by Susan Jeffrey

April 25, 2007 — Preliminary data from a phase 1/2a trial suggest that a novel Rho inhibitor (Cethrin, Bioaxone Therapeutic), formulated with a fibrin sealant and applied during spinal decompression and stabilization surgery, is safe and feasible used in patients with acute spinal cord injury.

Although the study was not powered to examine clinical outcomes, encouraging trends were seen in neurological recovery, at least compared with historical controls. Their findings were presented at the 75th Annual Meeting of the American Association of Neurological Surgeons in Washington, DC.

"In a nutshell, we found that the drug was safe, and there were no drug-related adverse events that occurred," lead author Michael G. Fehlings, MD, PhD, head of the Krembil Neuroscience Center at the University Health Network, in Toronto, and professor of neurosurgery at the University of Toronto, told Medscape.

"It's going to require of course more studies and a blinded, prospective, randomized study, but patients are not being harmed, and the recovery rates appear to be better than historical controls, although one always has to be very cautious when interpreting historical data," he noted.

Plans for a randomized controlled trial are under way and they hope to begin within the year, Dr. Fehlings added.

A New Approach to Acute Spinal Injury

Preclinical data have shown that the molecule Rho, which is downstream of the NgR receptor, is a key pathway blocking the regeneration of axons and increasing traumatic neural cell death, the authors write. Work in animal models has shown that blocking Rho reduces the amount of cell death and enhances nerve-cell regrowth and regeneration, Dr. Fehlings said.

"One of the challenges has been how to deliver this recombinant protein into the injured nervous system," he said. In the strategy used here, the recombinant Rho-inhibitor protein has been formulated with fibrin glue, commonly used in neurosurgical operations. The sealant along with the Rho inhibitor is delivered locally during surgical decompression and reconstruction surgery, resulting, again from the animal work, in high concentrations of the Rho protein locally, but low concentrations in the bloodstream.

In this phase 1/2a non–placebo-controlled dose-ranging study, 37 patients with complete cervical or thoracic spinal cord injuries were enrolled from 9 sites in the United States and Canada. All patients were classified as American Spinal Injury Association (ASIA) A, a complete thoracic or cervical injury with no sensation below the level of the injury. The ASIA scale goes from A to E, with E being normal, and grades B through D reflecting decreasing levels of disability.

The study had a dose-escalation component; patients received 0.3, 1.0, 3.0, or 6.0 mg of the Rho inhibitor given extradurally to the injured spinal cord within 5 days of the injury during surgical decompression and reconstruction. The average time between the injury and application of the drug was 53 hours. All patients but 1 were reassessed at 24 to 72 hours and found to still be ASIA A.

Patients were then followed and neurological outcomes were measured using ASIA standards at day 0, day 2, and months 1.5, 3, 6, and 12.

"What I presented at this meeting were the 6-month follow-up data," Dr. Fehlings noted. "We'll have complete 1-year follow-up data after July."

Safe and Feasible

There were no serious adverse events thought to be related to the use of the Rho inhibitor, the authors note. Two deaths occurred: 1 patient with a thoracic spinal injury died of acute respiratory distress syndrome 19 days postinjury, and 1 patient died of a brain glioblastoma that had been present but undetected on the initial examination. Other events included 1 patient who had prolonged hospitalization due to fever, 1 patient with a thoracic injury who deteriorated by 5 sensory levels at 6 weeks and then recovered 2 levels by 3 months, 1 patient who had additional elective surgery for hardware repair, and 1 patient who showed deterioration by 3 levels due to the presence of a syrinx.

Of 330 adverse events, 290 were felt to be unrelated to the drug, 40 were thought unlikely to be related, and 0 were deemed to be possibly, probably, or definitely related to the treatment.

Preliminary analysis of the neurological outcomes in this study "appears promising," the authors note. Patients with this type of injury do show some spontaneous recovery, Dr. Fehlings noted, "but the recovery rates are generally felt to be fairly low, perhaps on the order of about 5% to 10%. What we found in this study was about a third of the patients showed neurological improvement." At 6 months, 27.8% of patients showed improvement from ASIA A to B, C, or D.

Conversion From ASIA A to ASIA B, C, D, or E
Time Point (mo)- n/36 (%)
1.5 - 11 (30.6)
3 - 12 (33.3)
6 - 10 (27.8)

By 6 months, 7 patients had improved by 2 grades or more, with 5 at ASIA C and 2 at ASIA D.

Conversion by 2 Grades or More From ASIA A to ASIA C, D or E
Time Point (mo) - n/36 (%)
1.5 - 3 (8.3)
3 - 5 (13.9)
6 - 7 (19.4)

The rate of conversion from ASIA grade A to B, C, or D correlated with the dose administered at 6 weeks and 3 months, but the correlation was not seen by 6 months.

"While we recognize that, given the lack of randomization and a placebo control arm in our phase 1/2a trial, no conclusions can be made regarding efficacy, it is relevant to place the extent of neurological recovery seen in our patient cohort into context," the researchers note. For 2-grade or better improvement to ASIA C, D, or E, their rate of 19.4% at 6 months was 1.5 to 3-fold higher than seen in previous studies.

"So at the end of the day, what we can say is that it's safe, it's feasible, and the results look promising," Dr. Fehlings concluded. "The next step will be to do a prospective randomized study, and the plans for that are now in the works. We hope to initiate that within the next few months."

The study was supported by BioAxone Therapeutic, Montreal, Quebec. Dr. Fehlings disclosed that he has received support from BioAxone, as did all other coauthors.

75th Annual Meeting of the American Association of Neurological Surgeons: Abstract 647. April 14-19, 2007.