Danicamtiv, a Selective Agonist of Cardiac Myosin, for Dilated Cardiomyopathy: A Phase 2 Open-Label Trial

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.

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).

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.

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%]).

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).