Regenerative Therapeutics Program
Cethrin®, a Rho Inhibitor
A spinal cord injury usually begins with trauma to the spine that damages the nerves within the spinal canal. The spinal cord is then unable to send and receive messages from the brain to the rest of the body below the level of injury, resulting in a lifetime of disability in the most severe cases. There are about 11,000 spinal cord injuries each year in the United States. Currently there is only one accepted, although unapproved, therapy, methylprednisolone. If used in very high doses no later than 8 hours after the injury, methlyprednisolone has demonstrated a modest ability to improve the neurological outcome following SCI.
Recent evidence shows that mature nerve cells can be stimulated to grow new connections under certain circumstances. It is also known that nerve growth is influenced by both stimulatory and inhibitory pathways and compounds. In fact, under certain conditions, nerve growth (nerve repair, or axon regeneration) can be enhanced by overcoming the inhibitory pathway. One of the important inhibitory switches in nerve regrowth is an enzyme called "Rho kinase", or simply "Rho." The Rho pathway controls cellular functions including motility, growth and differentiation.
Following an acute injury to the spine, the Rho/Rho kinase pathway is activated and prevents axons from regrowing. Recent research has shown that inhibiting the Rho signaling pathway with certain compounds or drugs may contribute to axon regeneration and functional recovery of movement and sensation following spinal cord injury. Alseres Pharmaceuticals' Rho inhibitor, CethrinŽ, is such a drug.1
Therapeutic Approach
In January of 2007 Alseres Pharmaceuticals announced that it had acquired worldwide rights, through an exclusive license, to develop and commercialize Cethrin, a "first-in-field" therapy for treatment of acute spinal cord injury. Cethrin is an investigational recombinant fusion protein that may help promote the regrowth and repair of axons after a major injury to the spinal cord.
Following a spinal cord injury, about two-thirds of patients undergo decompression/stabilization surgery. In this surgery, Cethrin is delivered in a single dose using a fibrin sealant directly onto the injured region of the spinal cord without the need for further invasive procedures.
Clinical Development
Phase I/IIa clinical trial of Cethrin
This trial is a multi-center, open-label, dose-escalation study designed to evaluate the safety, tolerability and pharmacokinetics of Cethrin in two types of spinal cord injury patients: those with a complete cervical injury or a complete thoracic injury. Dose levels from 0.3 mg - 6 mg have been tested. The first patient was enrolled in February 2005, and by June 2006, 37 patients from nine centers in the US and Canada had been enrolled. A 9mg dose extension arm was authorized by Health Canada and the USFDA. The trial is ongoing.
Interim Post-treatment Results
To date, Cethrin was found to be safe and well-tolerated with no-adverse events attributable to the drug. In addition, the trial had an efficacy component which used the validated impairment assessment scale developed by the American Spinal Cord Injury Association (ASIA). The ASIA impairment scale is scored using 5 categories from A to E, with A being the most serious injury and E being normal. All patients in the Cethrin study were either cervical or thoracic ASIA A category when they were enrolled. Interim results reported to date on the thirty-seven patients enrolled in the first four dose groups, indicate that Cethrin is well tolerated. The interim efficacy anlysis in these groups indicates that Cethrin treated patients experience a frequency of post-treatment conversions from ASIA A to ASIA B or greater which is four times the conversion rate seen with the standard of care reported in the literature (6.7%, Burns, J. Neurotrauma, 2003). When subgroups of patients treated with Cethrin are analyzed, patients with cervical injuries exhibit a more pronounced response compared to patients with thoracic injuries, showing a conversion rate that is six to seven times greater than the full patient group treated with the standard of care reported in the publication above. In patients with cervical injuries, the interim efficacy data also suggest that the response rate observed is dose dependent at the doses treated to date.
Orphan Drug Designation
Cethrin® has been granted Orphan Drug designation. Orphan Drug designation is granted by the U.S. Food & Drug Administration to a drug or biologic intended for use in a rare disease or condition. A rare disease is classified as one that affects fewer than 200,000 people in the United States. Cethrin's Orphan Drug Status provides Alseres with considerable strategic advantages including seven-year market exclusivity after FDA approval of Cethrin®, effectively preventing directly competitive products from entering the market during this exclusivity period. In addition, select fees are waived and the requirements for clinical development are streamlined, potentially helping to accelerate the approval process and reduce costs. Orphan Drug designation also provides certain tax advantages and the potential to receive clinical development grants earmarked for orphan drug indications.
For a list of websites providing information on Spinal Cord Injury, click here.
1 Fehlings, M., and Baptiste, D., (2006). Pharmacological Approaches To Repair the Injured Spinal Cord. J. Neurotrauma 23, 318-334.