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A novel approach to gene therapy appears to benefit patients with severe heart failure, according to results of a phase II trial published online June 27, 2011, ahead of print in Circulation. The therapy aims to increase the expression of an enzyme that is deficient in the cardiomyocytes of failing human hearts.

For the CUPID (Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease) trial, researchers led by Mariell L. Jessup, MD, of the Hospital of the University of Pennsylvania (Philadelphia, PA), randomized 39 patients with advanced heart failure to receive intracoronary infusion of placebo or gene therapy consisting of the enzyme—sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a)—delivered directly to the heart muscle during routine cardiac catheterization. An adeno-associated virus type 1 vector was used to deliver the gene therapy.

Gene therapy was administered in 3 doses:

• Low: 6 × 10¹¹ DNase-resistant particles (DNP; n = 8)
• Mid: 3 × 10¹² DNP (n = 8)
• High: 1 × 10¹³ DNP (n = 9)

Results were assessed based on clinical outcomes as well as 7 efficacy parameters across 4 domains:

• Symptom: New York Heart Association (NYHA) class and Minnesota Living With Heart Failure Questionnaire (MLWHFQ)
• Functional status: 6-minute walk test and peak maximum oxygen consumption (VO₂)
• Biomarker: N-terminal prohormone brain natriuretic peptide (NT-proBNP)
• LV function/remodeling: ejection fraction and end-systolic volume

Positive Outcomes in High-Dose Group

Patients who received the highest gene-therapy dose met the prespecified criteria for success across all 7 efficacy parameters on multiple analyses at both the group and individual levels as well as with respect to cardiovascular hospitalizations at 6 months. These benefits were confirmed at 12 months.

At 6 months, the high-dose group showed improvement or stabilization across all reported parameters (table 1).

Table 1. Mean Changes in Parameters from Baseline to 6 Months

^a P < 0.02 vs. placebo.
^b Clinically significant worsening.

By 12 months, high-dose patients also experienced significant increases in time to clinical events and a decreased frequency of cardiovascular events (HR 0.12; 95% CI 0.03-0.49; P = 0.003). In addition, the mean duration of cardiovascular hospitalizations over 12 months was substantially shorter compared with placebo (0.4 vs. 4.5 days; P = 0.05).

Importantly, no major safety concerns arose during the trial.

New Treatment Paradigm?

“Many people are looking for new ways to treat heart failure,” Dr. Jessup told TCTMD in an e-mail communication. “It is a real unmet clinical need. The CUPID trial is exciting for many reasons, but mostly because it represents a gene study designed to address myocardial dysfunction. . . . It was a small study, but we believe [it provides evidence] of efficacy. It will have to be replicated in a larger study, of which plans are underway.”

According to Dr. Jessup, this novel gene therapy approach could feasibly be performed on a large scale, something that will hopefully be borne out as the method is evaluated in larger trials.

In a telephone interview with TCTMD, Warren Sherman, MD, of Columbia University Medical Center (New York, NY), agreed. “It’s a fairly simple delivery strategy—a simple coronary infusion,” he said. In contrast, stem cell-based strategies involve interrupting coronary flow in order to give time for progenitor cells to be absorbed into the coronary system, Dr. Sherman explained, adding that “since this is an off-the-shelf product, it doesn’t involve aspirating bone marrow, sourcing stem cells from the patient, or having to put patients through other challenging preparatory procedures.”

“Fortunately the adverse events were quite low, and this hasn’t always been the expectation with viral vectors,” he continued. “These are fairly strong signals . . . that suggest that this may be a viable approach to patients with heart failure or at least heart failure as manifested clinically in this patient population.”

To date, gene therapy has been limited to improving viability of cardiomyocytes, not increasing perfusion, so it cannot be used as a therapy for ischemic disease, an area where stem cell-based therapies hold some promise, Dr. Sherman explained. “Nevertheless, heart failure is such a colossal problem in the United States that having the focus narrowed to [this] population is not a small target population by any means,” he noted, stressing that this patient population truly requires novel forms of treatment.

Study Details

The trial’s prespecified definition of success was based on achieving efficacy at 6 months in the following:

• Concomitant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter
• Predefined clinically meaningful changes in 7 efficacy parameters
• Improvements in cardiovascular hospitalizations and time to terminal events

For success to be confirmed, efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. Based on these criteria, the likelihood of success due to chance was calculated to be 2.7%.

 

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Source:
Jessup M, Greenberg B, Mancini D, et al. Calcium Upregulation by Percutaneous administration of gene therapy In cardiac Disease (CUPID): A phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca²⁺-ATPase in patients with advanced heart failure. Circulation. 2011;Epub ahead of print.

 

 

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