Abstract
Aim: JNJ-54452840 (COR-1) is a novel investigational cyclopeptide with proposed mechanism of action that decreases circulating anti-β1-adrenergic receptor antibodies (anti-β1-Abs) in heart failure patients. In a phase-2, double-blind, placebo-controlled pilot study, effects of JNJ-54452840 were investigated on cardiac function at rest in patients with Dilated Cardiomyopathy (DCM) when administered in addition to guideline-recommended heart failure therapy versus 6-months of guideline-recommended therapy alone. Methods: Patients with DCM and circulating anti-β1-Abs received treatment with placebo or JNJ-54452840 (6 doses of 20, 80 or 160 mg administered intravenously every 4 weeks) in addition to guideline-recommended heart failure therapy. Results: Thirty-six patients (Caucasian, mean age 59.6 years, mean LVEF 32%) were enrolled. An increase (+5.4%) in centrally-assessed Left Ventricular Ejection Fraction (LVEF) was observed in 80 mg JNJ-54452840 group compared to a decrease (-1.6%) in the placebo group (primary efficacy endpoint). Among secondary efficacy endpoints, locally-assessed LVEF values were similar to primary results, suggesting lack of treatment effect from baseline to month 9. NT-proBNP values varied considerably between patients but were not significantly improved in JNJ-54452840-treated groups versus placebo. Compared to baseline, both JNJ-54452840 and placebo groups demonstrated a numerical increase in 6-minute walk test from baseline to month 6. The most common adverse events reported among JNJ-54452840-treated patients were cardiac failure and nasopharyngitis (n=4 each), and cough, sinusitis, increased heart rate (n=3 each). Conclusion: Considering that this phase 2 trial, originally planned to recruit 160 patients was amended to a pilot study for strategic reasons, no definitive statements on the efficacy of JNJ-5445280 in DCM patients with circulating anti-β1-Abs can be made, although centrally-assessed LVEF appeared to improve in the 80 mg dose group. No compound-related safety or tolerability signals were observed.
Highlights
Dilated Cardiomyopathy (DCM) is one of the major pathophysiological conditions causing cardiac chamber dilatation and left ventricular remodelling, often resulting in heart failure [1]
Men or women aged between 18−75 years with a diagnosis of heart failure due to DCM, New York Heart Association class II/III, Left Ventricular Ejection Fraction (LVEF)
The original study was converted to a pilot study instead of the initially-conceived phase 2 study of 160 patients, which would have allowed for a full statistical analysis
Summary
Dilated Cardiomyopathy (DCM) is one of the major pathophysiological conditions causing cardiac chamber dilatation and left ventricular remodelling, often resulting in heart failure [1]. In the Western population, annual incidence of DCM amounts to 100 patients/million, and is prevalent in 400 patients/million [1]. Anti-β1-Abs are considered negative prognostic markers that have been shown to be associated with a greater reduction in left ventricular function [3,4], and an increase in the prevalence of serious ventricular arrhythmias [3,5], sudden cardiac death [5], and cardiovascular mortality [3,6]. Development of new therapeutic strategies that potentially neutralize these autoantibodies may provide a viable alternative for the treatment of heart failure [7,8,9]
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