Spinal Cord Injury Treatments: Dr. Mikol’s Insights from ISCoS 2024 NVG-291 NervGen Pharma

Summary

The speaker discusses the development of NVG-291, a human analog peptide aimed at promoting spinal cord injury recovery. The talk covers the scientific background, focusing on the peptide's ability to enhance motor recovery, plasticity, and regeneration in preclinical animal studies. The speaker explains the ongoing clinical trial involving subacute and chronic injury patients, emphasizing the use of electrophysiological measurements to evaluate the peptide's efficacy. The goal is to see if NVG-291 can improve connectivity and motor function in humans, following its success in animal models.

Takeaways

• 🧠 NVG-291 is a potential treatment aimed at promoting neural repair after spinal cord injury by targeting specific receptors like PTP Sigma.
• 🦠 In 2015, a peptide called ISP, developed by Jerry Silver’s lab, was shown to improve neural repair and functional recovery in rats, both in acute and chronic spinal cord injury models.
• 🔬 NVG-291 is the human version of ISP, with a nearly identical structure, differing by only one amino acid.
• 🐀 Animal models have demonstrated significant improvements in motor recovery, such as mobility and forelimb function, when treated with NVG-291.
• 👩‍🔬 A Phase 1 clinical trial in healthy humans showed that NVG-291 is safe and well-tolerated across a range of doses.
• 🧪 The ongoing proof-of-concept trial focuses on patients with motor incomplete spinal cord injuries, divided into subacute and chronic injury cohorts.
• 🔋 Electrophysiology plays a key role in measuring the primary outcome of the trial by evaluating cortical spinal connectivity and motor evoked potentials in key muscle groups.
• 👨‍⚕️ The trial is designed to include clinical and electrophysiological assessments, leveraging a single-center design to reduce variability in measurements.
• 📊 Secondary endpoints include changes in motor scores, performance tests, and walking speed, which will help detect subtle motor recovery improvements.
• 🩻 Advanced imaging metrics of the spinal cord and brain will also be assessed to explore NVG-291’s potential impact on neural regeneration.

Q & A

What is the primary focus of the presentation?

The presentation focuses on NVG-291, a human analog of a peptide called ISP (intracellular Sigma peptide), which is being tested for promoting recovery after spinal cord injury by improving neural connectivity and motor function.

What is the historical scientific background behind NVG-291?

For over a century, it has been known that scar tissue formed after spinal cord injury inhibits axonal growth. In 1990, a class of molecules called chondroitin sulfate proteoglycans (CSPGs) was shown to inhibit neural repair. In 2009, PTP Sigma was identified as a receptor that mediates the inhibitory effects of CSPGs, and in 2015, a peptide (ISP) was developed to block this mechanism and promote recovery in preclinical models.

What are the key findings from preclinical studies using ISP?

Preclinical studies in rats showed that ISP promoted axonal regeneration, plasticity, and functional recovery. These studies included both acute and chronic spinal cord injury models and demonstrated significant motor recovery compared to vehicle-treated animals.

What makes NVG-291 different from ISP?

NVG-291 is the human analog of ISP. The structure of NVG-291 is nearly identical to ISP, with only a single amino acid difference in the wedge domain sequence of the protein.

What was the outcome of the Phase 1 trial for NVG-291?

The Phase 1 trial, completed in healthy subjects, demonstrated that NVG-291 was safe and well-tolerated across a range of doses.

What are the three main hypotheses being tested in the clinical trial?

The three hypotheses are: 1) NVG-291 might be effective in both subacute and chronic spinal cord injury, 2) NVG-291 may improve neural connectivity measurable through electrophysiological methods, and 3) a motor-incomplete population is the best target for clinical translation because the animal models also used motor-incomplete injury models.

What is the design of the ongoing clinical trial for NVG-291?

The trial is a single-center study at Shirley Ryan AbilityLab in Chicago, involving 20 chronic and 20 subacute spinal cord injury patients. The treatment involves daily subcutaneous injections of NVG-291 or placebo for 12 weeks, followed by four weeks without intervention. The trial includes both clinical and electrophysiological assessments to measure motor function and neural connectivity.

Why is electrophysiology important in this study?

Electrophysiological measurements are being used to assess changes in motor connectivity as primary endpoints. This approach offers a sensitive, objective marker of recovery, and could provide more detailed information about the effects of NVG-291, especially if clinical changes are not as clear.

What are the key eligibility criteria for participants in the trial?

Participants must have motor-incomplete spinal cord injuries and show measurable motor evoked potentials in two qualifying muscle groups: the tibialis anterior (TA) and the first dorsal interosseous (FDI). This ensures that there is some preserved connectivity at baseline for assessment.

What are the primary and secondary endpoints of the trial?

The co-primary endpoints are the change in motor evoked potential amplitudes in the TA and FDI muscle groups. Secondary endpoints include changes in motor scores, performance tests like the 10-meter walk test, and electrophysiological measures such as latencies and conduction times. The study is also exploring advanced imaging metrics of the spinal cord and brain.