"It could very well be that [unfractionated] bone marrow is a weaker product than using a specific cell type," said Dr. Perin. "Now we’ll start using parts of bone marrow, specific cells or cell combinations," he predicted, although he added that additional analysis of the FOCUS-CCTRN data must occur before he and his associates decide which cell types show the most promise. "Even though it’s not answered perfectly, the results definitely point us toward" using more selected types of bone marrow cells, he said.
"The most important lesson FOCUS-CCTRN showed was that as patients get older the number and potency of their stem cells decreases. It showed that if you give cells that aren’t potent they won’t work," said Dr. Henry, a co-investigator of the study and an active member of CCTRN. "That’s a really important insight, because if you treat patients with 100 mg of a beta blocker you get a consistent effect, but if you treat patients with autologous stem cells, every patient gets something different."
Development of stem cell therapies "has been on a normal track; each step takes time. It’s very similar to what happened with fibrinolytic therapy for treating acute myocardial infarctions" in the 1980s and 1990s, said Dr. Timothy D. Henry.
"The FOCUS results showed some evidence of an effect, but there are a number of ways to make it better," Dr. Henry said. One approach is to use selected cells, such as CD34+ cells. Another strategy is to deliver allogenic cells obtained initially from young and healthy donors, a way to avoid the issue of older patients and those with co-morbidities who may have compromised stem cells.
Administering selected or allogenic cells has another potential advantage: it opens the door to commercial involvement with a potentially saleable product, a strategy that can attract the interest of a company willing to shoulder the cost of a phase III trial.
"A challenge with [unprocessed] bone marrow is it’s too easy. Bone marrow is inexpensive, and anyone can do it," Dr. Henry noted. That’s one reason why it took several years for the REPAIR-AMI strategy to advance into a phase III trial, eventually moving forward when it received financial backing from the European Union. In contrast, the promising ACT34-CMI strategy quickly jumped to the phase III level, aided by financial support from Baxter.
But others cautioned against drawing too many inferences from FOCUS-CCTRN because it was a negative study and hence all its results must be considered suspect.
"I do not believe that post-hoc analysis of cell potency should be used to guide future trials. FOCUS was negative; the subgroup analyses and cell potency assays were attempts to glean some positivity from that study after the fact," said Dr. Marbán.
More Phase III Studies Coming, with Commercial Support
Another example of a selected, allogenic cell preparation with commercial support is the study of mesenchymal precursor cells (MPC), bone-marrow cells obtained from young, healthy donors and delivered by transendocardial injection to 45 patients with cardiomyopathy, New York Heart Association class II or III heart failure, and impaired left ventricular function in a phase II study presented by Dr. Perin last November at the American Heart Association’s Scientific Sessions in Orlando. The MPC preparation he and his associates tested was an "off-the-shelf" stem-cell product made by the Australian-based company Mesoblast.
The injections were safe, and the three different amounts of cells delivered showed various signs of efficacy. The lowest dose of cells tested showed a statistically significant improvement in left ventricular ejection fraction at 3 months compared with placebo; the highest cell dose tested showed a statistically significant improvement in left ventricular end-systolic volume at 12 months compared with the placebo control; and collectively, all three cell doses tested produced a statistically significant 20% reduction in the rate of major adverse coronary events compared with the placebo patients during a follow-up of up to 3 years, Dr. Perin reported last November.
"Given the very positive results we saw in the phase II trial, it would be logical to move on to a bigger trial," said Dr. Perin in an interview, but he added that he was unable to provide details about possible additional trials with this MPC product.
Another commercially-backed stem-cell product poised for a larger trial is cardiopoietic stem cells, made by a proprietary, patented method that uses a patient’s autologous bone-marrow stem cells and treats them in vitro to produce cells that are then injected into a patient’s myocardium where they produce new heart muscle. Researchers at the Mayo Clinic in Rochester, Minn. developed this process, and Mayo licensed it to a Belgian company, Cardio 3 BioSciences.