medwireNews: NG101, a recombinant monoclonal antibody targeting Nogo-A, does not improve motor recovery in patients with acute spinal cord injury overall, but shows potential benefit for those with motor-incomplete injury, suggest phase 2b study findings.
By 6 months, the change in validated Upper Extremity Motor Scale (UEMS) score from baseline was 1.37 points greater for patients with acute traumatic cervical spinal cord injury who were given NG101, compared with those given placebo, but this difference did not reach statistical significance.
The UEMS ranges from 0 (no voluntary motor function) to 50 (full voluntary motor function in the upper extremities); the mean scores increased from 18.23 points to 31.31 among the patients receiving NG101 and from 19.20 to 30.91 among those receiving placebo.
The trial researchers randomly assigned 129 patients to receive six 3 mL intrathecal injections of either NG101 45 mg (n=80) or phosphate-buffered saline as a placebo (n=49) at the L3 or L4 level every 5 days over a 4-week period. Enrolled patients (85% men) were aged between 18 and 70 years (median 51.5 years) with acute, complete, or incomplete cervical spinal cord injury in the preceding 4–28 days and neurologic levels of injury ranging from C1 to C8 (82% between C3 and C5).
A total of 49% of the treatment group and 52% of the placebo group had motor-incomplete injury, defined as American Spinal Injury Association Impairment Scale category C or D, and the mean time from injury to first dosing was 21.78 and 23.81 days in the NG101 and placebo groups, respectively.
The researchers stratified the enrolled patients according to their predicted clinical outcome at 6 months based on their motor and sensory score patterns and injury severity during screening, using unbiased recursive partitioning (URP) to give URP-node recovery profiles and greater patient homogeneity.
In addition to the primary endpoint, there were no significant differences between the groups for the majority of secondary endpoints, including Spinal Cord Independence Measure (SCIM) total score and subscores of respiration and sphincter management, and mobility; the Graded and Redefined Assessment of Strength, Sensibility, and Prehension; and total light touch and pinprick score.
The only exception was for improvement in independence at 6 months, which was significantly greater (without multiplicity correction) for patients given NG101 relative to the placebo group. There was a difference of 1.58 points in favor of NG101 at this timepoint on the 20-point self-care subscore of the SCIM, with a higher result indicating more independence.
Specifically, mean scores improved from 1.63 to 9.54 points among patients in the NG101 group and from 1.90 to 8.75 points among those in the placebo group.
The researchers note that the difference in improvement between the treatment groups was greatest, at 4.16 points, among patients with motor-incomplete injury.
When analyzing URP nodes in a post-hoc analysis, the 22 patients with motor-incomplete injury (node 10) had greater improvement in UEMS scores by 6 months if they received NG101 rather than placebo, with a difference of 4.40 points, which “might have contributed to greater functional independence,” the researchers say. They add that more NG101- than placebo-treated patients in this cohort, respectively, reached the highest level of independence by 6 months (45 vs 28%).
Moreover, among participants who underwent magnetic resonance imaging (MRI) during screening, those with motor-incomplete spinal cord injury saw a higher extent of preserved tissue bridges than those with motor-complete spinal cord injury and had lower levels of neurofilament light chain (NfL), a marker of tissue damage.
“These results support further investigation of antibodies to Nogo in people with motor-incomplete spinal cord injury,” write Norbert Weidner (Heidelberg University Hospital, Germany) and colleagues in The Lancet Neurology. They add that “[a]dvanced stratification methods that integrate structural integrity measures, such as tissue bridges and NfL, might refine treatment cohorts and improve the sensitivity and specificity of outcomes in future spinal cord injury trials.”
The investigators note that the antibody had a half-life of 10–11 hours in the blood, and that patients with motor-incomplete injury and higher cerebrospinal fluid NG101 concentrations seemed to benefit more than people with motor-incomplete injury and lower concentrations, “indicating possible variable underdosing between injections.”
Rates of treatment-related adverse events were similar between patients receiving NG101 and those receiving placebo, affecting 12.5% and 11.5%, respectively, as were rates of severe adverse events (14 vs 13%). There was only one death in the placebo group, which was unrelated to treatment.
The most common adverse event was infections, affecting 83% of the treatment group and 92% of the placebo group, followed by nervous system disorders, affecting 53% and 67% of patients, respectively.
In a related commentary, Karlo Pedro and Michael Fehlings, both from the University of Toronto in Ontario, Canada, write that the study “offers cautious optimism regarding monoclonal antibody therapy for spinal cord injury, despite the complex and heterogeneous recovery patterns in people with cervical injuries.”
They also advocate for a “a multidimensional outcome strategy (panel) to capture various aspects of recovery concurrently, to provide a robust foundation for assessing efficacy and advancing spinal cord injury therapies.”
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