Speaking at the recent World Spine meeting in Istanbul, was Dr Michael Fehlings, Medical Director of the Krembil Neuroscience Centre, Toronto Western Hospital and Professor of Neurosurgery, University of Toronto, Canada, who presented the results of the Cethrin Phase 1/11a prospective clinical trial.
Fehlings began his discussion by explaining the mechanisms of acute traumatic spinal cord injury, followed by outlining Cethrin and Cethrin delivery. Cethrin is a Rho inhibitor that consists of BA-210 (the active ingredient) and is combined with an approved fibrin sealant that is administered directly at the site of injury during surgery to repair spinal cord injuries.
In previous animal studies, Cethrin has demonstrated that it helps in the repair of damaged central nervous system (CNS) neurons. Some of the beneficial actions of Cethrin application following acute spinal cord injury are as follows:
Inhibition and even reversal of abnormal Rho GTPase activation after just a single dose.
Significant reduction of apoptosis at the site of injury.
Promotion of axonal regeneration.
Functional recovery in animals after spinal cord injury, as measured by hind-limb movements using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale.
The study sites were held in nine cities in the US and Canada, and the primary aim was to assess the safety and tolerability of the drug. The secondary endpoint was to examine the pharmacokinetic profile of Cethrin in blood and the neurological outcome, using the American Spinal Cord Injury Association (ASIA) scores.
The study took place over six weeks, with a 12-month follow-up, and dose escalations of a single application of Cethrin on dura mater, ranged between 0.3mg, 1.0mg, 3.0mg, and 6.0mg for thoracic and cervical patients. Thirty-seven patients were enrolled in the study, who were divided into the following catergories:
Safety overview
Following this, Fehlings reported that from the results, there were no drug related serious adverse events - one patient died or acute respiratory distress syndrome (ARDS) in the first three weeks after spinal cord injury (SCI), and one patient was diagnosed with a cerebral glioma (present after retrospective review of initial CT brain). There were no dose dependent serious adverse events and low systemic exposure (PK parameters). Overall, Cethrin application appeared safe in terms of normal parameters, explained Fehlings, such as vitals, clinical labs and neurological exams (MRI and ASIA). Other events included one patient who had prolonged hospitalisation due to fever, one patient with a thoracic injury who deteriorated by five sensory levels at six weeks and then recovered two levels by three months, one patient who had additional elective surgery for hardware repair, and one patient who showed deterioration three levels due to the presence of a syrinx.
According to Fehlings, 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," he explained. Patients with this type of injury do show some spontaneous recovery, 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 six months, 27% of patients showed improvement from ASIA A to B, C, or D.
According to the results, Fehlings reported that by six months, seven patients had improved by two grades or more, with five at ASIA C and two at ASIA D.
The rate of conversion from ASIA grade A to B, C, or D correlated with the dose administered at six weeks and three months, but the correlation was not seen by six months.
"While we recognise that, given the lack of randomisation 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," explained Fehlings. For 2-grade or better improvement to ASIA C, D, or E, their rate of 19% at six 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," Fehlings concluded. "The next step will be to do a prospective randomised study, and the plans for that are now in the works. We hope to initiate that within the next few months."
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