danicamtiv (MYK-491) / BMS, Kardigan - LARVOL DELTA

Danicamtiv, a Novel Direct Enhancer of Cardiac Myosin Motor Function, Improves Cardiac Performance and Output in the setting of Myosin Dysfunction: In vitro and In vivo Evidence. (AHA 2025) - "The responses to DANI were assessed under control conditions and in the setting of myosin dysfunction, resulting from either DCM-pathogenic MYH7 mutations (in recombinant cS1), or via pharmacological cardiac myosin inhibition (MYHi: CK-274 or CK-586) in vitro/in vivo. DANI enhanced the ATPase cycling rate of cS1 in wild-type and five DCM MYH7 variants (AC50, WT: 3.8 µM vs. F764L: 3.2µM). Danicamtiv can directly improve the function of cardiac myosin in the setting of (genetic or induced) dysfunction, increasing the number of myosin heads forming productive cross-bridges, thus increasing/restoring force generation and systolic performance in vivo. These observations, if confirmed in humans, could suggest a potential novel mechanism-based targeted therapy for a subset of patients with DCM"

Late-breaking abstract • Preclinical • Cardiomyopathy • Cardiovascular • CNS Disorders • Depression • Psychiatry • MYH7 • TTN

Danicamtiv, A Selective Agonist of Cardiac Myosin, for Dilated Cardiomyopathy: A Phase 2 Open-Label Trial. (PubMed, J Am Coll Cardiol) - P2 | "Selective in vitro enhancement of cardiac myosin motor function and myofilament force generation by danicamtiv prompted clinical evaluation. A short course of danicamtiv was generally well tolerated in participants with DCM. Echocardiography outcomes were consistent with a danicamtiv-induced enhancement of myosin function/availability; MYH7 and TTN cohorts generally had the most favorable responses in contractile function. (Exploratory Study of Danicamtiv in Patients With Primary Dilated Cardiomyopathy Due to Genetic Variants or Other Causalities; NCT04572893)."

Journal • P2 data • Cardiomyopathy • Cardiovascular • MYH7 • TTN

KINSHIP-DCM: A Study of the Efficacy and Safety of Danicamtiv in Participants With Symptomatic Genetic and Familial Dilated Cardiomyopathy (clinicaltrials.gov) - P2/3 | N=332 | Recruiting | Sponsor: Kardigan, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiomyopathy • Cardiovascular

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

Danicamtiv Discussant (HFSA 2025) - No abstract available

Late-breaking abstract

KINSHIP-DCM: A Study of the Efficacy and Safety of Danicamtiv in Participants With Symptomatic Genetic and Familial Dilated Cardiomyopathy (clinicaltrials.gov) - P2/3 | N=332 | Not yet recruiting | Sponsor: Kardigan, Inc.

New P2/3 trial • Cardiomyopathy • Cardiovascular

Danicamtiv restores ventricular and atrial function in patients with dilated cardiomyopathy caused by genetic variants that depress sarcomere function (HFSA 2025) - No abstract available

Clinical • Late-breaking abstract • Cardiomyopathy • Cardiovascular

Danicamtiv increases cardiac mechanical efficiency. (PubMed, J Physiol) - "The mechanism of the increased efficiency resides in the increase of muscle force-length work greater than the increase of muscle heat. This study demonstrates that danicamtiv is a cardiac myotrope that not only enhances mechanics, but also exerts its enhancement effect on energetics."

Journal

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

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

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