Abstract 12733: The Effect of Mavacamten Treatment on Hemolysis Biomarkers in Patients With Obstructive Hypertrophic Cardiomyopathy in the EXPLORER-HCM Study

Abstract

Introduction: In patients with obstructive hypertrophic cardiomyopathy (HCM), blood flow changes from left ventricular outflow tract (LVOT) obstruction can lead to hemolysis and release of red blood cell proteins into circulation. Increased cell-free plasma hemoglobin (Hb) and reduced haptoglobin (Hp) are biomarkers of intravascular hemolysis. Mavacamten, a cardiac myosin inhibitor, reduced LVOT obstruction in the phase 3 EXPLORER-HCM study; however, its effect on hemolysis biomarkers is unknown. Aim: To assess the effect of 30 weeks of mavacamten treatment versus placebo on levels of intravascular hemolysis biomarkers in patients with obstructive HCM. Methods: Hemolysis biomarkers were measured as part of exploratory proteomic analyses from randomized EXPLORER-HCM (NCT03470545) patients at baseline and Week 30 (mavacamten, n = 115; placebo, n = 120) using a proteomic platform (SomaScan v4.1). Results: At Week 30, mavacamten treatment showed decreases in cell-free plasma Hb (Log 2 fold change = -1.57, FDR = 1.7х10 -4 ) and increases in cell-free plasma Hp (Log 2 fold change = 1.83, FDR = 1.2х10 -4 ) vs placebo (Figure). Hb and Hp levels were negatively correlated at baseline and at Week 30. In general, patients can be grouped into high- or low- hemolysis biomarker profile (high Hb with low Hp or low Hb with high Hp, respectively) at baseline and Week 30. Patients who received mavacamten and changed from high- to low hemolysis biomarker profile at Week 30 trended towards greater LVOT reductions under resting and Valsalva conditions. No changes were detected for either group in whole blood Hb or hematocrit. Conclusions: Reduced cell-free plasma Hb and increased cell-free plasma Hp levels, suggest a reduction in intravascular hemolysis by mavacamten in obstructive HCM. These results are consistent with improved hemodynamic effects (less outflow obstruction) and indicate that mavacamten may reduce shear forces on red blood cells in the heart.