September 30, 2025Journal of the American College of Cardiology
Danicamtiv, a Selective Agonist of Cardiac Myosin, for Dilated Cardiomyopathy
Neal K. LakdawalaRay E. HershbergerPablo García‐PavíaPerry ElliottJonathan GinnsBenjamin MederScott SolomonJonathan W. CunninghamJuan R. GimenoRoberto Barriales‐VillaEric AdlerBrenda GerullNaveen L. PereiraBrian P. HallidayWanying LiPraneeth JarugulaSonomi MaruyamaSaffie MohranMaria A. PapadakiAnu AntoRobert L. AndersonHéctor M. Rodrı́guezCarlos del RíoJay M. EdelbergGregory KurioJuan Diego MayaJames L. Januzzi
Key result
Danicamtiv demonstrates acceptable tolerability in dilated cardiomyopathy, with adverse events in ~54% of patients.
- n=41
Why the study?
Precision therapies for dilated cardiomyopathy are lacking despite diverse manifestations and clinical trajectories based on underlying etiology, including pathogenic MYH7 and TTN variants impairing cardiac myosin function.
Does danicamtiv improve cardiac function safely in patients with dilated cardiomyopathy?
Key Points
- Translationally evaluate danicamtiv, a selective cardiac myosin activator, from in vitro functional assays to a phase 2a clinical trial in patients with dilated cardiomyopathy harboring MYH7, TTN, or other etiologies.
- Assessed danicamtiv in vitro on cardiac myosin enzymatic activity and skinned left ventricular fiber force generation.
- Conducted a phase 2a, baseline-controlled, open-label trial (NCT04572893) across 41 adults with dilated cardiomyopathy stratified into MYH7 (n=12), TTN (n=14), or other cause (n=15) cohorts.
- Administered oral danicamtiv at 25 mg twice daily during treatment period 1, adjusting to 10 or 50 mg twice daily during treatment period 2 to evaluate safety, tolerability, and echocardiographic function.
- Treatment-emergent adverse events occurred in 22 of 41 participants (53.7%), all mild or moderate, with 1 treatment discontinuation and asymptomatic cardiac troponin increases in 3 participants in the other causes cohort.
- Left ventricular ejection fraction improved after treatment period 2 by 8.8% (95% CI: 5.03% to 12.64%) in the MYH7 cohort and 5.9% (95% CI: 2.59% to 9.28%) in the TTN cohort, compared to 4.4% (95% CI: -0.90% to 9.73%) in the other causes cohort.
Structured PICO
Does danicamtiv improve cardiac function safely in patients with dilated cardiomyopathy?
P
Population
41 participants with dilated cardiomyopathy (mean baseline LVEF 33.4%) due to MYH7, TTN variants, or other causes.
I
Intervention
Oral danicamtiv 25 mg twice daily for 1 week (treatment period 1), with dose adjustment to 10 or 50 mg twice daily in treatment period 2.
C
Comparator
Baseline (no separate control group)
O
Outcome
Safety/tolerabilitysafety
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Danicamtiv worked. It increased the force of contraction vis-à-vis increased left atrial and left ventricular function measured by echocardiography. It did so without significant hazard in the form of troponin release, especially in patients with myosin-related dilated cardiomyopathy. This is an important step toward precision therapies for dilated cardiomyopathy. For too long, we have treated this disease as a homogenous entity.”
“The positive Phase 2a results for danicamtiv showed clinically meaningful improvements in direct activation of both ventricular and atrial function in the MYH7 and TTN cohorts, a finding we believe to be unique to danicamtiv. These findings represent an important step forward in the development of a potential first-in-class targeted treatment for patients with familial and genetic dilated cardiomyopathy.”
“There is a critical unmet need in the DCM community to match the right treatment to the right patient, especially for those whose disease is caused primarily by mutations impacting sarcomeric function. The data presented at HFSA supports our hypothesis that danicamtiv directly activates myosin and corrects the dysfunction resulting from sarcomeric mutations in DCM patients. These positive results pave the way for ongoing development of danicamtiv in an upcoming clinical trial, KINSHIP-DCM, which is planned to initiate later this year.”
Implication
A short course of the novel cardiac myosin agonist danicamtiv was well tolerated and improved left ventricular ejection fraction in patients with dilated cardiomyopathy, particularly those with MYH7 and TTN genetic variants.
Abstract
BACKGROUND: Precision therapies for dilated cardiomyopathy (DCM) are lacking despite diverse manifestations and clinical trajectories based on underlying etiology. DCM-associated pathogenic variants in cardiac beta-myosin heavy chain (MYH7) and titin (TTN) can impair the function/availability of cardiac myosin. Danicamtiv is a novel investigational small molecule that selectively enhances cardiac myosin function. OBJECTIVES: The study sought to translationally evaluate danicamtiv in the setting of myosin dysfunction, from in vitro assessments to a clinical trial exploring its safety and efficacy in DCM due to MYH7 or TTN variants, or other causes (either positive or negative genetic results). METHODS: The danicamtiv effects on DCM-variant cardiac myosin enzyme activity and skinned left ventricular (LV) fiber force generation were assessed in vitro. A phase 2a, baseline-controlled, open-label trial enrolled individuals with DCM into cohorts by variants (MYH7 or TTN) or other causes. In the week of treatment period (TP)1, participants received oral danicamtiv 25 mg twice daily with dose adjustment in TP2 to 10 or 50 mg twice daily. The primary endpoint was safety/tolerability; secondary endpoints included echocardiography-assessed changes in cardiac structure/function. RESULTS: In vitro, danicamtiv increased the activity of wild-type and DCM myosin, increasing force production in cardiac fibers. Forty-one participants were enrolled in the trial (mean age 49.6 ± 13 years; mean baseline LV ejection fraction 33.4% ± 8.0%). Twelve had MYH7 variants, 14 had TTN variants, and 15 had other cause DCM. Treatment-emergent adverse events were reported in 22 (53.7%) of 41 participants (all mild or moderate; 1 discontinuation); an asymptomatic increase in cardiac troponin was detected in 3 participants in the other causes cohort. After TP2, the MYH7 and TTN cohorts showed improvements from baseline in LV ejection fraction (MYH7: 8.8% [95% CI: 5.03%-12.64%]; TTN: 5.9% [95% CI: 2.59%-9.28%]) but less in the other causes cohort (4.4% [95% CI: -0.90% to 9.73%]). CONCLUSIONS: 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).
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Cite This Study
Lakdawala et al. (2025) studied Dilated Cardiomyopathy (n=41). Danicamtiv vs. Baseline was evaluated on Safety/tolerability. Danicamtiv was generally well tolerated in participants with dilated cardiomyopathy, with treatment-emergent adverse events reported in 53.7% of participants.