California's Menlo Park-based Geron Corporation announced today that the U.S. Food and Drug Administration (FDA) granted clearance of the company's Investigational New Drug (IND) application for the clinical trial of the world's first human embryonic stem cell (hESC)-based therapy in patients with acute spinal cord injury.
Geron plans to initiate a multi-center Phase I clinical trial that is designed to evaluate the safety of the therapy in patients with spinal cord injuries.
"The FDA's clearance of our...IND is one of Geron's most significant accomplishments to date," said Thomas Okarma, Ph.D., M.D., Geron's president and CEO. "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. The ultimate goal for the use of (the stem cell therapy) 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."
"The neurosurgical community is very excited by this new approach to treating devastating spinal cord injury," said Richard Fessler, M.D., Ph.D., professor of neurological surgery at the Feinberg School of Medicine at Northwestern University. "Demyelination is central to the pathology of the injury, and its reversal by means of injecting oligodendrocyte progenitor cells would be revolutionary for the field. If safe and effective, the therapy would provide a viable treatment option for thousands of patients who suffer severe spinal cord injuries each year."
The Stem Cell Clinical Program
Patients eligible for the Phase I trial must have documented evidence of functionally complete spinal cord injury with a neurological level of T3 to T10 spinal segments and agree to have the cells injected into the lesion sites between seven and 14 days after injury. Geron has selected up to seven U.S. medical centers as candidates to participate in this study and in planned protocol extensions. The sites will be identified as they come online and are ready to enroll subjects into the study.
Although the primary endpoint of the trial is safety, the protocol includes secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established and the FDA reviews clinical data in conjunction with additional data from ongoing animal studies, Geron plans to seek FDA approval to extend the study to enable access to the therapy for as broad a population of severe spinal cord-injured patients as is medically appropriate.
Preclinical Evidence of Safety, Tolerability and Efficacy
Geron submitted evidence of the safety, tolerability and efficacy of its hESC therapy, GRNOPC1, to the FDA in a 21,000-page IND application that described 24 separate animal studies requiring the production of more than five billion GRNOPC1 cells. Included in the safety package were studies that showed no evidence of teratoma formation 12 months after injection of clinical grade GRNOPC1 into the injured spinal cord of rats and mice. Other studies documented the absence of significant migration of the injected cells outside the spinal cord, allodynia induction (increased neuropathic pain due to the injected cells), systemic toxicity or increased mortality in animals receiving GRNOPC1.
In vitro studies have shown that the GRNOPC1 hESC therapy is minimally recognized by the human immune system, which allows a low-dose of immunosuppression drugs.
Also included in the IND application were published studies in animals that showed that administration of the GRNOPC1 hESCs significantly improved movement of animals with spinal cord injuries when injected seven days after the injury (Journal of Neuroscience, Vol. 25, 2005). Histological examination of the injured spinal cords treated with GRNOPC1 showed improved axon survival and extensive remyelination surrounding the rat axons. These effects of GRNOPC1 were present nine months after a single injection of cells. In these nine-month studies, the stem cells were shown to migrate and fill the lesion cavity, with bundles of myelinated axons crossing the injury site.
Production and Qualification of GRNOPC1 hESCs
GRNOPC1 cells are produced using current Good Manufacturing Practices (cGMP) in Geron's manufacturing facilities. Geron's cell production process and clean-room suites have been inspected and licensed by the state of California. The cells are derived from the H1 human embryonic stem cell line, which was created before August 9, 2001 and is on the list of former President Bush's approved human enbryonic stem cells. Studies using this line qualify for U.S. federal research funding, although no federal funding was received for the development of Geron's therapeutic product or to support the upcoming clinical trial.
The FDA has a tough line to walk to try and get medications to people that can receive benefit, but not so early as to miss major problems. When side effects occur only in 0.1% of the subjects, you need to have 10s of thousands of subjects to really see it become statistically significant from placebo. Yes, it is sad that this happens, but there is just no way to prove that drugs are conclusively safe before they are approved.
Posted by: Ajlouny | May 31, 2009 at 09:25 PM