BioWorld International Correspondent

BOSTON - Stem cells now are in the clinic, but the ability to make any profit from them still is in doubt, despite the fact that they offer the hope of therapies for many intractable diseases. "A number of cell therapies have been commercialized in the past 15 years, but none are commercially successful," John McPherson, head of biological products R&D at Genzyme Corp., told delegates at the BIO 2007 Convention.

Genzyme has commercialized three cell therapies and carried out clinical trials of three others that failed to show efficacy. Most recently, in December, the company halted a trial of a cell therapy for acute renal failure.

"We know the challenges," McPherson said. One of the main issues is the regulatory landscape. While Genzyme's first registered cell therapy, Epicel, a skin replacement, was not regulated by the FDA, its second, Carticel, a cartilage replacement, was. "Between the two, the situation changed, and it continues to change for cell therapy," he said.

Despite all Genzyme's expertise, manufacturing continues to be a challenge, too. "With cell therapy, it is difficult to demonstrate comparability when you scale up, and likewise, quality control has proved difficult. How can you measure the potency of a cell?" McPherson asked.

Animal efficacy data are not predictive of the human clinical experience. In each of Genzyme's failed programs, the preclinical data were promising. And, he said, "Clinical trials of cell therapies also proved to be very complicated and time consuming, and that's something that is not appreciated in the challenges in taking it to commercialization." McPherson counseled that companies in the field should focus on areas of unmet medical need and ensure the cell therapy fits with existing medical practice, which Carticel, for example, did not. The other key is to know the mechanism of action. "For two of the three failed programs, we didn't know how they worked, though preclinical data said they did," he said.

Addressing the issue of how cell therapies are regulated was Steven Bauer, head of the FDA's Office of Cellular Therapies. He described the review proceedings as a team effort, pulling together manufacturing, characterization, clinical trial design, pharmaceutical toxicology, statistics and program management.

The review team also carries out its own research to inform the regulatory process. The goal is to develop simple predictive tests for characterization of cell-based products so they can be manufactured efficiently.

Bauer noted that the features of stem cells that make them so promising also make them challenging from a regulatory perspective. For example, there is still a poor understanding of how cells interact with their microenvironments, inadequate markers for predicting cell state and fate, questions about where cells go after they are implanted, and the safety concern of tumorigenicity.

Bauer urged companies in the field to contact the FDA as early as possible in their development programs, "so we can tell you what pitfalls we've seen, and so we can guide you in the approaches you need to get to predictive assays."

Chris Mason, of the Stem Cell and Regenerative Medicine Bioprocessing unit at University College London, noted that the focus has shifted from research to translation. He highlighted some of the problems in scaling up manufacturing from academic, manual approaches, to commercial environments. "We can't meet the clinical demand with the current methods of production, Mason said, and recommended automating processes from the earliest stages of development, despite the extra costs. "We need to change the paradigm: Research and translations need to be done in parallel."

The Israeli firm Gamida Cell Ltd. is about to start a Phase III trial of a bone marrow transplant therapy produced from umbilical cord blood. Arik Hasson, head of stem cell projects, said it took 10 years to reach this stage, and noted that the company encountered many difficulties in the development process.

Those included quality control of the basic material, problems over sourcing other raw materials, deciding which serum to use once concerns were raised about fetal bovine serum, adopting analytical methods developed by academics that needed the academics to make them work, and validating animal models.

"These problems emphasize the need for communication," Hasson said. "You need collaboration between industry and academic groups, and you need national and international associations."

Speaking from the physician's point of view, Anthony Mathur, consultant cardiologist at Bart's and London Hospital Trust in the UK, said the main problem currently is managing patients' expectations. "There is so much hype that patients believe stem cells have arrived." At the same time, that could put their use further back, as the hype is making cardiologists highly skeptical. "The result is they will need more data to be convinced," Mathur said.