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HEART FAILURE 2010: Genetically targeted therapy shows promise in severe heart failure

Embargo: Sunday 30 May, 14.15 CET

The risk for clinical cardiovascular (CV) events was reduced by 50% for patients with severe heart failure receiving an innovative genetically targeted enzyme replacement therapy opposed to placebo, reports the CUPID study presented at the Heart Failure Congress 2010, organised by the Heart Failure Association of the European Society of Cardiology, in Berlin (29 May to 01 June 2010) in the Late Breaking Trials Session I (Sunday 30 May, 14.15, Berlin Room, final programme number 112).
Heart Failure

Furthermore, the phase II study showed  that patients treated with MYDICAR® , especially those receiving the highest dose, did better in prospectively defined endpoints in the symptomatic and functional domains of heart failure, along with favourable effects on biomarker levels and cardiac remodelling.

“The results provide the first placebo controlled evidence of efficacy for MYDICAR® and raised no safety concerns. These findings provide strong support for moving forward to Phase III studies using larger numbers of patients conducted over longer periods of time,” said Professor Barry H Greenberg, the presenter of the trial, from University of California San Diego. “MYDICAR® has the potential to change the treatment landscape for patients with severe heart failure by offering us a new tool in the box.”

New treatments, he added, are particularly needed for this group of patients who have yearly mortalities of 10 to 20%, or greater. “Current options for patients with severe heart failure include  cardiac transplantation and left ventricular assist devices, both of which are expensive, can have  problems associated with use and furthermore aren’t applicable to all patients.”

MYDICAR®, is a genetically targeted enzyme replacement therapy designed to restore levels of SERCA2a, an enzyme found in the myocardium that regulates calcium cycling and contractility.  The heart’s ability to contract, and thus to pump blood and maintain oxygenation of the body, is determined by a continual re-loading of the sarcoplasmic reticulum with calcium ions.  Studies have established  clear associations between depleted SERCA2a enzymes in cardiac cells and progression of end stage heart failure. “As the heart begins to fail the SERCA2a levels get depressed, leading to a vicious cycle where the heart fails even more,” explained Greenberg.

With MYDICAR®, developed by CelladonCorporation (La Jolla, California), the SERCA2a gene is delivered using recombinant adeno-associated viral vector (AAV), a naturally occurring virus that approximately 90% of the population have been exposed to with no evidence of harm.  MYDICAR® is provided in a single dose delivered directly into the coronary arteries  during a short outpatient procedure, performed in a standard cardiac catheterization laboratory via a small incision in the upper leg.  MYDICAR® is then carried to the heart muscle where it is taken up within the cells of the heart. Previous studies using reagents similar to MYDICAR® have shown delivery of the SERCA2a gene to skeletal muscle in humans results in persistence of gene activity for longer than four years.

The CUPID (Calcium Up-regulation by Percutaneous administration of gene therapy In cardiac Disease) trial enrolled 37 patients from 16 centres in the US with NYHA Class III and IV.  Additional inclusion criteria  included being aged 18 to 75 years, having ischemic or non-ischemic cardiomyopathy, maximal oxygen consumption of <20 mL/kg/min, left ventricular ejection fraction less than 35% and ICDs implanted. In the study, patients were randomised  to placebo (N=14),  low dose MYDICAR® (6x 10 11 DNase Resistant Particle, N=8); mid does MYDICAR(R)  (3x10 12 DNase Resistant Particle, N=8) or high dose (1x10 13 DNase Resistant Particle,N=9) . All patients received standard treats including beta blockers, angiotensin converting enzyme inhibitors and diuretics.


Results of the primary analysis, undertaken after six months showed:

  • For the functional domain there was evidence of less deterioration with MYDICAR® than placebo in distance covered during a six-minute walk test and on peak oxygen consumption on a treadmill (V02max)
  • For the symptomatic domain, New York Heart Association Functional classification (NYHA,  a way of classifying the extent of heart failure ) and the Minnesota Living with Heart Failure Questionnaire (MLWHFQ, measuring the effects of heart failure and treatments on an individual’s quality of life), MYDICAR®  produced favourable effects compared to placebo
  • For the biomarker domain, increases seen in placebo treated patients were not observed in patients  treated with MYDICAR®
  • For the remodelling domain, MYDICAR® treatment was associated with less reduction in left ventricular ejection fraction compared to placebo and with a reduction in left ventricular end-systolic volume (as compared to an increase in  placebo treated patients)
  • The risk of  multiple clinical CV events (defined as worsening heart failure, use of left ventricular assist devices, transplant and death) was reduced by 50 % for patients taking the highest dose of MYDICAR® in comparison to those taking placebo (HR 0.50, CI 0.026-0.497, P=0.040)
  • The duration of cardiovascular hospitalisation was 2.1+_ 3 (should underscore be there) for patients taking placebo, compared to 0.2 +-0.7 days for patients taking the high dose of MYDICAR® (p=0.08)
  • There were no signals of greater adverse events among those taking MYDICAR®.
    “Throughout the study for all of the effects there appears to be greater benefit for patients taking the higher dose of MYDICAR® than the lower doses,” added Greenberg.

Notes to editor

CUPID is presented as part of the Late Breaking Trials - Session I on Sunday 30 May  2010 - 14.15 - 15.45 - Room Berlin

Heart Failure Congress 2010 is organised by Heart Failure Association of the ESC, and takes place from 29 May 2010 - 01 Jun 2010 at ICC Berlin in Germany

The mission of the HFA of the ESC is to improve quality of life and longevity, through better prevention, diagnosis and treatment of heart failure, including the establishment of networks for its management, education and research.

The European Society of Cardiology (ESC) represents more than 62,000 cardiology professionals across Europe and the Mediterranean. Its mission is to reduce the burden of cardiovascular disease in Europe.