Benzinga | Jun 30, 2021 07:31AM EDT

Cytokinetics Highlights Presentation Of Additional Results From GALACTIC-HF At European Society of Cardiology Heart Failure 2021

Cytokinetics, Incorporated (NASDAQ:CYTK) today announced that additional results from GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) were presented at Heart Failure 2021, an International Congress of the European Society of Cardiology, including a prespecified subgroup analysis of the influence of atrial fibrillation or flutter (AFF) on the treatment effect of omecamtiv mecarbil in a Late Breaking Clinical Trial Session. Other analyses were presented in the Clinical Trial Updates Session related to which patients in GALACTIC-HF achieved an increased treatment effect with omecamtiv mecarbil.



"These new analyses add to other data from GALACTIC-HF underscoring that patients with markers of more severe heart failure derived greater treatment benefit from omecamtiv mecarbil," said Fady I. Malik, M.D., Ph.D., Cytokinetics' Executive Vice President of Research & Development. "Many patients with severe heart failure still remain at risk, despite available guideline-directed therapy. Omecamtiv mecarbil may offer a new treatment option for these more severe heart failure patients who are also in greatest need."

GALACTIC-HF: Patients Without Atrial Fibrillation or Flutter Have Increased Treatment Effect with Omecamtiv Mecarbil

Scott Solomon, M.D., the Edward D. Frohlich Distinguished Chair, Professor of Medicine, Harvard Medical School and Director of Noninvasive Cardiology, Brigham and Women's Hospital, presented additional analyses from GALACTIC-HF assessing how baseline AFF in patients impacted the effectiveness of omecamtiv mecarbil in GALACTIC-HF. Of the 8,256 patients enrolled in GALACTIC-HF, 2,245 patients (27%) had AFF at baseline; these patients were older, more likely to be randomized as inpatients, had a higher New York Heart Association (NYHA) class and had higher NT-proBNP compared to patients without AFF. The effect of treatment with omecamtiv mecarbil on the primary composite endpoint of heart failure events (heart failure hospitalization and other urgent treatment for heart failure) or cardiovascular (CV) death was greater in patients without baseline AFF compared to those patients with AFF at baseline (interaction p=0.012). Importantly, the modification of the treatment effect by AFF was concentrated in patients with AFF using digoxin (n=692) with minimal evidence of effect modification in patients with AFF not using digoxin (n=1553). Digoxin did not modify the treatment effect of omecamtiv mecarbil in patients without AFF. These findings suggest caution should be exercised when treating patients with AFF using both digoxin and omecamtiv mecarbil. Interestingly, given prior observations of the positive impact of omecamtiv mecarbil on left atrial function, an exploratory analysis from GALACTIC-HF indicated fewer serious adverse events of atrial fibrillation in patients without AFF at baseline in patients treated with omecamtiv mecarbil compared to placebo (55 events in 2,974 patients treated with omecamtiv mecarbil vs. 78 events in 3,013 patients treated with placebo, p=0.046).

GALACTIC-HF: Patients with Higher Baseline NT-proBNP Have Increased Treatment Effect with Omecamtiv Mecarbil

In a separate analysis, John McMurray, M.D., Professor of Medical Cardiology & Honorary Consultant Cardiologist, Institute of Cardiovascular & Medical Sciences, BHF Cardiovascular Research Centre, University of Glasgow, presented analyses on the effect of treatment with omecamtiv mecarbil according to baseline NT-proBNP in patients without AFF, as well as in all patients in GALACTIC-HF. NT-proBNP is a biomarker of ventricular wall stress in which higher levels reflect more severe heart failure. Among the 5,971 patients who did not have AFF, the median (Q1, Q3) NT-proBNP level was 1,675 (812-3579 pg/ml). In patients without AFF, the treatment effect of omecamtiv mecarbil on the primary composite endpoint was increased in patients with a baseline NT-proBNP above the median (hazard ratio, 0.81; 95% confidence interval 0.73-0.90) compared to patients with baseline NT-proBNP equal to or below the median (HR, 0.94; 95% CI 0.80-1.09; interaction p=0.095). The same pattern was observed in the overall population in which patients with a baseline NT-proBNP greater than the median experienced an increased treatment effect (HR, 0.88; 95% CI 0.80-0.96) compared to patients with a baseline NT-proBNP equal to or below the median (HR, 1.01; 95% CI 0.90-1.15; interaction p=0.035.) Examined as a continuous variable, there was an interaction between treatment with omecamtiv mecarbil and baseline NT-proBNP that showed an increased treatment effect on the primary outcome in patients as baseline NT-proBNP increased both in those without AFF (interaction p=0.024) and in the overall population (interaction p=0.005). These findings suggest the benefit of treatment with omecamtiv mecarbil increased progressively as baseline NT-proBNP increased consistent with other analyses from GALACTIC-HF that suggest more severe heart failure patients may derive increased benefit from treatment with omecamtiv mecarbil.

GALACTIC-HF: Patients with Severe Heart Failure Have Increased Treatment Effect with Omecamtiv Mecarbil

Michael Felker, M.D., Professor of Medicine, Duke Clinical Research Institute presented an analysis of the treatment effect of omecamtiv mecarbil on the primary composite endpoint in patients from GALACTIC-HF classified as having severe heart failure based on modified criteria from the Heart Failure Association of the European Society of Cardiology (ESC-HFA) advanced heart failure position statement. Patients in this subgroup had NYHA class III-IV symptoms, EF ? 30%, and hospitalization for heart failure within the prior six months. Of patients enrolled in GALACTIC-HF, 2,258 (27%) met these criteria for severe heart failure. Patients with severe heart failure had markers of more advanced disease and higher baseline risk, with event rates in patients treated with placebo that were approximately twice those of patients without severe heart failure. In patients with severe heart failure, the treatment effect of omecamtiv mecarbil on the primary composite endpoint was increased (HR, 0.80; 95% CI 0.71-0.90) compared to patients without severe heart failure (HR, 0.99; 95% CI 0.91-1.08; interaction p=0.005). The results for CV death were qualitatively similar; patients with severe heart failure experienced a trend towards treatment benefit from omecamtiv mecarbil (HR, 0.88; 95% CI 0.75-1.03) while patients without severe heart failure did not (HR, 1.10, 95% CI 0.97-1.25; interaction p=0.028). Furthermore, as the severity of heart failure increased, as indicated by the number of the three severity criteria met, both the incidence of the primary composite endpoint and the treatment effect of omecamtiv mecarbil increased. Omecamtiv mecarbil was equally well tolerated in patients with and without severe heart failure, with no significant changes in blood pressure, renal function, or potassium compared to placebo. These results from GALACTIC-HF demonstrate a potentially clinically important treatment effect of omecamtiv mecarbil in patients with severe heart failure.

About Omecamtiv Mecarbil and the Phase 3 Clinical Trials Program

Omecamtiv mecarbil is an investigational selective cardiac myosin activator, the first of a novel class of myotropes1 designed to directly target the contractile mechanisms of the heart, binding to and recruiting more cardiac myosin heads to interact with actin during systole. Preclinical research has shown that omecamtiv mecarbil increases cardiac contractility without increasing intracellular myocyte calcium concentrations or myocardial oxygen consumption.2-4 Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction.

Omecamtiv mecarbil is being developed for the potential treatment of HFrEF and is the subject of a comprehensive Phase 3 clinical trials program composed of GALACTIC-HF and METEORIC-HF. The results from GALACTIC-HF, published in the New England Journal of Medicine, demonstrated a statistically significant effect of treatment with omecamtiv mecarbil to reduce risk of the primary composite endpoint of time to first heart failure event (heart failure hospitalization and other urgent treatment for heart failure) or cardiovascular (CV) death compared to placebo in patients treated with standard of care (hazard ratio, 0.92; 95% confidence interval [CI] 0.86, 0.99; p=0.025). No reduction in the secondary endpoint of time to CV death was observed in the overall population.5 Supplemental analyses indicated a greater treatment effect in patients with a lower LVEF (LVEF ?28%, n=4,456, hazard ratio, 0.84; 95% CI 0.77, 0.92; interaction p=0.003). Effects in GALACTIC-HF were observed without evidence of an increase in the overall rates of myocardial ischemic events, ventricular arrhythmias or death from cardiovascular or all causes.