv in Patients With Primary Dilated Cardiomyopathy (DCM) Due to Genetic Variants or Other Causalities (clinicaltrials.gov) - P2 | N=41 | Terminated | Sponsor: Bristol-Myers Squibb | Trial completion date: Feb 2026 ➔ Feb 2024 | Recruiting ➔ Terminated; Business objectives have changed

Trial completion date • Trial termination • Cardiomyopathy • Cardiovascular • MYH7

Exploratory Study of Danicamtiv in Patients With Primary Dilated Cardiomyopathy (DCM) Due to Genetic Variants or Other Causalities (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Jan 2025 ➔ Feb 2026

Trial completion date • Cardiomyopathy • Cardiovascular • MYH7

A Study to Assess the Relative Biological Availability and the Effect of Food on the Drug Levels of Danicamtiv in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=21 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed

Trial completion

Effect of the Novel Myotrope Danicamtiv on Cross-Bridge Behavior in Human Myocardium. (PubMed, J Am Heart Assoc) - "Background Omecamtiv mecarbil (OM) and danicamtiv both increase myocardial force output by selectively activating myosin within the cardiac sarcomere. Conclusions This is the first study to directly compare the effects of OM and danicamtiv on cross-bridge kinetics. At a similar level of force enhancement, danicamtiv had a less pronounced effect on the slowing of cross-bridge kinetics and, therefore, may provide a similar improvement in systolic function as OM without excessively prolonging systolic ejection time and slowing cardiac relaxation facilitating diastolic filling at the whole-organ level."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Assess the Relative Biological Availability and the Effect of Food on the Drug Levels of Danicamtiv in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=21 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Assess the Effect of Danicamtiv on the Drug Levels of Midazolam in Participants With Stable Heart Failure (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Assess the Relative Biological Availability and the Effect of Food on the Drug Levels of Danicamtiv in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=21 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

New P1 trial

Danicamtiv Recruits Myosin Motors to Aid the Failing Heart. (PubMed, Circ Res) - No abstract available

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Assess the Effect of Danicamtiv on the Drug Levels of Midazolam in Participants With Stable Heart Failure (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

New P1 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge Cycling in Cardiac Muscle. (PubMed, Circ Res) - "As demonstrated by the detailed studies of Danicamtiv, increasing myosin recruitment and altering cross-bridge cycling are 2 mechanisms to increase force and calcium sensitivity in cardiac muscle. Myosin activators such as Danicamtiv can treat the causative hypocontractile phenotype in genetic dilated cardiomyopathy."

Journal • Cardiomyopathy • Cardiovascular

A Study to Evaluate the Safety, Tolerability, and Drug Levels of Danicamtiv in Healthy Japanese and Caucasian Participants (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Evaluate the Safety, Tolerability, and Drug Levels of Danicamtiv in Healthy Japanese and Caucasian Participants (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

New P1 trial

Exploratory Study of Danicamtiv in Patients With Primary Dilated Cardiomyopathy (DCM) Due to Genetic Variants or Other Causalities (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: Bristol-Myers Squibb | N=24 ➔ 40 | Trial primary completion date: Dec 2022 ➔ Nov 2023

Enrollment change • Trial primary completion date • Cardiomyopathy • Cardiovascular • MYH7

Elucidating the mechanism of Danicamtiv on force, kinetics, and myosin structure and function. (PubMed, Biophys J) - No abstract available

Journal

Discovery of sarcomere modulator Danicamtiv (ACS-Sp 2023) - "The presentation also includes pre-clinical characterization of the molecule. Currently, the compound is undergoing clinical evaluation in a subset of HF patients with dilated cardiomyopathy (DCM)."

Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications. (PubMed, Int J Mol Sci) - "Nevertheless, the systolic ejection time was significantly prolonged, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also observed upon danicamtiv treatment in vivo. Taken together, danicamtiv improves cardiac systolic function, but it can also limit diastolic performance, especially at high drug concentrations."

Journal • Preclinical • Anesthesia • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study to Evaluate the Effect of Co-administration of Itraconazole or Diltiazem on the Single-dose of Danicamtiv in Healthy Participants (clinicaltrials.gov) - P1 | N=30 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed | Trial completion date: Mar 2022 ➔ Jul 2022 | Trial primary completion date: Mar 2022 ➔ Jul 2022

Trial completion • Trial completion date • Trial primary completion date