Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial

Voors, Adriaan A.; Tamby, Jean Francois; Cleland, John G.F.; Koren, Michael; Forgosh, Leslie B.; Gupta, Dinesh; Lund, Lars H.; Camacho, Albert; Karra, Ravi; Swart, H.; Pellicori, Pierpaolo; Wagner, Frank; Hershberger, Ray E.; Prasad, Narayana; Anderson, Robert L.; Anto, Anu; Bell, Kaylyn M.; Edelberg, Jay M.; Liang, Fang; Henze, Marcus; Kelly, Cynthia M.; Kurio, Gregory; Li, Wanying; Wells, Kate; Yang, Chun; Teichman, Sam L.; Río, Carlos del; Solomon, Scott D.

doi:10.1002/ejhf.1933

Cited by 63 publications

(50 citation statements)

References 29 publications

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“…Danicamtiv binds selectively to human cardiac myosin isoform without binding to skeletal or smooth muscle isoforms resulting in the elevation of ATPase turnover rate (+85% in ventricular myofibrils) and increased Ca 2+ sensitivity (+0.35 pCa unit) [ 53 ]. In acutely treated male beagle dogs with induced HF ( n = 7), administration of Danicamtiv prolonged SET and improved LVEF in addition to cardiac output [ 53 ].…”

Section: Contractile Activators As Treatments For Heart Failure Anmentioning

confidence: 99%

“…No changes in diastolic blood pressure or heart rate were reported except for a minor reduction systolic blood pressure in high concentration cohort. Moreover, no signs of cardiac ischemia were reported at the doses used [ 53 ]. Most of these results are rather similar to OM; however, the effects of chronic treatment have not been studied.…”

Section: Contractile Activators As Treatments For Heart Failure Anmentioning

confidence: 99%

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Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

Alsulami

Marston

2020

IJMS

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Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities, which is mainly due to dysfunction in the contractile proteins that make up the contractile unit known as the sarcomere. To date, pharmacological treatment options are not disease-specific and rather focus on managing the symptoms, without addressing the disease mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere indirectly (inotropes) resulted in unwanted effects. In contrast, targeting the sarcomere directly, aided by high-throughput screening systems, could identify small molecules with a superior therapeutic value in cardiac muscle disorders. Herein, an extensive literature review of 21 small molecules directed to five different targets was conducted. A simple scoring system was created to assess the suitability of small molecules for therapy by evaluating them in eight different criteria. Most of the compounds failed due to lack of target specificity or poor physicochemical properties. Six compounds stood out, showing a potential therapeutic value in HCM, DCM or heart failure (HF). Omecamtiv Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin inhibitors) and AMG 594 (Ca2+-sensitiser) are all small molecules that allosterically modulate troponin or myosin. Omecamtiv Mecarbil showed limited efficacy in phase III GALACTIC-HF trial, while, results from phase III EXPLORER-HCM trial were recently published, indicating that Mavacamten reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved the health status of patients with HCM. A novel category of small molecules known as “recouplers” was reported to target a phenomenon termed uncoupling commonly found in familial cardiomyopathies but has not progressed beyond preclinical work. In conclusion, the contractile apparatus is a promising target for new drug development.

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Section: Contractile Activators As Treatments For Heart Failure Anmentioning

confidence: 99%

Section: Contractile Activators As Treatments For Heart Failure Anmentioning

confidence: 99%

Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

Alsulami

Marston

2020

IJMS

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“…Better results can be expected from drugs not acting through an increase in intracellular calcium. Danicamtiv, a novel cardiac myosin activator, improved stroke volume, global longitudinal and circumferential strain and left atrial function in experimental models and in a phase 2a trial in patients with HFrEF 19 . In patients hospitalized for acute HF, istaroxime had beneficial effects on left ventricular function, without hypotension, tachycardia, or serious cardiac adverse events 20 …”

Section: Treatment Of Heart Failure With Reduced Ejection Fractionmentioning

confidence: 99%

September 2020 at a glance: focus on heart failure with preserved ejection fraction and medical therapy

Tomasoni

Adamo

Metra

2020

European J of Heart Fail

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Type 2 diabetes mellitus and obesity increase heart failure (HF) risk. 1-4 Dang et al. 5 showed that delivery of longevity-associated variant of the human BPIFB4 gene in obese mice with diabetes improves cardiac function. Biomarkers Usefulness of biomarker measurements may be lower in patients with HF and preserved ejection fraction (HFpEF). 6,7 Henkens et al. 8 performed a systematic review of studies investigating the diagnostic value of novel biomarkers for HFpEF. The risk of bias was high in all studies. The main limitations were use of case-control designs, poor diagnosis of HFpEF, absence of pre-specified cutoff points, lack of external validation, inadequate and variable reference standards.

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“…Some are on the horizon; they are termed myosin activators. Danicamtiv is one of these agents, and its experimental and clinical effects are reported in the manuscript by Voors et al 3 published in this issue of the Journal. To better understand the mode of action of myosin activators, one needs to have a look at the smallest force-generating unit of the heart muscle, the acto-myosin cross-bridge cycle (Figure 1).…”

Section: This Article Refers To 'Effects Of Danicamtiv a Novel Cardimentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Is myosin activation a new treatment for heart failure?

Hasenfuß

2020

European J of Heart Fail

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Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial

Abstract: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.

Cited by 63 publications

References 29 publications

Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

Small Molecules Acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases

September 2020 at a glance: focus on heart failure with preserved ejection fraction and medical therapy

Is myosin activation a new treatment for heart failure?

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