Presentation Abstract

Session: AOS.502.01-Novel Cell, Tissue Engineering and Gene-Based Strategies for Heart Failure
Presentation: 10667 - Long Term Follow-up of Patients With Advanced Heart Failure Following a Single Intracoronary Infusion of Aav1/serca2a
Pres Time: Tuesday, Nov 19, 2013, 9:00 AM - 9:15 AM
Location: Hall B-5
Pres. Time: Tuesday, Nov 19, 2013, 9:00 AM - 9:15 AM
Specialty: +502. Cell, Tissue Engineering, and Gene Based Therapies
Keywords: Heart failure; Gene therapy; Calcium; Excitation-contraction coupling (ECC); Sarcoplasmic reticulum
Authors: Krisztina Zsebo, Alex Yaroshinsky, Jeffrey Rudy, Kim Wagner, Celladon, San Diego, CA; Mariell Jessup, Univ of Pennsylvania Heart and Vascular Ctr, Philadelphia, PA; Barry Greenberg, UCSD Medical Ctr, La Jolla, CA; Roger Hajjar, Mount Sinai Sch of Med, New York, NY
Abstract: The Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID) study was a phase 1/phase 2 first-in-human clinical gene therapy trial using adeno-associated type 1 vector (AAV1) carrying the cardiac sarcoplasmic reticulum ATPase pump (SERCA2a) which was injected in patients with advanced heart failure. Although improvements in clinical events were reported 12 months following a single intracoronary infusion of AAV1/SERCA2a, the long term effects of gene therapy in these patients are unknown. In the present report, the final 3-year follow-up of the patients in CUPID is presented.
A total of 39 patients with advanced HF who were on stable therapy were randomized to receive intracoronary infusion of AAV1/SERCA2a (MYDICAR®) in one of 3 doses (low dose - 6 x 1011 DRP [DNAse Resistant Particles], middle dose - 3 x 1012 DRP and high dose - 1 x 1013 DRP) versus placebo. Clinical events such as worsening heart failure, ventricular assist device (VAD) placement, cardiac transplantation, intravenous inotropic treatment, myocardial infarction and death were longitudinally tracked. Three years post-administration, 13 deaths occurred in total and the survival probability over time tended to be higher for patients in all AAV1/SERCA2a groups compared to the placebo group, but especially in the high dose AAV1/SERCA2a group, in which there was a trend for better survival versus placebo (p=0.11, log rank test) as shown in the figure. Throughout the 3 years of follow-up, the number of clinical events was high in the placebo group and high but delayed in the low and mid dose groups. Few events occurred in the high dose group where we found evidence of transgene expression. No safety concerns were noted following gene transfer of AAV1/SERCA2a.
The long term results presented here are promising and indicate that AAV1/SERCA2a gene therapy may offer a new therapeutic strategy for the treatment of HF.
Disclosures:   K. Zsebo, CELLADON Corporation, Significant,Employment; CELLADON Corporation, Significant,Ownership Interest; A. Yaroshinsky, CELLADON Corporation, Significant,Employment; CELLADON Corporation, Significant,Ownership Interest; J. Rudy, CELLADON Corporation, Significant,Employment; CELLADON Corporation, Significant,Ownership Interest; K. Wagner, CELLADON Corporation, Significant,Employment; CELLADON Corporation, Significant,Ownership Interest; M. Jessup, None; B. Greenberg, Gilead, Modest,Speakers Bureau; GE Healthcare, Modest,Consultant/Advisory Board; Alere, Modest,Consultant/Advisory Board; Gambro, Modest,Consultant/Advisory Board; Otsuka, Significant,Speakers Bureau; Novartis, Significant,Consultant/Advisory Board; Celladon, Significant,Consultant/Advisory Board; Zensun, Significant,Consultant/Advisory Board; R. Hajjar, CELLADON Corporation, Modest,Ownership Interest; IP, Ownership, Significant,Ownership Interest.

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