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CUPID-2: Gene transfer fails to improve outcomes in HFrEF
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LONDON — The use of gene transfer therapy to correct an enzyme abnormality involved in myocardial contraction and relaxation did not improve outcomes in patients with HF with reduced ejection fraction, according to data presented at the European Society of Cardiology Congress.
The phase 2b CUPID-2 study was based on the observation that the deficiency of sarcoplasmic reticulum CA2+ ATPase (SERCA2a) is linked to progression of HF and that the use of gene transfer to correct this abnormality might improve cardiac function in patients with moderate to severe HF, according to a press release.
Researchers enrolled 250 patients with HF with reduced ejection fraction (HFrEF) and NYHA class II or IV HF due to ischemic or nonischemic cardiomyopathy at 67 centers in the United States, Europe and Israel. Patients were randomly assigned to one dose of gene therapy (n = 121; mean age, 60.3 years; 82.6% men; mean left ventricular ejection fraction, 23%) or placebo (n = 122; mean age, 58.4 years; 80.3% men; mean LVEF, 24%) and were followed for at least 1 year (median follow-up, 17.5 months).
The primary endpoint was time to recurrent events, defined as hospitalizations or ambulatory treatment for worsening HF. The secondary endpoint was time to first terminal event, defined as all-cause death, heart transplant or mechanical circulatory support device implant.
Over the course of follow-up, patients who received gene therapy did not show improvement in the primary or secondary endpoints compared with those who received placebo. Overall, there were 104 recurrent events and 36 terminal events in the gene-therapy group and 128 recurrent events and 29 terminal events in the placebo group (HR = 0.93 [P = .81] and HR = 1.27 [P = .4]).
Barry Greenberg
“CUPID-2 failed to support the hypothesis that AAV1/SERCA2a at the dose used has clinical benefits in patients with moderate to severe HF and reduced ejection fraction. There was no evidence of improvement for these endpoints in any predefined or exploratory subgroup [and] there were no beneficial effects on exploratory efficacy endpoints,” Barry Greenberg, MD, distinguished professor of medicine and director of the advanced heart failure treatment program at University of California, San Diego, and Cardiology Today Editorial Board member, said during a press conference.
Further, no safety concerns with gene therapy emerged, according to Greenberg. The only treatment-emergent serious adverse event occurring in 2% or more of either group was a higher rate of implantable cardioverter defibrillator insertion in the placebo group (4.9% vs. 0%; P = .03). The researchers observed no evidence of cell-mediated immune response; no clinically meaningful changes in vital signs, ECG parameters or arrhythmias on ICD interrogation; and no significant differences related to change in medical therapy during the course of the study, he said.
CUPID-2 is the largest study on gene transfer in this population.
“Although deficiencies in SERCA2a activity and their correction by gene transfer have been demonstrated in animals, it is possible that these findings are not applicable in human heart failure and that raising the level of SERCA2a activity cannot alter the trajectory of the disease,” Greenberg said.
He noted that these data provide important information for future research. – by Katie Kalvaitis
Reference:
Greenberg B, et al. Hot Line V: Heart Failure. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 2, 2015; London.
Disclosure: The CUPID-2 study was funded by Celladon. Greenberg reports consulting for and receiving honoraria from Celladon.