The Race To Treat Spinal Cord Injury: A Comparative Analysis

Summary

• Four biotech companies are pursuing the treatment of spinal cord injury with the use of stem cell transplantation.
• Each company demonstrated efficacy in pre-clinical studies.
• The race is in the early stages but InVivo Therapeutics is clearly leading the pack based on its strategic approach to accelerated HDE approval and initial trial results.

There are four small biotech companies vying to develop a new standard of care for spinal cord injury; InVivo Therapeutics (NASDAQ:NVIV), StemCells, Inc. (STEM), Neuralstem, Inc (CUR) and Asterias Biotherapeutics (AST). All four companies use some form of stem cell therapy as part of its overall therapeutic platform. What follows is a comparative analysis of each company.

Spinal Cord Injury Basics

First some spinal cord injury basics to set the foundation. As defined on the Mayo Clinic's website, "A spinal cord injury is damage to any part of the spinal cord or nerves at the end of the spinal canal -- often causing permanent changes in strength, sensation and other body functions below the site of the injury."

Spinal Cord Injury [SCI] comes in two types; complete injury, which means there is no function below the level of injury, and incomplete injury, which means there is some function below the level of injury.

In order to get a better perspective of various injury types and where they occur, below is a graphical picture of the spine and the areas of the body that are influenced:

The standard for determining the extent and severity of a patient's spinal cord injury is the ASIA Impairment Scale (see below).

A muscle grade of 3, which is the key distinction between ASIA C and ASIA D, is active movement through full range of motion against gravity.

In an extensive study of thoracic and lumbar injuries, only 22.4% of thoracic (T4-T9) or thoracolumbar (T10-T12) spinal cord injury patients improved one or more ASIA levels. Only 4.1% of ASIA A thoracic/thoracolumbar patients showed neurologic improvements. As you would expect, thoracic patients had the least potential for neurologic improvement.

Another large study of thoracic vs. cervical spinal cord injuries showed marked recovery (improvement of at least two grades from AIS at baseline at week 26) for ASIA A patients of 15.5% for cervical vs. 7.0% for thoracic. The study included both complete and incomplete injuries.

In addition to severity and location, time is a critical factor in neurologic improvement after injury. Shortly after injury and extending up to six months, there can be varying degrees of spontaneous recovery. When evaluating and comparing trial results among the different therapeutic approaches, it's important to keep in mind the possibility of spontaneous recovery.

Therapeutic Approaches

StemCells and Neuralstem are pure play neural stem cell companies. They use adult neural stem cells in their therapeutic approach. The cells are transplanted directly into the spinal cord of spinal cord injury patients.

Asterias on the other hand uses oligodendrocyte progenitor cells. Oligodendrocyte progenitor cells are the precursors to oligodendrocytes, which support axons and provides a myelin sheath for nerve cells to improve transmission. Similar to StemCells and Neuralstem, the cells are transplanted directly into the spinal cord of spinal cord injury patients.

InVivo has taken a different approach compared to the other three companies. It uses a neuro-spinal scaffold, which is a bioresorbable polymer scaffold that is designed for implantation at the site of injury. The next phase of InVivo's approach will be to load neural stem cells onto the scaffold, thereby taking advantage of the beneficial properties of both therapies.

Pre-Clinical Studies

This is where the comparisons get interesting. It's hard to make an apples to apples comparison between companies with such diverse therapeutic approaches but results are results and they start with pre-clinical studies.

All four companies used the BBB locomotor rating scale, which provides a baseline for data comparison. Below are the results:

StemCells

Neuralstem

Asterias

InVivo

Each of the companies show improvement with their respective treatments. However, what jumps out to the reader is the degree of separation between InVivo's scaffold + high-dose hNSCs results and the control arm.

Rat models do not always correlate with human results and clearly there were different methodologies in the pre-clinical studies that may have skewed the data, but InVivo's results seem compelling above and beyond the other companies.

Trial Criteria

StemCells' trial criteria for Phase I/II were as follows:

• Thoracic spinal cord injury (T2-T11)
• AIS Grade A, B, or C
• Minimum of six weeks post injury.
• Must be stable stage of medical recovery after injury.

Neuralstem's trial criteria for Phase 1 are as follows:

• AIS A complete (T2-T12)
• At least 1 year but no more than 2 years from time of injury.

Asterias trial criteria for Phase I were as follows:

• AIS A complete spinal cord injury (T3-T11).
• Transplant 7-14 days post injury.

InVivo's trial criteria for its Pilot Study:

• AIS A complete spinal cord injury (T3-T12/L1) confirmed occurring within the past 21 days.
• Non-penetrating contusion injury no less than 4 mm diameter and limited to 2 continuous vertebral levels.

As indicated above, the main trial criteria have significant variability between each of the trials, which is important to consider when reviewing results.

Trial Updates

StemCells:

StemCells announced positive results of its Phase I/II study on May 14, 2015. The company reported on seven AIS A patients and five AIS B patients. Three of the seven AIS A patients and four of the five AIS B patients showed signs of positive sensory gains. Two of the AIS A patients progressed to AIS B. Given that the patients must be in the stable stage of recovery, it is highly likely the improvements were the result of the treatment.

StemCells has initiated its Phase II proof-of-concept study, which will include cervical spinal cord injury patients grade A, B, or C with minimum 12 weeks post injury.

Neuralstem:

Trial was approved in November, 2014. No trial results to date.

Asterias:

The Phase I trial of five patients was completed with no serious adverse events. No major sensory neurological changes were observed.

The company initiated a Phase I/IIa study for patients with sub-acute complete cervical spinal cord injury. It will be dose escalating administered once between 14 and 30 days.

InVivo:

On July 6, 2015, InVivo announced significant improvement in the second and third patient. It had already been reported that the first patient had improved from AIS A to AIS C, which occurs in fewer than 5% of AIS patients with T10 - T12 injury. Based on the update, patient number three improved from AIS A to AIS B, which occurs in fewer than 4% of patients with a T4 injury.

It should be noted that InVivo's results, which appear exceptional are based on scaffold only. As previously mentioned, the company plans to load the scaffold with neural stem cells in future trials. Based on pre-clinical results, the addition of stem cells should substantially improve efficacy results.

InVivo's strategy around using the biomaterial scaffold before stem cells is also providing an accelerated path to commercialization. The company received humanitarian use device designation in 2013, which is a simpler and quicker path to approval by providing safety and probable benefit through the humanitarian device exemption (HDE). The timeline based on HDE approval is provided below,

Conclusion

I am long InVivo but had no preconceived notion of where this comparative analysis would take me. InVivo's scientific platform of using both a biomaterial scaffold and neural stem cells appears best in class when compared to the stem cell only approach. InVivo is not, however, a stem cell company presently. The corporate presentation states "InVivo plans to partner with a stem cell company to accelerate project timelines." Ultimately, InVivo will need a stem cell company to achieve maximum success. However, based on InVivo's early success with the scaffold only, the stem cell companies may need InVivo even more!

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Disclaimer: Nothing in this article constitutes investment advice. Investing in developmental-stage biotech is highly speculative and risky. The road to commercialization is long, and full of peaks and valleys. Take profits when offered, and most importantly, diversify.

Editor's Note: This article covers one or more microcap stocks. Please be aware of the risks associated with these stocks.

Analyst’s Disclosure: I am/we are long NVIV. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Comments

[gamuril]

It is interesting to note that Dr. Ed Wirth of Asterias was formerly employed at Invivo. Here's some info on the Asterias current study:
http://bit.ly/1EMJ3ki

[climbthemtns]

I'd like to have someone familiar with Invivo's
procedure to comment on this assertion.

[bufnyfan1]

neurostimulation is nothing new--I don't know why this is being "hyped" has some kind of advancement--it was disappointing when it was first developed--unless something has changed I doubt it will be a "game changer"

[pennywatchdog]

Well, tell that to those guys who are able to ambulate now after two years... so far the spinal scaffold has only been used in fresh injuries, so I think there are a whole lot of people with old injuries who NVIV cannot help, and the title of the article suggests to me that there is no winner at this time, and I also think that multiple avenues to improve lives is crucial since not all spinal cord injuries are created equally. I think it is good to know what else is out there, it makes us better investors, and that's what these forums are all about. I am very interested in this field and there has been a lot of advancements, but no one winner, yet. I am anxious to see what happens with the addition of stem cells, it has to be good...

[bufnyfan1]

patients aren't "ambulating" their essentially "standing" but even then it is with ++assistance/support-n... has been around since the 1970's-there have not been a lot of changes in its application which makes me very skeptical about what is being touted as being an "advancement"

[pennywatchdog]

RestoreAdvanced stimulator is made by Medtronic...

[pennywatchdog]

Did anyone see the news about the four men paralyzed from the chest down for more than two years who are now moving and walking after a spinal cord electrical stimulator was implanted into their spines?

The link is from Reuters: http://reut.rs/1DLM2mV

FYI

[Monte3343]

Does anyone have any information at all, on which stem cell provider NVIV may use?

[Avittorini]

NVIV has a patent on their bio-degradable scaffold through 2026 I believe so it cannot be duplicated!

[Intrepid Investor]

what is it about InVivo's scaffold that others could not duplicate?

[JMY Investments]

InVivo has extensive IP around the scaffold. The most recent one was issued a month ago: http://bit.ly/1TGSV2e

[Kevin Cwayna]

Why isn't InVivo implanting seeded scaffold already??? Ethically I'm alarmed, and pragmatically I'm mystified that patients 1-3 have received unseeded scaffolding. Getting the good stuff later, the usually conciliation prize for controls in Pharma, is worthless here.

I know we might check a vehicle for SAE's, and we may have no choice if it's components have no precedent of use in humans. However safe resorbed vehicles are plentiful and have no long term rejection concerns? Certainly the case could be made that the benefits already outweigh the risks for seeded scaffolding.

Help me Rhonda.

Help me, help me, Rhonda.

[Avittorini]

NVIV needs to complete the pilot before the FDA will let them begin seeding tge scaffold with cells. Once they begin that process things will really start to get interesting

[BigJoey]

" help me Rhonda, help help me Rhonda".

[Kevin Cwayna]

thank you Avittorini,

Cwayna.

[JMY Investments]

Valid points. I can't speak for the company, but I assume they are touting the hemisection injury model because it provides the desired outcome. The contusion model suggests physiological benefits of the scaffold but, as you correctly state, no BBB score improvements.

Regarding the HUD route, trials are long and costly. A strategy that allows for accelerated approval makes perfect sense to me.

Only 3 patients have been treated to date. The combined probability of the degree of improvements strongly suggests the scaffold is efficacious. Time will tell. Thanks for the insightful comment.

[User 1021899]

The rodent scaffold contusion preclinicals didn't show a BBB benefit, but it did show other benefits - such as increased tissue growth and increased white matter. There weren't primate scaffold preclinicals for the contusion model that I am aware. Why so far do we appear to see better results in human contusion injuries with the scaffold than rodents?

Recall the hemi-section rodent preclinicals weren't nearly as impressive as the primate hemi-section preclinicals. And note per the following, primates more approximate humans:

http://bit.ly/1fSlQ5g

Hence maybe it isn't unreasonable that the hemi-section primates doing better than the hemi-section rodents in preclinicals is an explanation for why we are currently seeing scaffold-treated contusion humans doing better than the pre-clinical contusion rodents? Perhaps the scaffold doesn't work as well in rodents as it does in primates and humans?

[User 9088981]

If InVivo had demonstrated "efficacy" in preclinical studies, then why did it go down the HUD route which is exempt from effectiveness requirements?

Also, why is the company still touting the results from its 2002 rodent study rather than the "larger rat contusion studies"? These studies used a spinal cord contusion injury model which is more relevant to humans than the unilateral spinal cord hemisection injury model used in the 2002 rodent study. The company's 10-K clearly states "In [the contusion] model, the BBB score was not improved by the scaffold device."

[The Lawman]

The early NVIV studies with monkey subjects showed far greater improvement when scaffolds were seeded with stem cells, rather than with unseeded scaffolds. That bodes well for the use of seeded scaffolds in human subjects, given the good results the first three subjects have attained using unseeded scaffolds.

[User 797590]

A difference between these companies not covered is their pipeline of other new potential products being developed. Neuralstem's website lists some under "Pharmaceuticals: Creating a New Class of Neurogenic Drugs". http://bit.ly/1SpqDGV

[bufnyfan1]

I would like to ask something about what CUR/STEM are doing---for years there have been many patients who have gone to China/East Asia as "medical tourists" to have stem cells implanted due to spinal cord injury etc--the results to date have been minimal to very disappointing---its understood that the microenvironment around an acute/chronic spinal cord injured area is very "inhospitable" to stem cells (ie. macrophages/cytokines etc)--hence what exactly are CUR/STEM doing that is different than what has been done before?? In Vivo however is doing something completely different--the polymer scaffold will act like an "anchor" to protect/shield these stem cells and help them grow/sprout axon connections/differenti... excellent results with the first three patients using the scaffold alone seems to be due to a decrease in the cyst formation/inflammatory response that occurs after acute spinal cord injury (and they haven't even started using stem cells yet)--my money is on In Vivo (in an earlier SA article Jason Napadano stated that In Vivo approached CUR about a partnership and were essentially "rebuffed"--I think this may come back to haunt CUR)

[MJack1]

Egos typically get in the way of most pure progress in the world. I would tend to agree it will come back to haunt them. First stem company to partner with InVivo gets the spoils.

[perkin78]

Dr. Langer (co-founder of NVIV) sits on the BOD of Ocata Theraputics (OCAT). Their current work is focused around regenerative ophthalmology but they have a huge IP portfolio surrounding developing pluripotent stem cells. Maybe the writing is on the wall. Maybe not. Either way if their tech fits the bill Langer would at least know about and perhaps be able to guide it in the right direction.