First Embryonic Stem-Cell-Based Therapy Trial in Spinal-Cord Injury Gets FDA Nod

Susan Jeffrey

January 27, 2009

January 27, 2009 — Geron Corp announced it has received US Food and Drug Administration (FDA) approval for a phase 1 trial of GRNOPC1, a cell therapy derived from human embryonic stem cells (hESC), in patients with acute spinal-cord injury.

The FDA clearance of the investigational new drug (IND) application marks the first approval of a trial investigating a therapy derived from hESC. The trial will examine the safety of GRNOPC1 in patients with complete American Spinal Injury Association (ASIA) grade A subacute thoracic spinal-cord injuries, the company noted in a January 23 press release.

"The ultimate goal for the use of GRNOPC1 is to achieve restoration of spinal-cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient's injured spinal cord," said Thomas B. Okarma, PhD, MD, president and CEO of Geron, in the release.

During a Webcast press conference, Dr. Okarma outlined the design of the study, expected to begin enrolling in early summer of 2009. Eligible patients for the phase 1, single-dose, open-label trial will have subacute, functionally complete injury between T3 and T10 spinal segments. Transplantation will be undertaken between 7 and 14 days after the injury, the window thought to be past the inflammatory stage where transplanted cells may be destroyed but before any significant scarring takes place, he said.

Patients will receive 2 x 106 cells, a dose that had been tested in the company's preclinical work. The primary end point is safety, both neurological and overall safety. Secondary end points of efficacy will also be assessed, including the ASIA sensory score and the Lower Extremity Motor Score. Patients will be followed for the year after transplantation and assessed at 7, 30, 60, 90, 120, 180, 270, and 365 days postinjection.

Preclinical evidence suggests that these cells are not recognized by the immune system, Dr. Okarma noted; however, while 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," he said. The dose will be tapered beginning at day 45 and stopped at day 60.

Up to 7 US sites will participate in this study and in planned protocol extensions, he noted. The sites will be identified when they are ready to enroll subjects into the study.

Preclinical Support

The IND was supported by data from 24 animal studies showing that infusion of these cells was not associated with teratoma formation up to 12 months after injection, confirming an absence of significant migration of the cells into the spinal cord of the rats and mice in these studies, as well as absence of allodynia induction, systemic toxicity, or any effect on mortality in the animals from treatment.

In animal models, treatment with GRNOPC1 also produced significant improvements in locomotor activity and kinematic scores in animals injected 7 days after spinal-cord injury, the company noted. Histologic examination showed increased axonal survival and extensive remyelination surrounding the axons 9 months after injection. Cells were shown to migrate and fill the lesion cavity, with bundles of myelinated axons crossing the injury site, the press release states.

"In addition to the myelination function, these oligodendrocytes produce many neurotrophins, or nerve growth factors, and we believe now that part of the mechanism of action here will be the stimulation of nerve regrowth" by these factors, Dr. Okarma added during the conference call. "This also leads to the notion that these glial cells, OPC1, may have other clinical applications, such as multiple sclerosis, stroke, or other degenerative diseases of the central nervous system."

Once safetyin patients with thoracic spinal injuries has been established, the company plans to seek FDA approval both to increase the dose of transplanted cells in this patient population and expand the study to include patients with cervical spinal injuries, where they also have promising evidence in animal models, and patients with severe incomplete (ASIA grade B or C) injuries. Cervical injuries are more common than thoracic injuries, thanks in large part to the widespread use of airbags, he noted.

A New Roadmap

Michael Fehlings, MD, PhD, chair of the neuroscience program and director of the Kremble Neuroscience Center at Toronto Western Hospital, in Ontario, commented on this latest development for Medscape Neurology & Neurosurgery on behalf of the American Association of Neurological Surgeons, where he is chair of the section on neurotrauma and critical care.

Dr. Fehlings called approval for this trial "a very important development and a milestone in the process of translation of regenerative medicine technologies from the laboratory into the clinical setting. It's a very important ruling by the Food and Drug Administration to permit the study of stem-cell technology in the setting of spinal-cord injury and will potentially pave the way for other regenerative medicine technologies."

In particular, it sets a "clear precedent," he said, for the level of evidence required to translate invasive regenerative technologies from basic laboratory work to clinical trials. The Geron submission, for example, was based largely on rodent work, he noted. "This is important because it sets a benchmark that one can proceed from rodent models into [humans] and doesn't need to validate all this work in large animal models such as primates."

Other types of stem cells are also under investigation, he noted. "It will take some years to sort out which will be the best strategy, and there will have to be a lot of back and forth between the clinic and the laboratory," he said. Still, "the Geron trial is critical because it has now set a road map that other scientists, clinicians, researchers and regulatory authorities can potentially use."

The Politics of Embryonic Stem Cells

The cells that will be used in this study are derived from the H1 hESC line, created before August 9, 2001, the company release points out. During his presidency, President George W. Bush had limited federal support to research involving stem cells to lines developed prior to that date. "Studies using this line qualify for US federal research funding, although no federal funding was received for the development of the product or to support the clinical trial," the company noted.

The company's production facilities are sufficient to commercially supply GRNOPC1 through the pivotal clinical trials and to supply the US market for more than 20 years, the release states. "This is the first cell therapy that can be scalably manufactured in the same way as a recombinant biological or monoclonal antibody," Dr. Okarma said during the Webcast.

During his campaign, President Barack Obama said that he supported reversing the limits on federal funding of stem-cell research, and his election had been generally welcomed by the research community as a bellwether of change in the White House on this issue.

However, both Geron and the FDA assert that the timing of the decision to approve the study was coincidental. FDA spokesperson Karen Riley told Medscape Neurology & Neurosurgery that there is a process for this kind of review, "and it isn't a fast process."

"Politics did not enter into the decision making on this," Ms. Riley stated. Instead, it had to do with the timing of Geron's response to the FDA's last review and with the statutory limits on the FDA's response time.

During the Webcast, Dr. Okarma said much the same thing. "We have no evidence that there was any political shadow over this process. The hold was resolved over a period of 7 months, which is really within the standard operating policy," he said. "Their prime concern was always around patient safety, and they had lots of issues that were rightfully queried."

At a total of 21,000 pages, the Geron IND was among the largest ever received by the FDA, he added, so there was "a lot of information for them to get their arms around. Our view of the review process was that it was entirely professional and appropriate, and in fact, the program has been enhanced by the rigor of that FDA review."

Other biotech companies conducting stem-cell research are now champing at the bit for a crack at human trials. In a press release this morning, a company called International Stem Cell Corp (ISCO), a California-based biotechnology company, is touting its own line of stem cells derived not from a fertilized embryo but from an unfertilized oocyte.

"ISCO's stem-cell lines behave just like embryonic stem cells but with the added advantages of solving certain moral dilemmas and addressing patient immune-rejection issues," CEO Kenneth C. Aldrich said in the release. "The FDA's approval of Geron clinical trials marks an enormous step forward for the field of stem-cell research and clears the way toward ISCO to hopefully begin human trials by the end of next year."