ENCORE: Extension of the ANTHEM-HF Study Evaluating Autonomic Regulation Therapy in Reduced Ejection Fraction Heart Failure

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cardiomyocytes impairs cardiac relaxation and contractility. In animal models of HF, increasing SERCA2a expression by genetic enzyme replacement therapy improves cardiac function and survival. In patients, the phase 2a CUPID 1 trial reported that SERCA2a enzyme replacement with a novel recombinant adeno-associated viral vector containing human SERCA2a cDNA (AAV1/SERCA2a) promoted reverse left ventricular remodelling and improved symptoms, functionality and the clinical course. Purpose: CUPID 2 was a multinational, multicenter, double-blind, placebo controlled, randomized phase 2b trial in 250 patients designed to determine if a single intracoronary infusion of AAV1/SERCA2a, in addition to optimal HF therapy, reduced the rate of HF associated recurrent events (hospitalizations and ambulatory treatment) in patients with moderate to advanced systolic HF. Methods: Patients enrolled in CUPID 2 were between the ages of 18 and 80 years, had a diagnosis of NYHA class II-IV chronic HF of either ischemic or non-ischemic etiology and a left ventricular ejection fraction (EF) of #35% and were at high risk for HF hospitalizations. Patients with circulating neutralizing AAV antibodies (O1.2) were excluded. Eligible patients were randomized in a 1:1 ratio to receive a single intracoronary infusion of either AAV1/SERCA2a or placebo. The primary endpoint was time from treatment to HF-associated recurrent events in the modified intentto-treat population (n5243), defined as patients who received MYDICAR or placebo. Analysis was done using a semi-parametric joint frailty model to account for withinsubject correlated events and informative censoring from terminal events. The secondary efficacy endpoint was time to first terminal event (all-cause death, heart transplant, or LVAD implantation). The study had 80% power at the 0.05 two-sided significance level to detect a 45% recurrent event risk reduction. CUPID2 exceeded the pre-specified 186 adjudicated recurrent events by the time all patients had completed at least 12 months of follow-up (or had terminated early) post-randomization. Results: Treatment with MYDICAR did not result in an improvement in the primary endpoint of recurrent HF events compared to placebo (HR 5 0.93, 95% confidence interval 0.53-1.65; p50.81). The MYDICAR to placebo comparison of the secondary endpoint of all-cause death, need for a mechanical circulatory support device, or heart transplant, likewise failed to show a significant treatment effect. No safety issues were noted. Conclusion: The results of CUPID 2 failed to support the hypothesis that AAV1/SERCA2a improves the clinical course of high risk HF patients with reduced EF.