This just in: data has been published in the Journal of Neurotrauma
from an acute SCI Phase I/IIa (safety) trial for a drug called Cethrin. The primary author is Michael Fehlings, M.D., Ph.D., University of Toronto, a member of the Reeve Foundation’s Science Advisory Council, a key advisor to the NeuroRecovery Network a principal investigator in the Foundation's North American Clinical Trials Network (NACTN).
In a nutshell, Cethrin appears to be safe and is well tolerated. Those with cervical injuries achieved significantly higher motor and sensory recovery than would be expected. Patients with thoracic injuries were not affected much by the drug.
According to the authors, “a cervical ASIA Grade A-injured patient is likely to spontaneously improve by approximately 10 motor points during the first year after SCI, while we observed average improvements of 21.3 and 27.3 points, at 12 months.”
The trial was not blinded nor did it feature a placebo control; nonetheless, say the authors, it is “very encouraging.”
The authors concede that many SCI folks “show some recovery after the first few days in under intensive care, and it has been argued that an ASIA assessment at 24 hours is not as reliable as one taken at 72 hours when the patient is more stable.”
But there appears to be more going on than spontaneity. “The continued improvement that we observed between week 6 and week 52 is also encouraging. If some recovery were due to regeneration of injured fibers, this would be expected to be a slow process, similar to what was observed.”
Further, the authors note: “While much emphasis is typically placed on motor recovery, the fact that the cervical patients achieved substantial sensory recovery is also noteworthy, as such sensation may have a crucial protective function for skin areas that are sensitive to pressure sores, and the sensory feedback may help in seating balance.”
Wondering why cervical injuries would respond more favorably? The authors of the paper expected this result, “based on the anatomy of the spinal cord, motor innervation patterns, and their relative contribution of these differences to ASIA scoring.” In other words, a change in cervical-level function has a much greater effect on the ASIA score. Put another way, a one-level improvement in the neck area has more impact on ASIA score than a one-level gain in the mid-back.
Also, “thoracic injuries are often associated with significantly more trauma to surrounding tissues than are cervical injuries, creating an environment that is more likely to allow for systemic absorption of the locally-administered Cethrin …”
How does it work? Cethrin is a recombinant (engineered) version of C3 transferase, which is derived from Clostridium botulinum; it is, therefore, a cousin of Botox. The drug blocks the common pathway, called Rho, by which myelin-related inhibitory proteins affect spinal cord nerve cells. If these various inhibitors (e.g. Nogo, proteoglycans) are activated by trauma, spinal cord axons are stopped dead in their tracks. Animal models have shown that blocking Rho spurs spinal cord axons to regenerate; Cethrin also has a protective effect on other nerve cells. Treated animals improved functional recovery.
Five different doses of Cethrin were studied in the trial, from 0.3mg to 9mg. Forty-eight patients were enrolled in the trial, aged 16-70 years; 35 completed the trial – 23 with complete thoracic SCI, 12 with complete cervical SCI. Of those that did not complete the study, nine were lost to follow-up, two died (unrelated to treatment), one withdrew consent, and one refused to return to complete visit. There were no serious adverse events attributed to Cethrin, including pain.
Motor score ASIA assessments were completed within 12 hours prior to surgery and between 48-72 hours following surgery, as well as at 3, 6 and 12 months later.
Here’s what is meant by the ASIA score:
A = Complete: No motor or sensory function is preserved in the sacral segments S4-S5.
B = Incomplete: Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4-S5.
C = Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3.
D = Incomplete: Motor function is preserved below the neurological level, and at least half of key muscles below the neurological level have a muscle grade of 3 or more.
E = Normal: Motor and sensory function are normal.
From the paper: “While the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 [working name of Cethrin] may increase neurological recovery after complete spinal cord injury.”
The next step will be to do a prospective randomized study; the Fehlings group hopes to get that going within the next few months.
The Cethrin trial was funded by BioAxone Therapeutics and Alseres Pharmaceuticals, based on the basic science of Lisa McKerracher, University of Montreal.
By Sam Maddox