may the force be with you

As a quadriplegic, I've read a lot of hype about paralysis cures. So I was eager to find out if Geron, a California stem cell company, had the substance to back up its claims of being poised to launch the world's first clinical trial of an embryonic stem cell-based therapy to treat spinal cord injury.

Going into my interview with Tom Okarma, the company's CEO, I knew this trial would not benefit me directly because it will focus on recent injuries -- I was injured nine years ago in a car accident that rendered my body paralyzed from the shoulders down.

My concern was that Geron's scientists were being hasty. If the first embryonic stem cell trial failed miserably because the company's researchers weren't cautious enough, funding for other research projects would likely diminish and ultimately keep me paralyzed longer.

After an hour of speaking to Okarma, fears of a half-baked trial dissipated. He readily answered my many questions. If he didn't have the animal data to answer a query, he didn't try to dance around that fact.

Okarma outlined a structured but malleable trial. I initially had reservations about safety, but Okarma emphasized that if the animal data is not good, the study will not move forward until problems are addressed.

I'm reassured the trial will proceed with as safe a framework as is possible. Whether it will work remains to be seen. That's why we have clinical trials.

Wired News: In April of 2005, Geron was conducting preliminary toxicity studies (known as pre-investigational new drug, or pre-IND, studies) in animals to address Food and Drug Administration concerns. How are they going?

Tom Okarma: We will complete our IND-enabling studies, which are now in process and still on track, and file our IND during the fourth quarter of this year, assuming the preclinical data continue to go well. That starts a 30-day review clock by the FDA, who then has 30 days to either accept our IND and allow us to proceed or, at that point, they have questions that we must answer before we can begin. We are on track for that. So, assuming they bless the IND, we would hope to be in the clinic in the first quarter of (2007).

The toxicity studies that we do are fairly standard for any new product going into man, with the addition that we do chronic toxicity because this is not a drug that would be excreted in 24 hours. There are cells that will stay in, hopefully indefinitely, so both the toxicity and the tumorigenesis (tumor growth) studies are six and 12 months in duration.

WN: Will patients have to worry about immune rejection with the cells you're injecting (called oligodendrocyte progenitor cells, or OPCs)?

Okarma: It turns out that the differentiated cells that we make and put into animals are not recognized by the human immune system, and we published this last year. It's a striking finding.

WN: In the animal studies that you're doing, how do you deliver the OPCs?

Okarma: Directly into the injury site. In the clinical human trials, they will be injected directly into the injured spinal cord site either during spine stabilization surgery or, depending on when that's performed, percutaneously (through the skin) in a separate procedure. We've developed a gizmo that has a fiber-optic device to enable the neurosurgeon to visually watch the needle as the instrument places it appropriately into the spinal cord and injects the cells so they migrate once they're injected into the cord in between the injured axons and find their way to create the myelin sheath (the protective coating of nerve fiber).

WN: Last year, scientists reported that some of the embryonic stem cells approved for federal funding and available at the National Institutes of Health are contaminated by animal cells. Will the cells you transplant be grown in all-human media, free of animal products?

Okarma: Better than that. Not only all-human, it's all defined chemically. So there's no serum in it. There's no conditioned medium that has undefined materials in it. So it's very squeaky clean, as is the differentiation process now done under good manufacturing practices (GMP) here.

We've got the world's only GMP master cell bank of human embryonic stem cells with lines that are fully qualified for human use which, by the way, are two of Bush's approved lines. So the stuff you hear published that all of those lines are irrevocably contaminated with mouse materials and could never be used in people -- hogwash. If you know how to grow them, they're fine.

WN: The primary focus for Phase 1 trials are safety. What outcomes are you looking for in these first trials to convince you to move into Phase 2 trials?

Okarma: We're (planning on) doing a Phase 1-2, it's a combination. We will test this in patients with the injury. A pure Phase 1 is done in people without a disease; we're doing this in diseased patients, so it's a Phase 1-2. It will be a controlled trial -- not randomized, not blinded, but controlled. We do expect that there will be some patients who will not want the cells, and we would hope that they would be willing to be in the control group, meaning they're matched by the extent of the injury and other patient characteristics to the patients who get the cells so that we can actually compare the rehab progress of these patients with and without the cells.

We recognize that the world's spotlights are going to be on this. So we want to structure out as much subjective stuff as we possibly can. That's the first point. The second point, again to your point of safety, is that the initial patients in the trial a) will get a very low dose of cells, which is always done with a new therapy. They just start with less than the therapeutic range because you want to be sure there's no toxicity associated with this.

How are we going to monitor for toxicity in a patient that has a complete thoracic injury, that has no sensation below the point of injury? Well, if we start with a T3 lesion (an injury at the third vertebra in the thoracic region of the spinal cord), the question will be: Do we see evidence of an ascending paralysis? In other words, changing patients' physiology from a T3 lesion to a T2 or a T1, ascending toxicity.

We start with complete patients because they have no hope of recovery and we want to offer them something. We're starting with thoracic lesions because there's no significant impact for the patient should we see toxicity go from, say, a T3 to a T2 lesion. If we had started with cervical complete lesions and went from C4 to C2, that would be significant because we would reduce respiratory drive.

We're turning every single stone over that we can to reduce -- if not eliminate -- the risk to these patients who volunteer to get the cells for the first time. Once we go through the initial safety cohorts ... then we start looking at incomplete lesions. For all these patients, the efficacy is based on three simple principles: Do we restore sensation in any way or conversely reduce neuritic plan? Do we change bowel or bladder control? Do we see patients enjoying some degree of local motor recovery?

All of these things are monitored by America Spinal Injury Association, which have been developed to follow patients with incomplete lesions who can respond modestly to intense physical therapy. All of those endpoint measures are all validated and ready for us to use. We didn't have to invent anything.

Our fondest hope is that, even in cases that have no hope of spontaneous recovery, we actually provide value. Now that may not happen. We may not see any responses in the first cohorts of patients who have complete lesions, which is why we're progressing thereafter to patients with incomplete lesions which resemble more closely the animal model, which is where the excitement began. Those animals are models of incomplete lesions. But for reasons of ethics and safety and appropriateness, we can't start with patients who resembled the animal model. You have to start way upstream.

WN: Will those who choose to be in the control group receive methylprednisolone, the currently recommended treatment for acute spinal cord injury?

Okarma: Everybody in both groups will get that.

WN: That sounds good. Thank you for your time, and I hope you have a good day.

Okarma: You, too. Bye-bye.

source:http://www.wired.com/news/technology/medtech/0,70521-1.html?tw=wn_story_page_next1