Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Data from animal studies prompted the clinical hold, which highlights the various kinks yet to be worked out.

Geron’s Phase I trial with its human embryonic stem cell (hESC) therapy is off again. The FDA placed the IND application for GRNOPC1, a potential treatment for spinal cord injury, on clinical hold on August 18 after reviewing dose-escalation data from animal studies. The company had not yet started enrolling patients.

In January the agency cleared the company to proceed with this much-heralded trial, which would have been the first use of hESCs in humans, thus lifting a hold placed in May 2008. At the time of the January approval, other players in the hESC business indulged in some semihysterical enthusiasm, believing that the path to clinical trials with hESCs was clearing.

“It’s the first clear evidence of the FDA’s willingness to permit cells derived from pluripotent stem cells to go into human trials,” Kenneth Aldrich, chairman and CEO of International Stem Cell, commented at the time. “It’ll make it easier for us and everyone else, because we now have a roadmap. We know what the FDA wants.”

Geron president and CEO, Thomas B. Okarma, Ph.D., M.D., commented on the go-ahead, saying that “this marks the beginning of what is potentially a new chapter in medical therapeutics—one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function achieved by the injection of healthy replacement cells.”

But one analyst,’s Adam Feuerstein, said in February that “the only thing Geron has done exceedingly well in its 13 years as a public company is surf the waves of stem cell hype and use that momentum to raise lots of money.”

And on February 19, Geron completed a public offering of 7,250,000 shares of the company’s common stock at a price of $6.60 per share. With the latest FDA delay, however, Geron’s stock dove 14%, dropping to a 52-week low of $3.76.

Positive Preclinical Data with hESC Treatment

Geron was planning a Phase I multicenter trial, in patients with complete American Spinal Injury Association (ASIA) grade A subacute thoracic spinal cord injuries. The therapy contains hESC-derived oligodendrocyte progenitor cells that demonstrated remyelinating and nerve growth stimulating properties.

Studies done in animal models published in the Journal of Neuroscience in 2005 by Geron and the University of California, Irvine, showed that GRNOPC1 improved locomotor behavior following implantation in the injury site seven days after injury. Later research found that the lesion site of animals nine months after injury and subsequent injection of GRNOPC1 was filled with GRNOPC1 and myelinated rat axons crossing the lesion, according to the company.

Risks and Predictability Yet to Be Ascertained

The FDA’s highly cautionary approach reflects ongoing concern in the scientific community about undefined risks and lack of predictability of hESC-derived treatments in humans. The agency convened a committee of scientists last April to discuss these risks including the potential for hESCs to develop into teratomas, undifferentiated cell masses that can, albeit rarely, develop into malignant teratocarcinomas.

“It’s not ready for prime time, at least not in my mind, until we can be assured that the transplanted stem cells have completely lost the capacity for tumorogenicity,” noted Steven Goldman, M.D., Ph.D., Rykenboer professor and chairman of the department of neurology, University of Rochester, and a committee participant.

Other concerns include incomplete characterization of the cell product as well as unwanted cell proliferation and differentiation. Geron said that in animal studies, which the FDA is currently review, a very low frequency of injected animals developed microscopic cysts. These cysts were reportedly nonproliferative, confined to the injury site, and had no adverse effects. Animals did not developed teratomas or any other ectopic structure.

Geron says it has developed new candidate markers and assays that are linked with cyst formation across all animal studies in which cysts were found. A manufactured lot of GRNOPC1 that was assessed using these markers and assays showed no cysts in another recently concluded animal study.

Yet another problem is the cells’ immunogenicity. Animal studies have shown that transplanted hESCs induce cellular and humoral immune responses, resulting in infiltration into the grafts of inflammatory cells and hESC rejection. Immunosuppressive drug treatments similar to those used to prevent rejection in human organ transplant recipients have thus far been needed to maintain the injected cells’ viability in animal models.

Geron said that the 10 patients in its proposed trial would likely require only temporary use of low doses of immune-suppressing drugs. During a webcast press conference, Dr. Okarma said that transplantation “will be undertaken between seven and fourteen days after the injury, a time period thought to be past the inflammatory stage where transplanted cells may be destroyed but before any significant scarring takes place.”

Dr. Okarma also noted that preclinical evidence suggested that the company’s cells “are not recognized by the immune system,” but since the blood-brain barrier is disrupted by the injury and the surgical intervention, “we’re covering these patients with very low-dose tacrolimus to give an added level of protection and give the cells the opportunity to engraft and mature.” The dose was to be tapered beginning at day 45 postinjection and stopped at day 60.

Regarding hESC therapies in development, Dr. Goldman commented that “nothing in the literature to date has convinced me that this (tumorogenicity) shouldn’t be a significant problem. My concern is the potential for residual undifferentiated cells, whether these are persistent hESC cells that can become teratomas or partially differentiated neural epithelial cells that can become tumors. Geron’s product is not selected for postmitotic oligodendrocytes, or myelinating cells, that can no longer divide.

“It is not a question of being pessimistic about the technology,” Dr. Goldman asserts though. “As we realize what the problems are in these strategies, we can solve them.”

Patricia F. Dimond, Ph.D., is principal, BioInsight Consulting. Email: [email protected].

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