Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase 1/2 Clinical Trial

doi:10.1016/j.cardfail.2009.01.013

Journal of Cardiac Failure

Volume 15, Issue 3, April 2009, Pages 171-181

https://doi.org/10.1016/j.cardfail.2009.01.013 Get rights and content

Abstract

Background

SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer in patients with advanced HF.

Methods and Results

A total of 9 patients with advanced HF (New York Heart Association [NYHA] Class III/IV, ejection fraction [EF] ≤30%, maximal oxygen uptake [VO₂ max] <16 mL·kg·min, with maximal pharmacological and device therapy) received a single intracoronary infusion of AAV1/SERCA2a in the open-label portion of this ongoing study. Doses administered ranged from 1.4 × 10¹¹ to 3 × 10¹² DNase resistant particles per patient. We present 6- to 12-month follow-up data for these patients. AAV1/SERCA2a demonstrated an acceptable safety profile in this advanced HF population. Of the 9 patients treated, several demonstrated improvements from baseline to month 6 across a number of parameters important in HF, including symptomatic (NYHA and Minnesota Living with Heart Failure Questionnaire, 5 patients), functional (6-minute walk test and VO₂ max, 4 patients), biomarker (NT-ProBNP, 2 patients), and LV function/remodeling (EF and end-systolic volume, 5 patients). Of note, 2 patients who failed to improve had preexisting anti-AAV1 neutralizing antibodies.

Conclusions

Quantitative evidence of biological activity across a number of parameters important for assessing HF status could be detected in several patients without preexisting neutralizing antibodies in this open-label study, although the number of patients in each cohort is too small to conduct statistical analyses. These findings support the initiation of the Phase 2 double-blind, placebo-controlled portion of this study.

Section snippets

Study Overview

The CUPID trial is a multicenter, Phase 1/2 trial. The Phase 1 portion is an open-label, sequential dose escalation study. The Phase 2 portion is a randomized, double-blind, placebo-controlled, parallel-group, dose ranging, feasibility trial that compares the use of intracoronary administered AAV1/SERCA2a at 2 or 3 dose levels with placebo. Detailed information about the study design rationale and protocol has been published elsewhere.⁴ Patient data available through mid-September 2008 were

Results

The results include data from the Phase 1 portion of this ongoing study for Cohorts 1 and 2 (12-month follow-up), and Cohort 3 (6-month follow-up).

Discussion

Despite pharmacological and device therapies, morbidity and mortality in HF is significant, and hence investigation of new therapeutic platforms such as cell and gene therapies is warranted. In this first in man study of gene transfer in HF, AAV1/SERCA2a appears to have an acceptable safety profile, given the high expected morbidity and mortality in the HF study population.34, 36, 37 These data are consistent with the safety profile established for other recombinant AAV vectors, which has been

Conclusions

Early results of the Phase 1 open label portion of this first-in-human study of AAV1/SERCA2a in advanced HF showed no unexpected safety concerns. Biological activity was assessed across independent parameters important in evaluation of HF status. Although the number of patients in each cohort was small, quantitative evidence of biological activity could be detected in individual patients without preexisting NAbs. Further clinical evaluation is therefore warranted.

Acknowledgments

The authors would like to thank Anthony N. DeMaria, MD, and Ajit B. Raisinghani, MD, for their evaluation of echocardiograms at the UCSD Medical Center Echocardiography Core Laboratory; Craig A. Thompson, MD, MMSc, for his contribution to the infusion protocol method; Jeffery J. Rudy for managing the study; Kim Wagner, MA, for manuscript preparation; and Alex Yaroshinsky, PhD, for data summaries and assessment of clinically meaningful changes in efficacy end points.

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: Funding for this study was provided by Celladon Corporation, La Jolla, CA. RJH is supported in part by grants from the National Institutes of Health: R01 HL078691, HL080498, HL 78731, HL083156, and a Leducq Transatlantic Network.

: R.J. Hajjar: Celladon Corporation, ownership interest (includes stock and stock options, and rights in patents); D.M. Mancini, Celladon Corporation, consultant/advisory board; B. Greenberg, Celladon Corporation, consultant/advisory board; H. Dittrich, Celladon Corporation, ownership interest (includes stock options), consultant/advisory board; K. Borow, Celladon Corporation, significant, consultant/advisory board; K.M. Zsebo, Celladon Corporation, employment.

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Clinical TrialCalcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase 1/2 Clinical Trial

Abstract

Background

Methods and Results

Conclusions

Section snippets

Study Overview

Results

Discussion

Conclusions

Acknowledgments

Lancet

J Card Fail

Mol Ther

Surg Clin North Am

Am J Transplant

J Am Coll Cardiol

J Mol Cell Cardiol

Blood

J Card Fail

J Clin Epidemiol

Chest

J Am Coll Cardiol

Mol Ther

Mol Ther

J Mol Cell Cardiol

Heart Disease and stroke statistics—2009 update. A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee

Circulation Epub

Implantable left ventricular assist devices

N Engl J Med

Overwhelming evidence of the beneficial effects of SERCA gene transfer in heart failure

Circ Res

Modulation of ventricular function through gene transfer in vivo

Proc Natl Acad Sci

Gene therapy in the treatment of heart failure

Physiology

Heart failure: a silver bullet to treat heart failure

Gene Ther

Relation between myocardial function and expression of sarcoplasmic reticulum Ca2+–ATPase in failing and nonfailing human myocardium

Circ Res

Unchanged protein levels of SERCA II and phospholamban but reduced calcium2+ uptake and calcium2+–ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts

Circulation

Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium

Circ Res

Clinical Trial
Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase 1/2 Clinical Trial

Relation between myocardial function and expression of sarcoplasmic reticulum Ca²⁺–ATPase in failing and nonfailing human myocardium

Unchanged protein levels of SERCA II and phospholamban but reduced calcium²⁺ uptake and calcium²⁺–ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts