Q&A: Sustained functional recovery the goal for spinal cord injury treatment

Q&A: Sustained functional recovery the goal for spinal cord injury treatment

Key takeaways:

• There is an urgent need to enable functional recovery in people with spinal cord injuries.
• The goal of NVG-291’s development is to improve neural connections in humans with SCI.

Topline results from the chronic cohort of an ongoing phase 1b/2a clinical trial of an investigational therapeutic peptide, NVG-291, found the novel treatment led to increased electrical connectivity between the brain and an important hand muscle (first dorsal interosseous) in those with a spinal cord injury.

The strength of motor connectivity to the first dorsal interosseus muscle achieved a three-fold increase among the 10 trial participants with cervical chronic spinal cord injury who received the peptide, licensed by NervGen, compared with 10 participants who received placebo.

Changes from baseline through 12 weeks included an increase from 6.207 to 18.773 in the normalized motor evoked potential amplitude for the group receiving NVG-291 and from 6.527 to 7.76 for the placebo group (P = 0.0155). Healio spoke with NervGen chief medical officer Daniel Mikol, MD, PhD, as well as James Guest, MD, PhD, FAANS, professor of neurological surgery at the University of Miami, who was involved in the study’s design, to find out more about these results, reported at the American Spinal Injury Annual Meeting.

Healio: Can you explain the mechanism behind NVG-291 and how it aims to promote natural repair processes disrupted by a spinal cord injury?

Mikol: Chondroitin sulfate proteoglycans (CSPGs) are upregulated in areas of central nervous system damage, such as the glial scar that forms after spinal cord injury (SCI). CSPGs are known to be key inhibitors of nervous system repair.

In 2009, the late Jerry Silver, PhD, and colleagues at Case Western Reserve University and Harvard University1 identified a receptor for CSPGs called protein tyrosine phosphatase sigma (PTP-sigma) that could mediate the inhibitory effects of CSPGs on neural repair. NervGen’s lead compound, NVG-291, is a 35-amino acid peptide containing a sequence derived from the intracellular wedge domain of human PTP-sigma.

In preclinical studies of nervous system damage, particularly acute and chronic intervention models of SCI, the rodent version of NVG-291 (NVG-291-R) has been shown to promote neural repair as well as recovery of motor and bladder function.

Healio: Can you discuss the process behind creation of the phase 1b/2a clinical trial?

Mikol: After SCI, connections between the brain and the rest of the body can be interrupted, resulting in loss of motor, sensory and autonomic function. Spontaneous recovery can occur after SCI, but the extent of recovery varies, and recovery plateaus around one year after injury. SCI is a heterogeneous condition, and this heterogeneity can present a challenge in SCI clinical trials.

Given the complexity of SCI, there are a number of important variables to consider in defining a clinical trial population, such as the type, level and severity of injury. Also, the best timing of intervention in relation to the injury needs to be determined. Importantly, previous SCI trials have enrolled either a broad population in terms of severity or have enrolled a severe “motor complete” population, consisting of individuals who have no voluntary motor function below the level of the injury. But here is an important disconnect, because in the preclinical models of SCI, animals do have some motor function below the injury.

Recognizing this disconnect and to increase the probability of successful clinical translation, we took a different approach in designing our trial by enrolling a “motor incomplete” population of individuals with some preserved voluntary motor function below the level of the injury. We also considered that another reason for potential failure of past trials might be that clinical outcome measures used may be insensitive to discern a meaningful treatment effect. We therefore incorporated electrophysiological testing as a quantitative biomarker of motor recovery, in addition to using a range of clinical outcome measures, such as measures of hand function.

Healio: Why was it necessary to split the study into chronic and subacute patient populations?

Guest: The majority of SCI trials are acute or subacute intervention studies, with treatment administered within the first approximately 24 to 48 hours, because results of preclinical studies supported early but not late (“chronic” SCI) intervention. Conducting acute SCI trials can be very challenging operationally, but also these studies have to contend with substantial variability given that participants are within the window of greatest spontaneous recovery (i.e. the first 3 months).

We decided to enroll two cohorts in our clinical trial, chronic (1 to 10 years post-injury) and subacute (20 to 90 days post-injury), given that preclinical efficacy was demonstrated when NVG-291-R was administered either soon after injury or after motor recovery had plateaued, which is remarkable for a spinal cord injury therapy.

Healio: Based on the results presented at the American Spinal Injury Association Annual Scientific Meeting, how would subsequent clinical trials be designed with what goals?

Mikol: I think it depends on the available preclinical/clinical data and the objective of a given clinical development program. In most SCI trials, the focus is to evaluate changes in motor strength and/or function, and for this purpose there are a variety of clinical outcome measures available. Consideration should also be given as to which is the most appropriate and most sensitive test for the target population (e.g. incomplete vs. complete, cervical vs. thoracic/lumbar). Based on our results presented at ASIA on June 3, biomarkers of recovery, such as motor evoked potential amplitude, may also be considered as key endpoints in phase 2 proof-of-concept trials.

Healio: What would you describe as the ultimate goal of NVG-291?

Mikol: NervGen’s goal is to show that by “inhibiting an inhibitor” of nervous system repair, NVG-291 can enhance neural repair mechanisms and improve function in people living with SCI and potentially other nervous system disorders.

Healio: What other SCI-related therapeutics are in the pipeline, and would these be tested for other types of neurodegenerative conditions?

Guest: There are several other therapeutics in the pipeline for SCI, mostly for acute SCI. (Treatments must be administered shortly after injury.) These include AbbVie’s elezanumab and Mitsubishi Tanabe’s unasnemab, both of which target repulsive guidance molecule A, and both of which are administered intravenously, along with the intrathecally administered anti-Nogo A monoclonal antibody NG-101. While these treatments are currently under investigation for acute SCI, to my knowledge there are no ongoing trials of these therapies in neurodegenerative disorders.

Reference:

NervGen Pharma reports positive topline data from the chronic cohort of its phase 1b/2a clinical trial evaluating NVG-291 in spinal cord injury. https://nervgen.com/nervgen-pharma-reports-positive-topline-data-from-the-chronic-cohort-of-its-phase-1b-2a-clinical-trial-evaluating-nvg-291-in-spinal-cord-injury/ Published June 2, 2025. Accessed June 2, 2025.

Shen Y, et al. Science. 2009; doi:10.1126/science.1178310.

For more information:

James Guest, MD, PhD, FAANS, can be reached at [email protected].

Daniel Mikol, MD, PhD, can be reached at [email protected].