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

Figures

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  Figure 1. Experimental studies – effects of danicamtiv on left ventricular (LV) and left atrial (LA) function, both ex vivo (A–C) and in vivo (heart failure dogs, D and E). Danicamtiv increased ATP turnover (ATPase) rates in LV and LA swine myofibrils (A), increasing Ca2+ sensitivity (pCa) in fibres (B and C; B: LV tension/pCa curve); LA muscle was less Ca2+ sensitive but had faster turnover rates than the left ventricle. In dogs with induced heart failure, danicamtiv prolonged systolic ejection time (SET), increasing indices of systolic LV function and stroke volume (D), while decreasing size and improving performance in the left atrium (E). (A–E) Mean ± standard error of the mean. (D–E) mean change (blue text). CTRL, control; 5HR, 5 h post‐treatment; LAEF, left atrial emptying fraction; LAFI, left atrial function index; LVFS, left ventricular fractional shortening; LVSV, left ventricular stroke volume; PRE, before dosing (i.e. baseline); Volmin, minimal volume.

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  Figure 2. Multiple‐dose trial – transthoracic echocardiography measurements, according to plasma concentrations of danicamtiv and change from baseline in: (A) global circumferential strain (GCS); (B) systolic ejection time (SET); (C) left atrial function index (LAFI); and (D) change in left ventricular stroke volume (LVSV) from baseline plotted against change in SET from baseline. The lines shown in panels A, B and C are from a non‐parametric LOESS (locally estimated scatterplot smoothing) method. The line shown in panel D, bound by the 95% upper and lower confidence limits, was generated from a mixed model regression accounting for within patient variation due to multiple measures taken from the same patient. Estimate of the slope is 0.1972 (P < 0.0001) with a 95% confidence interval of 0.1479–0.2465.