Periodic Reporting for period 5 - NISCI (Antibodies against Nogo-A to enhance plasticity, regeneration and functional recovery after acute spinal cord injury, a multicenter European clinical proof of concept trial)
Période du rapport: 2022-01-01 au 2023-06-30
Spinal cord injury following work, traffic, and sports accidents is a devastating neurological disorder that leaves patients with permanent paralysis. Projected to the total population of the EU of 507,4 million citizens, 10'000 people suffer from spinal cord injury yearly and more than 200’000 patients are living with spinal cord injury in the EU. Yet, no treatment is available and the impact on the individual quality of life and the economy are vast.
Today’s therapy focuses on minimizing secondary damage of the spinal cord (e.g. swelling) and on subsequent rehabilitation of function at best. Regeneration of interrupted nerve fiber tracts in the central nervous system is very limited. Important molecular impediments responsible for this lack of fiber repair are proteins which inhibit nerve fiber growth after brain or spinal cord injury. One of the most potent nerve growth inhibitory molecules is Nogo-A, a membrane protein comprising multiple inhibitory domains that activate independent receptors. Function blocking antibodies against Nogo-A neutralize this inhibitory activity and allow injured nerve fibers to regrow and reconnect. A number of publications have shown that anti-Nogo-A antibodies mediate significant improvements in functional recovery in rats, mice and monkeys with spinal cord injury. These results warranted translation to human spinal cord injured patients. A previous phase I clinical study has shown safety and feasibility in patients with complete spinal cord injury (Kucher et al., 2018). Accordingly, the objective of the present study was to test the efficacy of anti-Nogo-A antibody treatment to improve the outcome of patients with traumatic spinal cord injury during a clinical phase II study. The present study “Nogo-A inhibition to enhance plasticity, regeneration and functional recovery after acute SCI (NISCI) was an international, multi-center, double-blind, placebo-controlled trial to test the efficacy of the anti-Nogo-A antibody therapy to improve motor outcome and quality of life of patients suffering from acute SCI. Advancements in clinical trial design, and improved prediction algorithms of clinical outcomes allow for scrutinizing the effectiveness of this novel treatment in an unprecedented way. The NISCI trial also included exploratory research studies. In a dedicated biobank serum and cerebrospinal fluid samples (CSF) of all NISCI patients were collected and analyzed to identify protein-based biomarkers, which may objectively measure responses to the therapeutic intervention. Novel quantitative magnetic resonance imaging (MRI) methods were employed to identify microstructural changes in the spinal cord and brain.
Today’s therapy focuses on minimizing secondary damage of the spinal cord (e.g. swelling) and on subsequent rehabilitation of function at best. Regeneration of interrupted nerve fiber tracts in the central nervous system is very limited. Important molecular impediments responsible for this lack of fiber repair are proteins which inhibit nerve fiber growth after brain or spinal cord injury. One of the most potent nerve growth inhibitory molecules is Nogo-A, a membrane protein comprising multiple inhibitory domains that activate independent receptors. Function blocking antibodies against Nogo-A neutralize this inhibitory activity and allow injured nerve fibers to regrow and reconnect. A number of publications have shown that anti-Nogo-A antibodies mediate significant improvements in functional recovery in rats, mice and monkeys with spinal cord injury. These results warranted translation to human spinal cord injured patients. A previous phase I clinical study has shown safety and feasibility in patients with complete spinal cord injury (Kucher et al., 2018). Accordingly, the objective of the present study was to test the efficacy of anti-Nogo-A antibody treatment to improve the outcome of patients with traumatic spinal cord injury during a clinical phase II study. The present study “Nogo-A inhibition to enhance plasticity, regeneration and functional recovery after acute SCI (NISCI) was an international, multi-center, double-blind, placebo-controlled trial to test the efficacy of the anti-Nogo-A antibody therapy to improve motor outcome and quality of life of patients suffering from acute SCI. Advancements in clinical trial design, and improved prediction algorithms of clinical outcomes allow for scrutinizing the effectiveness of this novel treatment in an unprecedented way. The NISCI trial also included exploratory research studies. In a dedicated biobank serum and cerebrospinal fluid samples (CSF) of all NISCI patients were collected and analyzed to identify protein-based biomarkers, which may objectively measure responses to the therapeutic intervention. Novel quantitative magnetic resonance imaging (MRI) methods were employed to identify microstructural changes in the spinal cord and brain.
Within the last 18 months, all NISCI study centers were able to enroll 126 patients according to the predefined enrollment goal in July 2022. Recruitment of patients progressed very well in Germany, Switzerland, Spain and the Czech Republic. The external scientific advisory board and the data safety monitoring board (DSMB) met in March 2022 after inclusion of 96 patients and a final DSMB meeting took place in March 2023.
Continuous coaching (webinar, phone, meetings) regarding the drug (drug handling and application), re-labeling, clinical outcome including electrophysiological assessments and further issues related to the study was provided to the sites to ensure that professionals at all sites were well-trained to follow the study protocol accordingly.
After the last data were collected and the data base locked in March 2023, the evaluation of the results started according to the statistical analysis plan. Across the full cervical SCI patient cohort without distinguishing pre-defined subgroups, anti-Nogo compared to placebo did not achieve statistically significant benefit for the prespecified primary efficacy endpoint – superior motor recovery in arms and hands measured with the upper extremity motor score. However, in several of the predefined subgroups of patients, in particular in patients with incomplete SCI, remarkable improvement of the upper extremity motor score were observed in anti-Nogo-A antibody treated patients. Detailed analysis of these results and of all the secondary endpoints including locomotion, quality of life and bladder and autonomic functions is currently ongoing.
MRI studies for high resolution and quantitative evaluation of spinal cord and brain of patients were successfully conducted at all sites. The results show critical dimensions of remaining tissue bridges at the injury site correlated to remaining functionality and recovery potential. The pharmacokinetic analysis of antibody levels in CSF and blood allowed to reconstruct the exposure of the spinal cord and brain to the therapeutic antibodies over the the treatment period. First exploratory proteomic analyses of high-quality CSF and serum samples indicate promising candidate proteins, which may serve as objectively measurable markers of injury severity and help to identify differential biological responses depending on the type of treatment.
A new limb movement sensor, which was tailored to meet specific requirements of patients with cervical SCI, has been developed and validated. The technology will support objective monitoring of patient activities during the comprehensive inpatient acure care and rehabilitation.
To further public outreach, the NISCI website was continuously updated to provide the latest information regarding the clinical trial and first results of the ongoing analyses. In two project videos, the clinical trial and its scientific background are presented.
Continuous coaching (webinar, phone, meetings) regarding the drug (drug handling and application), re-labeling, clinical outcome including electrophysiological assessments and further issues related to the study was provided to the sites to ensure that professionals at all sites were well-trained to follow the study protocol accordingly.
After the last data were collected and the data base locked in March 2023, the evaluation of the results started according to the statistical analysis plan. Across the full cervical SCI patient cohort without distinguishing pre-defined subgroups, anti-Nogo compared to placebo did not achieve statistically significant benefit for the prespecified primary efficacy endpoint – superior motor recovery in arms and hands measured with the upper extremity motor score. However, in several of the predefined subgroups of patients, in particular in patients with incomplete SCI, remarkable improvement of the upper extremity motor score were observed in anti-Nogo-A antibody treated patients. Detailed analysis of these results and of all the secondary endpoints including locomotion, quality of life and bladder and autonomic functions is currently ongoing.
MRI studies for high resolution and quantitative evaluation of spinal cord and brain of patients were successfully conducted at all sites. The results show critical dimensions of remaining tissue bridges at the injury site correlated to remaining functionality and recovery potential. The pharmacokinetic analysis of antibody levels in CSF and blood allowed to reconstruct the exposure of the spinal cord and brain to the therapeutic antibodies over the the treatment period. First exploratory proteomic analyses of high-quality CSF and serum samples indicate promising candidate proteins, which may serve as objectively measurable markers of injury severity and help to identify differential biological responses depending on the type of treatment.
A new limb movement sensor, which was tailored to meet specific requirements of patients with cervical SCI, has been developed and validated. The technology will support objective monitoring of patient activities during the comprehensive inpatient acure care and rehabilitation.
To further public outreach, the NISCI website was continuously updated to provide the latest information regarding the clinical trial and first results of the ongoing analyses. In two project videos, the clinical trial and its scientific background are presented.
At the moment, there is no drug approved that improves the outcome after a severe spinal cord injury. In extensive preclinical studies, the anti-Nogo-A antibody therapy has been shown to elicit substantial functional recovery in SCI rodents and primates, which is the main prerequisite to predict efficacy in humans. Having shown proof-of-concept of anti-Nogo-A treatment in cervical spinal cord injured patients will advance the field of neuroregeneration with the goal to the improve the overall outcome of spinal cord injured patients. Results from this study will also lay the foundation for clinical studies targeting other neurological disorders, such as stroke and multiple sclerosis.
A new statistical model tailored for the analysis of intervention studies using the upper extremity motor score as primary endpoint (Buri et al, 2020, BMC Medical Research Methodology) established the description of potential treatment effects as log-odds ratios. Baseline upper extremity motor scores and neurological levels of injury are explicitly considered by this new model.
Hospitalization and rehabilitation after spinal cord injury generate enormous costs for the public health system and indirect costs due to loss of tax revenue, loss of payments into pension funds, and the inability to contribute to the work force. As the economy of spinal cord injury is not established in the European context, we illustrate the costs by studies performed in the US. There, the expected lifetime costs of a patient who suffered an injury at the age of 25 years is around US$ 2'342'000. Additional indirect costs that strongly depend on education, severity of injury, and preinjury employment history are estimated to an average of US$ 72'955 per year. With an incidence rate of 10'000 new cases per year in the EU, these costs are mammoth and a major burden to the public.
A new statistical model tailored for the analysis of intervention studies using the upper extremity motor score as primary endpoint (Buri et al, 2020, BMC Medical Research Methodology) established the description of potential treatment effects as log-odds ratios. Baseline upper extremity motor scores and neurological levels of injury are explicitly considered by this new model.
Hospitalization and rehabilitation after spinal cord injury generate enormous costs for the public health system and indirect costs due to loss of tax revenue, loss of payments into pension funds, and the inability to contribute to the work force. As the economy of spinal cord injury is not established in the European context, we illustrate the costs by studies performed in the US. There, the expected lifetime costs of a patient who suffered an injury at the age of 25 years is around US$ 2'342'000. Additional indirect costs that strongly depend on education, severity of injury, and preinjury employment history are estimated to an average of US$ 72'955 per year. With an incidence rate of 10'000 new cases per year in the EU, these costs are mammoth and a major burden to the public.