Nerve Damage and Inhibited Regeneration
The nervous system is the body’s command center, a complex network of nerves and cells that carry messages to and from the brain and spinal cord to various parts of the body. It controls, movement, thoughts, senses, heartbeat, breathing - everything vital to living.
Nerve damage affects millions of people with enormous healthcare costs and symptoms ranging from loss of sensation to paralysis. Nerve damage can occur from medical procedures and physical trauma such as car accidents and combat injuries. Certain diseases also result in nerve damage including multiple sclerosis, cardiac arrhythmia causing heart attacks, Alzheimer’s disease, and stroke.
Nerve damage affects millions and costs billions of healthcare dollars. There are currently no approved drugs available to regenerate damaged nerves and allow a person to regain key bodily functions such as movement, sensation, bladder and bowel control, and sexual function.
One of the most recognized forms of nerve damage is spinal cord injury. According to data retrieved from the National Spinal Cord Injury Statistical Center,
approximately 290,000 Americans are spinal cord injured;
approximately 17,000 new injuries occur each year;
the average lifetime costs for spinal cord injury patients, if the age of injury is 25, range from US$1.6 million to US$5.0 million, depending on severity of the injury; and
the average annual direct cost of spinal cord injury patients after the first year range from US$368,000 to US$1.1 million, depending on severity of the injury.
Our Solution: PTPσ Inhibitors
Our platform technology was developed in the laboratory of Dr. Jerry Silver, a renowned spinal cord injury and regenerative medicine researcher and Professor of Neurosciences at Case Western Reserve University in Cleveland, Ohio. Dr. Silver’s research focused on the glial scar which forms at sites of a physical injury such as spinal cord injury, as well as sites of inflammatory damage from neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease.
NervGen licenced the intellectual property underpinning this research from Case Western Reserve University and is now developing its technology platform, via multiple endogenous repair mechanisms, that unlocks the nervous system's ability to repair itself in a manner adapted to the site of injury and type of disease. Numerous repair mechanisms, including egeneration, plasticity and remyelination, have been observed in the various animal models such as stroke, spinal cord injury, multiple sclerosis, cardiac arrhythmia and peripheral nerve injury, as reported in over a dozen peer-reviewed papers.
The strong mechanistic data in preclinical animal models, the potential for a well-tolerated safety profile, and the opportunity to treat a life threatening, severely debilitating disease with no treatment options, are the basis for the Company’s plans to focus its early efforts on spinal cord injury. Notable ISP results and attributes from these preclinical studies include
locomotive recovery with a significant subset of spinal cord injured animals achieving near complete recovery;
100% of spinal cord injured animals experienced partial to complete recovery of bladder function at the higher doses tested;
results were reproduced in multiple studies, labs and preclinical models, including several separate spinal cord injury studies;
ISP was found to be relatively simple and non-invasive to administer, producing lasting improvement in locomotive and bladder functions after a finite period of daily injections; and
ISP was administered during an extended window post-injury which could make it relatively easier to conduct clinical trials and which could be potentially applicable to both acute (early) and chronic (long-term) nerve damage patients.
An illustrative sample of the preclinical data collected using the PTPσ inhibitor, ISP, is shown below. The results shown in the graphs below were published in Experimental Neurology in 2018.
The Baso, Beattie, Bresnahan ("BBB") rating score and the foot stepping angle ("FSA") are objective locomotor measures commonly used to assess locomotor recovery in preclinical models. BBB scores of about 21 and FSA of less than 20 degrees were recorded in rodents prior to injury. BBB scores of 1 and FSA of 150 degrees were recorded one week after injury. After seven weeks of daily treatment with ISP, BBB scores of 15-19 and FSA of 30-37 degrees were observed at week 12 after injury. Compared to non-treated rodents, the treated animals had remarkable improvement in BBB scores of 8-12 points and an improvement in FSA of 49-56 degrees at week 12.
Equally important is the observed dose dependent responses with the higher 500 microgram daily dose producing higher improvement in BBB scores and FSA. In the case of the 500 microgram dose, an average BBB score amongst responding animals of 19 was observed at week 12, nearly achieving the pre-injury average BBB score of 21. All improvements in treated animals were statistically significant compared to placebo animals and as well as when results were compared between the two doses. A response rate of 50-70% was observed. It should be noted that even though the treatments were halted on day 49, improvements continued and were persistent to the end of the experiment on day 84.
Recovery of urinary bladder function is a critical issue in the management of paralyzed patients. Eliminating or reducing catheterization may reduce urinary tract infections, hospitalizations, morbidity and healthcare cost. Improvement in bladder function was observed in a dose dependent manner as published in Nature in 2015. In the two highest dose groups, improvements were observed in 100% of the animals. Improvement in bladder function was also observed in the Rink et al study from 2018 in Experimental Neurology, as referenced below.
The purpose of the scar is to encapsulate the site of the injury to prevent further damage and begin the healing process, but it ultimately inhibits the body’s reparative mechanisms. The co-inventor of NervGen’s technology, Dr. Silver, discovered that a constituent of these scars, a protein called chondroitin sulfate proteoglycan (“CSPG”), is a major inhibitor of the body’s natural ability to regrow and regenerate. Dr. Silver, together with scientists at Harvard University, then identified protein tyrosine phosphatase sigma (“PTPσ”) as a key neural receptor that binds with the CSPG and therefore inhibits nerve regeneration through regions of scarring that results from nerve damage (Shen et al, 2009, Science). Dr. Silver’s research showed that the glial scar also impedes nerve regeneration as the protein within the glial scar binds and keeps the damaged nerves from regenerating.
Multiple studies with animal models for several diseases and medical conditions have shown that treatment targeting PTPσ receptors with a compound developed by Dr. Silver and his research team, known as intracellular sigma peptide (“ISP”), promoted regeneration of damaged nerves and improvement in function (Lang et al, 2015, Nature; Gardner et al, 2015, Nature Communications; Li, H., 2015, Scientific Reports; Rink et al. 2018, Experimental Neurology; and Luo et al. 2018, Nature Communications).
The potential application of PTPσ inhibitors to treat nerve damage in other diseases and medical conditions were also evaluated in various preclinical models.
ISP was also administered to rodent models of multiple sclerosis by researchers at Case Western Reserve University and was observed to
stimulate the production of oligodendrocyte precursor cells, a type of cells involved in the process of nerve repair and regeneration,
allow remyelination and regeneration of damaged nerves, and
increase specific proteases that digest and break down the glial scar tissue (CSPGs) that otherwise keep nerves from regenerating.
Clinical data from the planned Phase 1 trial will provide key foundational knowledge that is transferrable to multiple indications for developing NVG-291.
The Company is also leveraging the potential for NVG-291 to promote nerve remyelination as a therapy for multiple sclerosis. Currently, there is no cure for multiple sclerosis which is the most widespread disabling neurological condition of young adults around the world. Recent findings from a National MS Society study estimates nearly 1 million people in the United States are living with multiple sclerosis and 2.3 million people are living with the disease globally. A 2016 economic analysis of the disease found the total lifetime costs per person to be $4.1 million. The average yearly healthcare costs range from $30,000 to $100,000 based on the mildness or severity of the disease.
The essence of NervGen’s technology is that it unlocks a damaged nervous system’s natural ability to repair itself which, in addition to the treatment of spinal cord injury and multiple sclerosis, could translate to helping people suffering from Alzheimer’s disease.
Research over the past 20 years has confirmed the importance of the biological effect of proteoglycans in the central nervous system. In particular, the ability to shift microglia from the inflammatory phase to the phagocytic or housekeeping phase, as evidenced in both a spinal cord injury and multiple sclerosis model, is promising as it is the natural reparative process for removal of amyloid plaques. This demonstration of an immunomodulatory effect on the microglia will be of specific interest in the quest for a solution to Alzheimer’s disease. CSPGs are intimately associated with senile plaques, and the work with PTPσ knockout mice and other data with chondroitinase all suggest a pivotal role for PTPσ in Alzheimer’s disease.
The Plan Forward
NervGen is focusing its efforts on developing NVG-291, a close analogue of ISP that is structurally similar but different in composition. Initial development is being conducted for the spinal cord injury and multiple sclerosis markets. The Company will also consult with Alzheimer’s disease experts to create a research and development program for the treatment of the disease while increasing its business development efforts at the same time. These are prime targets due to the lack of non-surgical solutions, the dramatic effects on the quality of life, the high costs to the healthcare system and potential FDA Orphan Drug and Fast Track status that would minimize time and maximize support through clinical trials.
The Company plans to initiate a Phase 1a human clinical trial on healthy subjects in 2020 and an expansion to a Phase 1b in spinal cord injury patients. In addition, NervGen intends to commence a Phase 2a multiple sclerosis or remyelination clinical trial in 2021.
NVG-291 is being manufactured using well established peptide synthesis procedures by an approved contract manufacturing organization with a potential secondary source available. Materials to be used in clinical trials will be manufactured under Current Good Manufacturing Practices regulations enforced by the FDA. NVG-291 is a linear peptide comprised of common amino acids with several research batches successfully manufactured.
The Company plans to work in co-operation with other parties, including academic institutions, contract laboratories and not-for-profit foundations, to conduct additional research to further the development of NVG-291 and the advancement of the technology.