German, Spanish, Czech and Swiss researchers have reported the completion of the second phase of clinical trials of monoclonal antibodies for the rehabilitation of patients with cervical spinal cord injuries. Overall, the drug did not demonstrate significant effectiveness, but participants with partial loss of motor function showed possible benefits that merit further research with dose adjustments. The report on the work was published in The Lancet Neurology.
After spinal cord injury, the nerve fibers running through it do not regenerate, which leads to persistent movement and sensitivity disorders below the injury site. The worst consequences are caused by injuries to the cervical spine, which disrupt the functions of both the lower and upper extremities. The lack of regeneration of nerve fibers after injury is largely due to inhibition by endogenous molecules. One of the most important such inhibitors is Nogo-A, an isoform of the membrane protein reticulon-4 (Nogo), widely present in the myelin sheaths of nerve fibers.
The experimental anti-Nogo-A monoclonal antibody NG101 (ATI355) has demonstrated high neutralizing activity in vitro and in vivo experiments, promoting partial motor recovery after spinal cord injury in rodents and non-human primates. Its satisfactory tolerability and safety profile were confirmed in phase I clinical trials.
Norbert Weidner from Heidelberg University Hospital and colleagues conducted a double-blind, randomized, placebo-controlled phase 2b trial in 13 hospitals in Germany, Spain, the Czech Republic, and Switzerland. They enrolled 126 patients aged 18–70 years with acute (4–28 days after injury) cervical spine injury with complete or partial loss of motor function. The extent of injury was determined using MRI and cerebrospinal fluid analysis for neurofilament light chains (NfL).
The authors used unbiased recursive partial analysis to select participants so as not to include those whose maximum motor function recovery was expected within the next six months (since the drug was unlikely to provide any benefit to them). Seventy-eight patients received six intrathecal injections of 45 mg of NG101 at five-day intervals in addition to standard treatment starting 28 days after injury; the remaining 48 received placebo according to the same scheme. The primary endpoint was upper limb motor function according to the UEMS scale six months after injury.
On average, there were no statistically significant differences between the groups for the primary endpoint, nor for the dynamics of the MRI pattern and NfL concentration. The incidence of adverse events (most often infections), including severe ones, was also comparable. At the same time, the subgroup analysis showed that in cohorts that included only patients with incomplete loss of motor functions, the effect of therapy was significant: the improvement in UEMS was 4.40 (95% confidence interval 1.32–7.47) points, and in the SCIM self-care scale — 4.16 (95% confidence interval 1.95–6.36) points.
Among these participants, 18 percent were in the least independent SCIM category at day 168 with active treatment versus 32 percent with placebo, and 45 percent were in the most independent category versus 28 percent with placebo. Analysis of the pharmacokinetics of NG101 showed that its half-life in cerebrospinal fluid is relatively short, about 10–11 hours, which is why steady-state concentrations are not achieved with the regimen used.
Taking into account the set of data obtained, the authors of the study concluded that it makes sense to continue testing the drug in patients with incomplete loss of motor functions after adjusting the dosage regimen taking into account the identified pharmacokinetics.
Previously, American and Swiss scientists managed to precisely direct the regeneration of damaged axons and restore the ability to walk in mice after a complete transection of the spinal cord in the lower thoracic region. Mice also showed an effect when introducing polylactide-co-glycolide nanoparticles. Other experimental approaches include the use of stem cells and neurointerfaces.
