Chicago, IL - The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial failed to reach its primary efficacy end point of improving local or global cardiac contractility in patients with ischemic heart failure, but study investigators believe safety results and secondary outcomes of the study are still "encouraging" [1].

Dr Philippe Menasché

Presenting the results during the final late-breaking clinical-trials session here at the American Heart Association 2006 Scientific Sessions, Dr Philippe Menasché (Hôpital Européen, Paris, France) noted that neither a high nor a low dose of autologous skeletal muscle-cell injections improved regional contractility in the cell-transplanted infarcts or increased left ventricular ejection fraction (LVEF), measured by echocardiography. On a more positive note, the high-dose treatment did appear to reduce LV volumes, and no increase in arrhythmias was seen with myoblast therapy.

"With this particular protocol . . . we could not demonstrate, by echo, an improvement in regional or global function, but . . . there was clear evidence for reversal of remodeling—less dilation of the heart, which as you know may have some prognostic implications," Menasché commented. "So I think these are encouraging signals and this certainly justifies further exploring this strategy."

No magic bullet

The phase 2 MAGIC trial compared a placebo injection (of medium without active cells) with either a high- or a low-dose injection of myoblasts. Cells were initially harvested via muscle biopsy from patients' own thigh muscles and expanded at two specialized facilities (one in Paris, France and one in Cambridge, MA), where cell viability was verified to be 95% and myoblast purity to be 89%. MAGIC was originally designed to enroll 300 patients but was stopped early, with an intended enrollment of 120, after the data safety and monitoring board determined that the study was unlikely to show a benefit of treatment. Ultimately, only 97 patients with ischemic heart failure were actually randomized at 24 European centers. To be eligible for the trial, patients had to have reduced LVEF (15%-35%), a history of MI, and planned CABG.

The low-dose group (n=33) received approximately 400 million myoblasts delivered to 30 locations within and around the infarct site during the CABG procedure; the high-dose group (n=30) received roughly 800 million cells. Thirty-four patients were randomized to placebo treatment. Because of suggestions from earlier studies that cell transfer might be proarrythmogenic, all study participants also received implantable cardiac defibrillators before hospital discharge to monitor any increase in arrhythmias.

But, as Menasché told the session audience today, there were no signals of safety concerns in either of the cell-transfer groups over six months: major adverse cardiac event rates and ventricular arrhythmias were no different between the groups. None of the deaths in the myoblast groups were attributable to the procedure or to arrhythmias. Disappointingly, however, the coprimary efficacy end point of change in regional wall motion—defined as recovery of infarcted segments—and change in LVEF, as measured by echocardiography, was no different between either the high- or low-dose groups and the placebo group at six-month follow-up. More promising, measurements of LV end-diastolic volumes and LV end-systolic volumes showed that although patients' hearts that were significantly dilated at baseline showed no change in the placebo or low-dose groups at six months, dilation appeared to decrease in the high-dose group.

In a subset of patients in each group, LVEF was also measured using radionuclide angiography. In these patients, the absolute change in LVEF in the high-dose group was 3%, significantly greater than in the placebo group, where LVEF was unchanged from baseline at six months.

"The MAGIC study failed to reach its primary end point, but the negative study results need to be [viewed alongside] more positive data on LV volumes," Menasché said. "There is clear evidence for a reduction in remodeling in the high-dose group," he concluded.

Challenges ahead

Dr Timothy J Gardner

Commenting on the study, Dr Timothy J Gardner (Christiana Care Health Services, Wilmington, DE) observed, "The fact that the ventricular volumes were diminished certainly has us wondering whether this will result in a long-term clinical benefit. The challenge in the future is to have lots of patients randomized, but this is certainly an interesting study."

The actual method of delivering cells during open-heart surgery, as was done in MAGIC, limits its appeal, Menasché conceded. "Can we deliver the cells in a less invasive way? The answer clearly is yes," he said. "I'm sorry to say that, as a surgeon, but I must recognize that if the technique overall has a future it will probably be catheter-based."

To heartwire, Gardner agreed there is "no great enthusiasm for proceeding with a surgical approach. I wouldn't characterize this trial as completely negative, but certainly if this strategy is to move forward it's likely going to be in with a catheter-based approach."

The scheduled discussant for the MAGIC trial, Dr Richard D Weisel (University of Toronto, ON), congratulated Menasché and colleagues for conducting such a well-designed study, which he called "substantially better than any of the other surgical trials [of cell-based therapies] reported so far."

Early termination of the study, however, limits interpretation of the results, Weisel noted. "There is evidence of a beneficial effect, but we're in a quandary. . . . We can't recommend this therapy to our patients but we do recognize an unmet medical need."

Subsequent studies should confirm suggestions from this and other research that myoblast transfer reduces the tendency of infarcted myocardium to thin and dilate, he said, but future cell-based therapies should also address ways of boosting angiogenesis and cardiac rejuvenation, either through gene enhancement or cytokine-eluting biomaterials, Weisel suggested.