Effect of Omecamtiv Mecarbil in Patients with Ischemic and Non-Ischemic Heart Failure with Reduced Ejection Fraction: Results From COSMIC-HF

Abstract

Introduction: LV systolic dysfunction is a final common pathway of multiple etiologies in the pathogenesis of chronic heart failure (HF). We evaluated the influence of HF etiology (ischemic vs. non-ischemic) on the response to the selective cardiac myosin activator, omecamtiv mecarbil (OM), in patients with HFrEF. Hypothesis: OM would have similar effects in patients with HFrEF regardless of HF etiology. Methods: COSMIC-HF (NCT 01786512) was a Phase 2 multicenter, randomized, double-blind, placebo-controlled trial in outpatients (n = 448) with a history of optimally-treated chronic HF, LVEF ≤40%, and NT-proBNP ≥200 pg/mL (≥1200 pg/mL with atrial fibrillation). In the expansion phase, patients were randomized 1:1:1 to receive placebo (n = 149), OM at 25 mg BID (n = 150), or 25 mg twice daily with pharmacokinetic-guided increases to 50 mg twice daily (n = 149; OM PK-group) for 20 weeks. Interaction terms were used to assess for a differential effect of OM in the OM PK-group by etiology on various study endpoints. Results: In COSMIC-HF, 287 (64%) had ischemic etiology of HF and 161 (36%) had non-ischemic HF etiology. Previous COSMIC-HF results demonstrated nominally statistically significant changes in all pre-specified secondary efficacy endpoints compared to placebo in the OM PK-group at 20 weeks. The current analyses demonstrate similar findings of efficacy in patients regardless of HF etiology (Table). There was no difference in the change from baseline in troponin after 20 weeks of therapy between the ischemic and non-ischemic OM PK-groups. HF etiology did not modify the effectiveness of OM; there were no significant interaction effects of treatment group with HF etiology for any of these variables (Table). Overall and cardiac adverse events were similar between the placebo and PK-titration groups for patients with ischemic (Subject incidence; Overall: Placebo, 58.4% vs. OM, 62.0%; Cardiac: Placebo, 20.2% vs. OM 20.0%) or non-ischemic (Overall: Placebo, 65.0% vs. OM, 71.7%; Cardiac: Placebo, 30.0% vs. OM 23.9%) etiologies. Conclusion: These data from COSMIC-HF suggest that OM produced similar findings with regard to pharmacodynamic response, cardiac function, heart rate, biomarkers, and adverse events in patients with ischemic and non-ischemic etiology of HF.