High Profile Nerve Study Starts – Finally!

The world's first FDA approved study of a therapy based on human embryonic stem cells is under way. That's the story making headlines this recently. But what a long, winding, tortuous regulatory path it’s already been for owner Geron Corporation of Menlo Park, California.

On Monday, October 11, the long-awaited press release came out. On the immediately preceding Friday, a patient with a spinal cord injury was injected with a treatment containing human embryonic stem cells (hESC) and thereby formally kicking off the larger clinical trial of human embryonic stem cells to treat spinal cord injury.

In the rat model this therapy had restored locomotion. Geron bought the rights to the therapy and committed significant resources to the promise that these impressive results might be duplicated in humans. In other words, paralyzed humans may be able to move again—albeit in some limited way. No question, this trial marks a milestone in the hESC arena. But it is only the first glint of any light at the end of the tunnel for Geron.

Geron's Tortuous Road to Trials

Geron is a twenty-year-old biotech company laboring in the fields of biopharmaceutical treatments for such indications as cancer, spinal cord injury, heart failure and chronic degenerative diseases like diabetes. The company began in Delaware and but moved to biotech central in California. Geron Bio-Med is the corporation's wholly owned subsidiary based in Edinburgh, Scotland. Geron is one of only a few companies dedicated to developing clinical therapies with human embryonic stem cells. Most firms in the stem cell arena choose the quicker, adipose or allogenic adult stem cell pathway.

In January 2009, Geron received FDA clearance to commence with an Investigational New Drug (IND) application for the clinical trial of GRNOPC1 in patients with acute spinal cord injury. This clearance allowed Geron to set in motion a Phase I, multi-center study plan. Then, in August, the FDA placed a clinical hold on the IND for GRNOPC1 pending further review of a nonclinical animal study. The staff at the FDA thought that there might have been evidence of a higher frequency of cysts among animals in the study. In October 2009, after reviewing the data with the FDA, Geron agreed to conduct further preclinical studies and settle the cyst issue. This pushed Geron’s clinical trial back to late 2010.

Given that history, the news last week that the Phase I trial is ON was a clear positive for the company and its shareholders. The stock rose 10% on news. For Geron, it’s been an extraordinarily expensive process to get to this point. Fully $180 million has been spent over the past three years on preparing for this study and driving its other product development programs. With $115 million in cash left on the books, the company clearly needs to get a product to market sooner than later.

But, again, this is Phase I. A two-year Phase I. Then comes the negotiations with the FDA for Phase II.  Then phase II. It’s been twenty years already for Geron. Entire careers will have started and ended by the time Geron’s first products hit hospitals.

One of the pioneers of the regenerative technologies industry, Jamie Grooms, presently President of nerve allograft company AxoGen (which is bringing to market its own nerve product Avance) had this to say about Geron’s announcement. "This is exciting on two multiply fronts. First this [trial] is important to the United States. We have fallen behind in research and product development as it relates to stem cell programs. Assuming this technology moves through the clinical trial phase and become a commercial product it will establish a pathway for other stem cell programs. And health care needs these types of product belonging to my favorite class of technologies. This is truly Regenerative Technologies. Restoring both form and function back to the patient. Finally, restoring function to patients with spinal cord damage will bring tears to all those involved. A success with this trial will also bring hope to millions suffering with spinal cord damage as well as many other etiologies."

The Path to Trials

The trial’s principal study site is the private, non-profit Shepherd Center, of Atlanta, Georgia, a rehabilitation hospital and clinical research center for spinal cord and brain injuries.

Shepherd Center/Shepherd CenterAs might be expected, Geron’s trial actually fits within the context of years of previous research (over a decade to be exact in the case of this treatment). The treatment being tested by Geron originated from the work of UC Irvine neurobiologist Hans Keirstead and his team at the Reeve-Irvine Research Center. Using a rat model, Dr. Keirstead demonstrated that this particular stem cell approach was extremely promising and in the hands of Geron it has managed to make through the regulatory gauntlet to Phase I.

Keirstead's approach is, we think, instructive and explains why Geron has been able to get an hESC to Phase I where other firms have failed. Keirstead’s research focused on the processes required to push hESCs up the lineage and differentiate into oligodendrocytes. These hard-to-pronounce cells act as insulation for nerve fibers with their myelin exteriors. Keirstead theorized that if these protective cells could be re-grown, perhaps it might be enough of a connection to allow nerves to regenerate and form a viable pathway for neurological signals to move. Many spinal cord injuries, in fact, don't involve the severing of the cord. Instead, in most cases, the inability of nerves to transmit signals is due to damage to this myelin sheathing.

Keirstead’s rat studies clearly demonstrated that his hypothesis was correct. In his studies, paralyzed rats treated with hESCs regained locomotion and, in some cases, even recovered the ability to run.

And They're Off…

Keirstead’s treatment, now Geron’s product, is finally beginning the earliest stage of a clinical trial, Phase I. The FDA and the company will be measuring safety—for ten patients. The patients accepted are all suffering from a spinal cord injury (complete American Spinal Injury Association (ASIA) Impairment Scale grade A, between the third and tenth thoracic vertebrae). But this trial isn't for long-time spinal injury sufferers. Only those who were injured two weeks prior can qualify for receiving the injectable therapy.

X-ray of lumbar spine/Creative CommonsThe next step if all goes well in Phase I is to test for efficacy, with the host site moving to Northwestern University in Chicago, Illinois. Plans are in place to utilize a number of sites throughout Geron's clinical trial process, with a proposed seven centers eventually playing host. After the last patient is enrolled, the waiting and measuring period begins. The trial has a two year follow up requirement.

Meet GRNOPC1

The hESC being used in this trial specifically are derived oligodendrocyte progenitor cells, GRNOPC1. Initiating the GRNOPC1 clinical trial is a milestone for the field of human embryonic stem cell-based therapies, " said Thomas B. Okarma, Ph.D., M.D., Geron's President and CEO. "When we started working with hESCs in 1999, many predicted that it would be a number of decades before a cell therapy would be approved for human clinical trials. This accomplishment results from extensive research and development and a succession of inventive steps to enable production of cGMP master cell banks, scalable manufacture of differentiated cell product, and preclinical studies in vitro and in animal models of spinal cord injury, leading to concurrence by the FDA to initiate the clinical trial."

GRNOPC1 is the key to Keirstead's work. It contains oligodendrocyte progenitor cells from hESC which the research has shown regenerate myelin and also has properties that stimulate nerve growth according to Geron. These effects are linked to results like improved locomotion abilities and kinematic scores in animal models with spinal cord injury.

And although a spokesperson for the Shepherd Center told OTW they are not doing interviews for the clinical trials, they did release this statement by the center's medical director, Donald Peck Leslie, M.D., "We are pleased to have our patients participating in this exciting research. Our medical staff will evaluate the patients' progress as part of this study. We look forward to participating in clinical trials that may help people with spinal cord injury."

Geron is one of several stem cell companies tackling the problem of nerve injury. The New York Stem Cell Summit, sponsored by Orthopedics This Week, is featuring nerve regeneration as a separate section of the meeting and four companies will be presenting data on the ability of adult and embryonic stem cells to treat nerve injury.

As the only hESC-based nerve regeneration therapy, Geron is getting its fair share of publicity. Clearly, a study is long overdue. Now that the study has started, we would hope and expect to see a steady stream of information about the studies progress and, most importantly, these patients’s progress.

As Keirstead has often commented, success in this trial sets up the potential for these therapies to address such other significant nerve impairments as lack of bowel or bladder control or loss of sexual function.

Now, if only there was a stem cell therapy to address the degeneration and pain of the FDA.