A novel cardiac myosin agonist, danicamtiv, has shown favourable safety and efficacy signals in patients with dilated cardiomyopathy (DCM), particularly in those with specific genetic variants, according to results from a phase 2a open-label trial.¹ Precision therapies for DCM are currently lacking, despite its diverse clinical manifestations often linked to underlying genetic causes.²

Danicamtiv is an investigational small molecule designed to selectively enhance cardiac myosin function. By increasing the number of force-generating myosin motors, it aims to improve cardiac performance in conditions where myosin function or availability is impaired, such as in DCM associated with pathogenic variants in the cardiac beta-myosin heavy chain (MYH7) and titin (TTN) genes.

Methodology

The exploratory study (NCT04572893) was a phase 2a, baseline-controlled, open-label trial that enrolled 41 clinically stable adults with DCM and a left ventricular ejection fraction (LVEF) of ≤45%.¹ Participants were stratified into three cohorts based on the aetiology of their condition: those with MYH7 variants (n=12), those with TTN variants (n=14), and those with DCM from other causes, including other genetic variants or negative genetic testing (n=15).

The intervention consisted of a two-week sequential dosing period. In the first period, participants received oral danicamtiv 25 mg twice daily. In the second period, the dose was adjusted to either 10 mg or 50 mg twice daily based on systolic ejection time. The primary endpoint was safety and tolerability, with secondary endpoints including echocardiography-assessed changes in cardiac structure and function.

Results

Danicamtiv was generally well tolerated. Treatment-emergent adverse events were reported in 22 participants (53.7%), all of which were mild or moderate. The most common events were headache, diarrhoea, dizziness, and fatigue. One participant discontinued treatment. No serious adverse events or deaths were reported. An asymptomatic increase in cardiac troponin was detected in three participants in the 'other causes' cohort, but not in the MYH7 or TTN cohorts.

After the second treatment period, participants in the genetic cohorts demonstrated the most notable improvements in cardiac function. The mean LVEF from baseline increased by 8.8% (95% CI: 5.03%–12.64%) in the MYH7 cohort and 5.9% (95% CI: 2.59%–9.28%) in the TTN cohort. The improvement was less pronounced in the 'other causes' cohort, with a mean LVEF increase of 4.4% (95% CI: -0.90% to 9.73%).

In Practice

The findings suggest that targeting myosin function with danicamtiv may offer a potential therapeutic strategy for DCM, with a possibly greater benefit for patients with specific genetic underpinnings. The investigators concluded that the “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.”¹

Next Steps

These results justify further investigation of danicamtiv in larger, longer-duration clinical trials to confirm these initial observations and to further explore the potential for genotype-guided therapy in DCM.

This study was funded by Bristol Myers Squibb.

References

1. Lakdawala NK, Hershberger RE, Garcia-Pavia P, et al. Danicamtiv, a Selective Agonist of Cardiac Myosin, for Dilated Cardiomyopathy: A Phase 2 Open-Label Trial. J Am Coll Cardiol. 2025;86(25):2598-2612. https://doi.org/10.1016/j.jacc.2025.09.1511.

2. Fatkin D, Huttner IG, Kovacic JC, et al. Precision medicine in the management of dilated cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. 2019;74:2921-2938. https://doi.org/10.1016/j.jacc.2019.10.011.

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