Good morning, and welcome to the NervGen Research and Development Day. My name is Daniel, and I will be your moderator today. All participants are in listen-only mode. Following the presentations from both NervGen management and the guest presenters, we will hold a question and answer session. Analysts who have been provided with a separate link to participate in the Q&A will be able to unmute and ask their questions live when the session begins. Please note that today's event is being recorded.
A replay will be available on the Events and Presentations section of NervGen's website. Before we begin, please note that today's presentation contains forward-looking statements within the meaning of applicable Canadian and U.S. securities laws. These include statements about NVG-291, the CONNECT SCI study, the design and timing of the phase III RESTORE study, regulatory interactions, and the company's financial resources and operating runway.
These statements are based on current expectations and are subject to risks and uncertainties that could cause actual results to differ materially. Please refer to the cautionary note on this slide and to the risk factors in NervGen's most recent annual information form, Form 40-F, and other filings available on SEDAR+ and EDGAR. I will now turn the call over to Dr. Adam Rogers, Chairman and Chief Executive Officer of NervGen. Dr. Rogers?
Thank you very much. I am Adam Rogers, CEO of NervGen, and I want to thank everyone for joining us here today for our inaugural Research and Development Day. The spinal cord injury community remains one of the largest underserved populations, with over 300,000 affected individuals in the United States alone. Yet we have no FDA-approved therapeutic options available to improve function and independence.
This is our mission at NervGen, is to bring a drug to market that is going to improve the lives of individuals with spinal cord injury. As we initiate our pivotal phase III RESTORE study in individuals living with chronic cervical motor incomplete spinal cord injury, we are delighted to continue to shed light on the importance of NVG-291, NervGen's 35 amino acid peptide that is administered very conveniently at home as a once-daily subcutaneous injection.
Joining me today is Dr. Marc DePaul. This is from our management team. He is a Senior Director of Research. Marc came out of the lab of Dr. Jerry Silver and has been with the company since 2017. Christine McSherry, who is NervGen's Senior Vice President of Patient Advocacy and Clinical Affairs. If I could have the next slide, please. I am also delighted to have key opinion leaders here to provide their expertise.
Today, you are going to hear from guest speakers that are going to be scattered throughout the presentation. Dr. Ben Abramoff is the Director of the Spinal Cord Injury Program and is the Associate Professor of Rehabilitation Medicine at the University of Pennsylvania. Dr. Sukhvinder Kalsi-Ryan is from the University Health Network in Toronto.
Dr. Kalsi-Ryan is the lead developer of the GRASP assessment, which measures upper limb and hand function in individuals with cervicomedullary spinal cord injury, or as we will refer to as SCI throughout this presentation. GRASP quantitative prehension is NervGen's primary endpoint in our phase III RESTORE study. We will hear from Dr. Kalsi-Ryan regarding the development, validation, sensitivity, and reliability of the GRASP test.
We also have Dr. Philippa Warren. She is the Sir Henry Dale Fellow from the School of Neuroscience at King's College London. Dr. Warren will discuss the scientific rationale for targeting chondroitin sulfate proteoglycans, also known as CSPGs, and the preclinical use of NVG-291. Just a quick note, in her slide, she may use the term ISP, which stands for intracellular sigma peptide, which is the laboratory name of NVG-291. They are interchangeable.
Finally, we have Barry Munro, who is the Chief Development Officer of the Canadian Spinal Research Organization and also Director of the North American Spinal Cord Injury Consortium, who will discuss advocacy in the spinal cord injury community. Next slide, please. Today's agenda will focus on the continued and significant unmet need of spinal cord injury, the scientific rationale and nonclinical foundation of NVG-291, and what gives us at NervGen the confidence for continued translation into the clinic.
NervGen's clinical data generated in our phase I and phase I-B/II-A programs, the study design, rationale, and oversight plan for our phase III RESTORE study. We will conclude with the community and real-world advocacy perspectives. Next slide, please. NVG-291 has the potential to revolutionize recovery after spinal cord injury, positioning NervGen as a compelling and unique late-stage clinical development company.
Not only are we addressing a significant unmet medical need, with currently no approved drugs to restore lost function, improve independence, or quality of life for those with spinal cord injuries, but we are redefining what it potentially means to treat CNS damage in its entirety by regenerating neurons. This ability to regenerate neurons is a concept that was thought for many generations in medicine to be impossible.
Confidence in NVG-291 is supported by our I-B/II-A CONNECT study, a placebo-controlled study that demonstrated efficacy across functional, electrophysiological, and participant-reported measures. All of these that we will touch on later today in the presentation. This observed efficacy that we saw in the CONNECT study resulted in alignment with the FDA on our pivotal Phase III RESTORE study, which we have officially begun screening patients following initial site activation this past week.
The use of NVG-291 has the potential to extend well beyond spinal cord injury. Think of it as a pipeline and a product. Dr. Marc DePaul, our Senior Director of Research, will highlight the existing preclinical data across additional neurologic conditions and diseases that support our confidence in being able to target the upregulation of the inhibitory chondroitin sulfate proteoglycans, or CSPGs, following CNS disruption or trauma to the central nervous system.
There is a palpable excitement here at NervGen, as well as for the whole spinal cord injury community, and it is one that we have worked tirelessly over the last 18 months to arrive at. If you could turn to the next slide, please. During this time, over the past 18 months, we at NervGen have achieved key milestones that have successfully positioned our company to execute upon the RESTORE study.
We've demonstrated proof of concept of efficacy from our phase I-B/II CONNECT study. We've achieved alignment with the FDA on the phase III RESTORE study design. On a corporate level, NervGen successfully listed in January 2026 onto NASDAQ under the ticker NGEN, increasing the potential for broad investor awareness and to support the potential of continued financial growth.
Next slide, please. One of my missions since becoming CEO last July is to build a senior leadership team that brings with them the clinical, regulatory, and financial expertise to successfully execute upon a late-stage clinical development study. I put together a team that understands what it takes to win in areas of significant unmet medical need and bring NVG-291 to market to improve the lives of those living with spinal cord injury.
NervGen will continue to selectively grow as we advance through the RESTORE study and prepare to commercialize NVG-291 as potentially the first approved pharmacologic treatment for the spinal cord injury community. Next slide, please. Before I turn the presentation over to Dr. DePaul and Dr. Philippa Warren to discuss the non-clinical and scientific foundation of NVG-291, what I want to do is take a few minutes over the next handful of slides to highlight the significant unmet need of spinal cord injury that we're addressing. Next slide.
Spinal cord injury has a profound impact both globally and within the United States. Worldwide, there are over 15 million individuals living with spinal cord injury. In the United States, when you focus on those individuals just with traumatic injuries, there are over 300,000 individuals with an annual incidence of 18,000 new cases of traumatic spinal cord injury.
In RESTORE, we will be enrolling individuals similar to the CONNECT study with traumatic cervical motor incomplete spinal cord injury C7 or higher, which, as you can see towards the bottom right-hand side of the slide, represents a population of about 50% of the prevalent population here, or roughly 150,000 individuals in the United States. This is a very large population.
This is an enormous potential market opportunity for NVG-291, and it further gives us confidence at NervGen in our ability to successfully enroll, RESTORE, and commercialize NVG-291. Next slide. It cannot be understated the real-world impact that a spinal cord injury has on an individual, their family, and society at large. Later in today's presentation, towards the end, Christine McSherry and Barry Munro are going to contextualize for you all the continued unmet need and the work that's being done.
Statistically speaking, in the U.S., spinal cord injuries most commonly occur in middle age. The average age is roughly 44 years. As you can see on the slide right, more men are affected than women. Financially, spinal cord injury imparts a dramatic economic burden, both on society as a whole, there's roughly a $60 billion hit to the U.S. healthcare system, and to an individual, there's up to $8 million in lifetime costs for that person.
So any therapy that we can bring to market that has the potential to decrease that lifetime cost and economic burden to the system and allow for the potential of an individual to reenter the workforce or reduce the need for a caregiver, has the potential for a significant economic impact, and we firmly believe that NVG-291 has that potential. Next slide.
When we focus on traumatic spinal cord injury, which the phase III RESTORE is enrolling, the leading recovery priority for these individuals is improvement in hand function. This is going to resonate throughout our entire presentation today as we discuss the GRASP study, but you will see the number 77% that is on the right-hand side of the slide repeated many times throughout. Dr. Abramoff and Dr. Sukhvinder Kalsi-Ryan will discuss this importance of hand function in more detail, but as you can see, within the cervicomedullary spinal cord community, roughly 77% of all individuals who have a cervical spinal cord injury indicate that use of their hands would meaningfully improve quality of life.
That probably runs opposite of what most people would think, because as an outsider, most of us would think that just the ability to walk again, but it is really the use of your hand, which gives individuals the ability to use their iPhone, use their computer, the ability to cook or open a bottle of water up. It gives them independence.
It is this community feedback that we have received, along with the alignment with the FDA, as to why NervGen structured the RESTORE Study, really to focus on fine hand motor use via GRASP quantitative prehension as our primary endpoint for the study. Next slide. I am going to turn it over now to Dr. Marc DePaul and Dr. Philippa Warren to review chondroitin sulfate proteoglycans and NVG-291. Marc and Philippa, I am going to turn it over to you.
Huge thanks, Adam. Hi, I am Dr. Philippa, or Pip, Warren. It is absolutely lovely to speak to you guys today. I am a tenured research scientist and academic working in King's College London. That is in a surprisingly sunny United Kingdom. As Adam mentioned, I am going to talk to you about some of the science behind what he rightly pointed out is what I am going to refer to as intracellular sigma peptide, or ISP, which is just what research scientists refer to as NVG-291. Next slide, please. What you are looking at here is a spinal cord with an injury. What you can see in green is neurons which are trying to regrow, coming down from the top, and they hit the injury site. At that point, they cannot regenerate any further.
It is not because they do not want to, it is because they hit what we have here as a dark blue-purple substance which surrounds the injury site. What I am going to talk to you about is what that is and why it causes a problem. Next slide, please. I am not going to hold you in suspense. That substance which causes the failure to regenerate is called chondroitin sulfate proteoglycans. Adam has already talked about it. We are going to refer to it as a CSPG. What that looks like is a proteinaceous core, and attached to that protein are essentially sugar chains. Why does this exist in your spinal cord? It is really important in your development and your typical functioning. Next animation. This illustrates the eye.
Now, what an incredibly gifted scientist, Professor Jerry Silver, illustrated in the late 1970s and early 1980s is that eye development, the correct connections in your eye, require CSPGs. Essentially, a CSPG layer is put down and nerves grow alongside it to form their correct pathways and connections. CSPGs in development are essentially guidance molecules and pathfinding. Next animation. What researchers like Professor Silver and many others showed was that in fact, these are really important molecules when you are an adult as well, in your nervous system, when it is functioning as it should, as a stabilizing force around all of your neurons. They act as architecture.
Essentially, when you have formed these correct connections and when your neurons are in the right places, CSPGs come and surround your motor neuron, which is what you can see here in green around that motor neuron cell body, which is shown in red. They form a matrix, and they stop it from essentially changing.
They are a stabilizing force, enabling the correct connections to remain over the course of your lifetime. Next slide, please. But as we already showed, after injury, they do something slightly different in your spinal cord. What you can see here on the left is a spinal cord injury. Then the same spinal cord, just one section further on, is shown on the right, stained for those CSPGs. CSPGs exist in a huge proliferation. They are really intense at the site of injury, but also distal to it.
In multiple sections further away from the injury site, we get a huge increase in CSPGs. Now, you can ask why that happens, and there are a few reasons. But primarily, your body wants to protect any neurons or any residual function that they have. So your CSPGs perform the same function they always have. They go in, they surround what is left, they fill up what they can to protect any residual function. But unfortunately, they do not degrade over time. They remain there in the weeks, months to years after an injury. Just as they used to do, they do not stop. They stop any nerves growing through. What you see here is, on the left, a human spinal cord. Essentially, we are looking at the oval part. If your spinal cord was a tube, we are looking at the oval part.
What you can see is what we like to refer to as the butterfly of the spinal cord, where you have your neurons, which control motor function in the center and sensory motions around the outside. Underneath that, you see a human spinal cord injury. This is years after the injuries happened. You get very little recovery, and you can see that huge cavity being formed. Now, what the image to the right shows in red and green is a rat spinal cord injury. The majority of the work I am going to talk about is in rat models, and this is here to illustrate to you how similar rat models are to human spinal cord injury. Using the rat models, we can see the progression of an injury over time.
The major difference between them is that the rat progression tends to happen a bit quicker than humans. But essentially, these are really good models to discover what happens mechanistically after an injury. Next slide, please. Really importantly, this discovery of CSPGs being upregulated after an injury, which occurred in about the 1980s throughout the 1990s and early 2000s, although pioneered by, as I say, Jerry Silver, was not just pioneered by his group, of which I am honored to count myself a former member. This has been replicated by multiple labs, by thousands of different people across the world in a huge number of different animal models. This is as close as we can get to being a universally recognized phenomenon after spinal cord injury and therefore, something that is incredibly important to try and target in terms of a therapy. Next slide, please.
One of the things that was happening throughout, say, the late '80s towards the early 2000s was trying to work out how CSPGs inhibited regeneration. Next animation. The first thing that they discovered was that CSPGs are a chemical barrier. Now, you had that proteinaceous core and all of those sugar chains. There are different protein cores and there are different sugar chains, and here you see three different types in a spinal cord injury, all stained in green.
And what this basically shows you is that it doesn't really matter which protein we have. Some are more inhibitory than others, but they all upregulate after an injury, and they all prevent nerves or regeneration from happening. Next animation, please. The next thing that was discovered is CSPGs are a physical barrier to regeneration.
What you have in this image is a band of CSPGs over a culture of neurons, which are shown in green. And what this illustrates is that if a neuron or nerve axon is growing up to a CSPG barrier, it doesn't want to grow over it. It will, in fact, grow along its outside wall, its outside membrane, which is what you see on the top. If, however, you have a cell body really close to that CSPG barrier, a growth cone might come out of it and grow into the CSPG, but in fact, it doesn't want to grow there, so it just reverses back out again. This is a really clear illustration that CSPGs are a physical barrier to regeneration. They are a dense matrix formed of those sugar chains which don't want to let nerves grow through. Next slide, please.
Now, in 2015, a really fundamental discovery was made. The identification of the receptor for CSPGs was made, and that was determined as being PTP sigma. Next animation. What was shown, and here we have nerves in green again and CSPGs in red. And what they showed in A, in the image to the left, was that when you have PTP sigma, again, nerves do not want to grow along that CSPG.
However, in B, on the image to your right, if you knocked out PTP sigma, so if you knocked out a receptor, those nerves could grow quite happily on CSPGs. What a brilliant team of scientists led by Professor Silver did was develop intracellular sigma peptide, ISP. So a wedge domain mimetic for the PTP sigma receptor that alters the signaling associated with preventing that growth.
Now, what you can see here is that when NVG-291 is given to a nerve that has a growth cone, which is what you see in that middle image, that is trying to grow on CSPGs, essentially, the NVG-291 enables that growth cone to stop trying to collapse in on itself and stop growing. It enables it to expand outwards and continue growing.
In the bottom image, what you can see again is that band of CSPGs around those neurons that we described earlier, and you can see that with NVG-291 given, those neurons quite happily grow over those CSPG boundaries. This was a really fundamental and important discovery. Next slide, please. Now, slightly arrogantly, I am going to take some time to talk about the work which is done in my lab.
My lab focused quite a lot on recovery of function at chronic stages after spinal cord injury because the vast majority of individuals living with spinal cord injury are at these chronic or long-term stages after an injury. We of course do look at hand or, because I work mostly in rats, forelimb function, but we also like to look at respiratory function because the vast majority of people with a spinal cord injury have injuries in their neck.
Of those, 70% of those individuals tend to have dysfunction in their respiratory motor system, so deficits which lead to complications in the months to years after the injury has happened. I am going to say that the image that you have on your slide right now is kind of complicated. It looks at the organization of the respiratory motor system.
But really I just want you to think about this as just two important factors. Firstly, you are a bit like a mirror right down the center of your body. So when you have control of your left, that side, that tends to happen from the left side of your spinal cord. Control of your right tends to happen sort of in the right side of your spinal cord. This means that certainly in the lab, we can do very specific injuries that injure just one part of your spinal cord. In this instance, one half of your spinal cord. Next animation, please. Here we see a contusion injury that affects one half of the spinal cord. Everything below that injury is affected by the injury.
In this instance, we have affected the forelimb function, but also paralyzed the muscles that enable respiration just on one half of the body, so one half of the respiratory muscles. That primarily includes the diaphragm, the major muscle you use for breathing in and breathing out. All right. We are now going to move on to some videos in the next slide. I just want to warn you guys, we are going to see inside of a rat. If you do not want to look inside of a rat, please look away now, and I will tell you when you can come back. All right, so moving on to the videos. What you should be able to see in the top video is an injured animal. What you can see on the right is the paralyzed muscle. This is not contracting.
You can see it being pulled to the opposite side of the thoracic cavity. Essentially, what you are looking at is a muscle which in the months after an injury has not recovered any function. However, below, when you use a treatment which targets the CSPGs, you can see that that diaphragm is now contracting normally. There is no muscle being pulled to the opposite side of the thoracic cavity, and that animal is able to breathe essentially normally.
This illustrates not only the really great promise of targeting CSPGs, but essentially why it is really important to look at respiratory function. All right. Can we go back to the slide, please? Wonderful. I am going to talk about one of the studies that we have been doing. We used one of those, what we call unilateral contusion injuries, so one half of the cord.
We left the animal after the injury, well we looked after it, I promise, for four weeks. This is an animal that can absolutely breathe on its own, can walk around, eat, drink, normally cause a bit of a nuisance of itself because that is what rats tend to do. We left it for four weeks. In terms of humans, that is approximately about six months after the injury before we started NVG-291 treatment through daily subcutaneous injections.
That treatment lasted for eight weeks, and then we just left the animals again alone, looking after them while monitoring them to see whether or not if any function that we regained would last after the treatment end. Effectively what we have is uninjured animals which are injured with vehicle, and animals with NVG-291. Next slide, please.
Now what you can see here is a trace of a diaphragm as an animal breathes in. There is beautiful bursts of activity as an animal breathes in. You can see in green in the uninjured animal. After our injury, we have very little activity in that half of the diaphragm. But with NVG-291 as a treatment, we restore the function in that diaphragm. This is incredibly important.
Now this is the data associated with that, and I want to take a little bit of time to explain it. What we are looking at is during normal breathing in air, the percentage of effort that that muscle is doing, the diaphragm, based upon the maximal amount that that animal is capable of. So in an uninjured animal, very similar to humans, the animal breathes at about 55%-60% of its maximal output.
However, after injury, because of the injury, because of the paralysis we have caused, that animal has to breathe at much higher percentage of its maximal output. So here we have at about 75%-80% of its maximal activity. However, as you can see on the middle graph with NVG-291 on board, so with eight weeks after our treatment, not only do we get a reduction again in that maximal output, as you can see by the figure beforehand, we got recovery and function in that muscle. So the NVG-291 restored function and decreased the relative effort of breathing in our animals. This was really exciting data. But interestingly for us, if we then looked a further eight weeks after the end of treatment, the NVG-291 further decreased to about 35% of the relative effort for breathing.
This indicates that the recovery in breathing of that breathing muscle is happening even after the end of NVG-291 treatment, aiding ventilatory or breathing function. Next slide please. I mentioned that we also like to look at forelimb function, so in exactly the same animals, the injury that we produce affects their left forelimb. This looks at the activity, the ability of that forelimb to move in an open field. After an injury, because it is quite a severe injury as you saw.
Next animation, please. Our animals, certainly their left forelimb, the other ones are functioning just fine, only has very slight movements of their joints. Very minimal movement. This does improve even in our control animals over time. However, in that treatment window, when we started giving NVG-291, we got a dramatic improvement in forelimb function.
The animals with NVG-291 on board, even after that eight-week washout, were able to do coordinated stepping with good weight support. In fact, their steps were very close to normal. It was just some ever so slight discrepancies. Whereas the controlled animals, while they could step, it was not coordinated, and it was very inconsistent. NVG-291 significantly improved forelimb function compared to control.
I am going to hand over a bit because I suspect I have gone over time. Before I do hand over to Marc, I just want to thank the people that funded that work. That is the Wellcome Trust and the Royal Society, and of course, NervGen for giving me the ISP. I also want to thank my brilliant lab, who are a wonderful team of researchers who you can see on the screen now. Marc, over to you to conclude.
Oh, thank you, Dr. Warren. That was a fantastic background on CSPGs, its inhibitory nature, and how it plays a role in spinal cord injury recovery. CSPGs are not only involved in spinal cord injury, but they play a major role in many other indications as well. The upregulation you see in the spinal cord and in the central nervous system after injury is not unique to spinal cord injury.
Any time that there is damage to the central nervous system, you see a similar upregulation of CSPGs in and around the injury site. This includes injuries such as stroke or traumatic brain injury, as well as neurodegeneration, such as Alzheimer's disease, where the plaques are surrounded by CSPGs, or multiple sclerosis, where those plaques are also surrounded by CSPGs.
Since our technology targets this very basic response, it has been shown to be effective in many different models of nervous system injury. On the screen here, we have several of the models in which we have shown efficacy. Over the years, there have been over 30 peer review publications in different injury models, showing that ISP or NVG-291 is able to improve functional recovery by restoring regeneration and repair potential following injury to the central nervous system.
With that, we have the potential to possibly go into several indications within the clinic. I am going to be handing it back over to Dr. Rogers, who will describe our phase I in which we did in healthy volunteers that will position us to be able to enter into multiple indications or any indications going forward with a healthy volunteer phase I data set that we currently have.
So Dr. Adam?
Thanks, Marc, and I want to thank Dr. Warren. It was really an excellent review. Marc, as you could see, the potential of NVG-291 as a true pipeline and a product is well-supported with the data that you showed in these publications. It will allow us in the future to initiate proof of concept efficacy studies in any of these indications.
Switching gears, we're going to focus now on our phase I study, evaluating the safety, tolerability and pharmacokinetics or PK of NVG-291 in healthy individuals. This is not data that we discuss much, but we want to review it in the next few slides. NervGen's phase I study randomized 70 healthy individuals. This study took place in Australia. These individuals received either NVG-291 or placebo, and the study consisted of three parts.
Part one included six dose levels in a single ascending dose cohort, where individuals received one injection of either NVG-291 or placebo. Part two included three dose levels in a multiple ascending dose cohort, where individuals received daily dosing of either NVG-291 or placebo for 14 consecutive days. Finally, part three consisted of an additional male and female repeat dose cohort of a single dose level of 14 consecutive days.
We observed no dose-limiting toxicities. We did not reach a maximum tolerated dose within the range studied. Together with the PK findings, these results supported advancing NVG-291 into individuals with cervical motor incomplete traumatic spinal cord injury. Next slide, please. NVG-291 was safe and well-tolerated. There were no SAEs. There were no adverse event related discontinuations among participants who received NVG-291.
There was a mild to moderate injection site reaction, and this was the most commonly reported adverse event, and we see this as well in the I-B/II-A CONNECT study that we'll talk about shortly. Next slide, please. When we evaluate PK following single and repeat dosing, NVG-291 showed predictable plasma PK with rapid absorption after subcutaneous administration, as seen on the left side of the slide.
The median peak concentrations occurred within the first hour, and systemic exposure increased with dose. With repeat dosing on the right-hand side of the slide, we observed steady state by day eight and no meaningful accumulation over the 14-day dosing period. This PK data supports daily subcutaneous injection as the route of administration in the clinic, which is an advantage of NVG-291 as it provides ease of access and use of individuals.
Subcutaneous injection is really what enables us to administer this drug at home in the future trials. Next slide. We are now going to move on to the I-B/II-A CONNECT study that enrolled individuals with chronic motor incomplete spinal cord injury, who are 1- 10 years post-injury. In the CONNECT study, NervGen evaluated safety and whether the biologic rationale of daily subcutaneous administration of NVG-291 targeting CSPGs would translate into measurable changes in neural connectivity, leading to improvements in function, as well as perceived overall benefit of change by the participant. Marc DePaul and I are going to walk through a few of these results as well, especially some of the motor evoked potentials, which was our primary endpoint in this study.
I am also going to get some perspectives from Dr. Abramoff and Dr. Sukhvinder Kalsi-Ryan as well. To begin with, I would like to turn this over to Dr. Abramoff for the next handful of slides, to help set the clinical context of spinal cord injury. Next slide, please. Dr. Abramoff, I am going to hand it off to you to dive into individuals with spinal cord injury.
Thanks, Adam. Hi, everyone. Thanks for having me. I am a physiatrist and spinal cord injury specialist at the University of Pennsylvania, where I care for people with acute and chronic spinal cord injuries. My goal over the next few minutes is to give some clinical context for what it actually means to live with one of these cervical spinal cord injuries, and how physiologic improvement can be very meaningful to quality of life.
Next slide. When we think about somebody with a spinal cord injury clinically, there are really two major things that determine the deficit: where the injury is and how much of the spinal cord is affected. The area that is injured determines the clinical deficit, and we can think about that in two dimensions, the level along the spinal cord and the pattern of injury across the spinal cord. Next slide.
Longitudinally, the question is: What level of the spinal cord is injured? Cross-sectionally, the question is: Which pathways within the spinal cord are affected, and how completely? These two pieces of information together explain why two patients who have, for example, a cervical spinal cord injury can look very different clinically. Next slide.
The cervical spinal cord, the top part of the spinal cord, is particularly important because this is where the pathways and nerve roots controlling the upper extremities are located. Higher cervical levels also contribute to things like breathing through innervation of the diaphragm. As you move down the cervical cord, you progressively pick up more function. It goes from shoulder and elbow function to wrist function, and then finger and intrinsic hand function. Even a gain of one or two neurologic levels can make an enormous functional difference. Next slide.
After the initial spinal cord trauma, there are really two stages of injury. There is the primary mechanical injury, the shearing or compression of things like nerves and blood vessels, and then there is the secondary cascade that comes afterwards with things like inflammation, edema, ischemia, and oxidative stress that evolve afterwards.
A lot of the acute management of spinal cord injury is really directed at limiting that secondary injury and preserving as much neurologic function as possible. Next slide. This slide is important for understanding chronic spinal cord injury. Most spontaneous neurologic recovery occurs relatively early after injury and then slows substantially over time. Early on, there can also be a great deal of uncertainty about how much recovery someone will likely have, and the focus is on stabilization and intensive rehab in order to have clinical improvement.
Once somebody is a year or more out from their injury, we are in a very different phase. Neurologic function is much more stable and large spontaneous gains becomes very uncommon. We can absolutely continue to have improvement through things like rehabilitation, improved compensation for their injury, the use of equipment and technology, but that is very different from recovering previously lost neurologic function. This is also why a new neurologic change in the chronic phase is potentially so important.
Small gains in a particular muscle can change what somebody is able to do independently. Next slide. Now I am going to discuss some of the specifics about spinal cord injury level. When we describe spinal cord injury, we define the neurologic level as the lowest segment where motor and sensory function are still normal on both sides of the body.
This level gives us a framework for prognosis and for thinking about rehabilitation, equipment, and function. But it is important not to overinterpret the level in and of itself. Two people with the same neurologic level may have very different function depending on the completeness of the injury, the residual strength, what sensation they may have, and age, and pre-injury health status, as well as some of the technology that they use.
Again, neurologic level defines remaining by medical joint motion, muscle strength available. It determines things like prognosis, and the equipment they may use, and you can continue. Then the same neurologic level can produce very different function. Next slide. Okay, some terms that we have been using, complete versus incomplete injuries. In a complete injury, there is no sacral or motor preservation. In an incomplete injury, some pathways are still functioning below that level of injury.
Incomplete injuries are becoming increasingly common over time, and they create a much wider spectrum in terms of function. Next slide. We describe the severity and the completeness of a spinal cord injury using something called the ASIA Impairment Scale, also sometimes called AIS scale. ASIA A is a complete injury. ASIA B is a sensory incomplete injury, meaning there is no preserved sensation in the sacral segments and no qualifying motor function below the level of injury.
These patients can have very significant impairment despite having some preserved sensation. Next slide. ASIA C and D are what we call motor incomplete injuries. In ASIA C, fewer than half the key muscles below the neurologic level have anti-gravity strength. In ASIA D, at least half of the muscles do have that anti-gravity strength. But even an ASIA D injury does not mean somebody is mildly impaired or functionally normal.
Someone can be classified as AIS D and still have significant hand weakness, difficulty walking, bowel and bladder dysfunction, and really substantial dependence for day-to-day activity. Next slide. It is also important to note spinal cord injury is not just about impaired motor function and paralysis. Patients deal with many other complications, things like bone loss and fractures, heterotopic ossification, which is excess bone formation, neuropathic pain, overuse injuries, fatigue, and spasticity. Next slide.
There are also important systemic complications, respiratory diseases, autonomic dysfunction, cardiovascular disease, blood clots, bowel and bladder dysfunction, sexual dysfunction, sleep apnea. One of the things we see in chronic spinal cord injuries is that small physiologic problems tend to cascade into more problems, hospitalizations, loss of function, more caregiver dependence.
Just one example would be if you have weakened arms, and they get weaker over time, or you have an injury that weakens them further, that can lead to more difficulty with transfers, more likelihood of things like pressure injuries, which leads to more costs, more trips to the hospital, more trips to outpatient clinics, more need for nurses to come into the home. These things tend to spiral over time. Next slide.
Now I am going to dig a little bit deeper into specific spinal cord injury levels to give some more concrete examples what individuals living with these cervicomedullary spinal cord injuries may be experiencing. At the C2 to C4 level, even in motor incomplete injuries, arm and hand strength is often extremely impaired. Many patients require help with things like eating, dressing, and transfers. Some use power mobility or adapted controls.
At higher levels of injury, breathing support may even be necessary. In this setting, an improvement in things like reach or grasp can change how much you need to depend on other people for activities. Next slide. At the C5 level, shoulder movement and elbow flexion give you much more ability to bring the hand toward the body and toward the face, but wrist and hand function may be still very limited.
For example, someone may be able to position their arm for things like eating, but may not be able to hold objects for things like gripping the utensils, and they may need special equipment to hold that utensil, or they may need special equipment for dressing or help with dressing, and often need help with things like transfers. Next slide. At the C6 level, wrist extension, which comes into existence, so these individuals have preserved wrist extension.
This allows for things like something called tenodesis grasp, which is when you extend the wrist, it allows the fingers to passively close around an object. This may help with somebody being able to hold a cup or utensil even without having that normal finger movement. But often, again, in these individuals, fine motor tasks allowing for things like catheterization, buttons, manipulating small objects, these things continue to remain very difficult. Again, so even a small improvement in function and finger control can be very meaningful for these individuals. Next slide. Now we are talking about individuals who have a C7 level of injury, which allows for elbow extension. This substantially improves things like transfers, pressure reliefs, and wheelchair mobility. Again, hand remains the limiting factor for these individuals.
At all these levels that we've talked about, an individual may still be able to do things like walk despite the substantial hand impairment, but walking ability, again, does not alone tell you whether somebody can do all these day-to-day activities independently. Manage money, manage medications, button a shirt, do their own bowel program. That's where hand function becomes so incredibly important, and that's true for pretty much all cervical spinal cord levels. Next slide. I want to just hammer home this key clinical message. Motor gains translate into the ability to do very specific activities. Being able to bring the hand to the face changes eating and grooming. Wrist extension can create functional tenodesis grasp to be able to hold a cup. Triceps function can change transfers and the ability to do pressure reliefs and prevent pressure ulcers.
Finger control allows things like the ability to catheterize, dress, use keys, touchscreens, remote control. When we talk about motor change, we're not just thinking about this as an abstract exam finding or something that we see in the clinic. Even a modest motor gain may be the difference between somebody needing total dependence for day-to-day activities, or needing someone to help set you up for tasks, or even being able to do something completely independently. Next slide. We know this is also a leading priority for our patients. There's multiple studies that show this, a classic study that's illustrated here. About 77% of respondents with tetraplegia and impaired hand function reported that hand function would lead to an important or a very important improvement in quality of life. This makes total sense clinically.
Hand function affects dozens or even hundreds of activities throughout every day, and each gain reduces your dependence on somebody else to help you. Next slide. Given that hand function is one of the leading things that patients care about and would lead to some of the most important improvement in quality of life, it's important to have a really good measure that allows us to analyze this hand function.
This is where the GRASP measure serves this function. It has measures of things like strength, sensation, and prehension, which is grasp. All these things together help determine what someone's upper extremity function is, which you can't really get this through just a normal strength exam in the clinic. You need something more specific, and that's what our next speaker is going to touch on now. Thanks, and I look forward to some questions later.
Thank you, Dr. Abramoff. That's really helpful because we discuss our RESTORE study and our CONNECT study often, and we discuss C7 or higher injuries, but I think your discussion really puts it into perspective of each of the individual levels and how it affects the individual. Really how hand function or improvement in hand function, how it can dramatically improve the function of an ability of someone to live on a day-to-day basis, which is what we saw in the CONNECT study. That's what we're going to talk about now is we're going to get into the CONNECT study. This was designed to evaluate if 12 weeks of daily subcutaneous NVG-291 could improve neural connectivity, function, and perceived benefit of change in people living with chronic cervical motor incomplete traumatic spinal cord injury.
These are all individuals that had, as you mentioned, tetraplegia or what we used to call quadriplegia. We chose a well-defined population that we believe would be best positioned to respond to NVG-291 treatment. When an individual is classified as having motor incomplete, as we just discussed, they are considered to have intact electrical signals from the brain down to end organs or to the muscles.
So there are still some electrical impulses that are getting through the area of the injury. The CONNECT study was at a single center in Chicago. It enrolled 20 participants with cervical motor incomplete injuries. These individuals all were 1 to 10 years out from their injury, C7 or higher, and they were randomized in a 1:1 fashion to receive a fixed dose of daily NVG-291 for 12 weeks, compared with daily injections of placebo.
We chose chronic injuries to remove the potential for any spontaneous motor recovery that typically can be seen up to the first 6 - 12 months, but after 12 months, we rarely if ever see any spontaneous improvement, as Dr. Abramoff discussed. After the 12 weeks of daily injection, we discontinued treatment and followed these individuals again for an additional four weeks off treatment.
The co-primary endpoints in this study measured change in motor evoked potential. Also, we will refer to this as MEPs for short, and we tested a single muscle in either the hand or the leg with the intent to provide an objective measure of motor connectivity. Secondary measurements evaluated functional outcomes such as GRASP and patient global impression of change.
We will refer to that as PGIC as well, as well as blinded patient-reported outcomes or blinded exit interviews to understand how the biological changes might translate into benefits in everyday life. Next slide, please. Across both arms, the participants were roughly three and a half years out from their injury. The longest individual in the treatment arm was out slightly below nine years post-injury, and the longest in the placebo arm was just under 10 years post-injury.
So we had individuals that were not just around a year. These were really spread out over the 10-year period. The study was generally well-balanced in baseline clinical characteristics, as you can see on the right-hand side of the slide, as well as participant and injury characteristics that are on the left-hand side of the slide. The range of neurological injury spanned from C2 all the way down to C7.
When we go to the next slide, similar to our phase I study, NVG-291 was generally safe and well-tolerated over the 12 weeks of treatment. There were no SAEs or treatment discontinuations in the active treatment group. As observed, and what we saw in the phase I study, the most common AE was a mild or moderate injection site reaction. This did not occur with every injection.
It might occur for two or three or four injections, and then an individual may not get an injection site reaction for another month or two. So it was really fleeting and occurred sporadically. We also did see in about 30% of the control arm, we also saw injection site reactions in them as well. No participants discontinued treatment. There was a dosing regimen adherence of 99.9% in the NVG-291 arm and 99% in the placebo arm.
I think looking at this adherence to the drug regimen, it really speaks to the determination of the spinal cord injury community and their desire for a therapy to improve function. Next slide, please. Before we get into the primary outcome, which was motor evoked potentials, I am going to bring Marc DePaul back in to provide a brief overview.
Marc and I are going to go back and forth here on the next few slides. The first one, Marc is going to talk about motor evoked potentials. I will discuss the results that we saw, and then Marc is going to come back on, and we are going to discuss the startle motor evoked potential or startle MEP. Marc, if you could discuss the MEPs, how we conducted them, and really what story they tell us following muscle stimulation, that would be helpful to the audience. Marc, I am going to turn it over to you for this slide.
Thank you, Dr. Rogers. Yes, motor evoked potentials, or MEPs, are a way of assessing the connectivity between the central nervous system and the muscle, the end organ. This is conducted by providing an electrical impulse to the central nervous system and then measuring the response in the muscle. All of the individuals in our trial were motor incomplete, and they had some residual connections to the muscle. At baseline, every individual had a detectable signal in their muscle after stimulating the central nervous system. We asked a very simple question. We asked, when we stimulate the spinal cord at a given intensity, does the muscle response increase as time moves on, or does it stay the same?
The hypothesis is that as you repair the central nervous system circuitry and reengage the muscle units, the same stimulus should elicit a larger response in the muscles. To do this, we stimulated the central nervous system in two different spots, depending on if you are looking at the upper limbs or lower limbs. For the upper limbs, we stimulated just at the top of the spinal cord in an area known as the cervicomedullary.
That is right basically at the brain stem and the top of the spinal cord. That signal passes down the spinal cord through the injury and then out to the muscle in the hand, the FDI. For the lower limbs, the lower legs, we stimulated below the level of injury in the thoracic spinal cord. For this stimulation, the stimulation went through the spinal cord and then out to the muscles.
On the next slides, we'll show you the results, but the anticipated results, as we stated, was if we observe an improvement, that's read as increased connectivity between the central nervous system and the end organ muscle. If we go to the next slide, we can see exactly how the upper limbs and lower limbs fared in this assessment.
Thanks, Marc. Just stick around because I'm going to need you here in a second. After 12 weeks of NVG-291, we met the co-primary endpoint, and we achieved a statistically significant improvement in motor evoked potential amplitude compared with placebo after 12 weeks of treatment in the hand. In the hand, this was measured in the first dorsal interosseous, or as Marc pointed out, the FDI, and this is a muscle between the thumb and the forefinger.
The p-value that we achieved was 0.0155, which met our pre-specified threshold of 0.025 or less, and that achieved the study design for allowing success in either the upper or lower extremity. We hit success in the upper extremity. You can see that on the left-hand graph here, where the blue line shows an elevation above the baseline placebo.
The key finding in all of this study here is that NVG-291 provided objective evidence supporting improved corticospinal connectivity to the hand in people with chronic cervical motor incomplete spinal cord injury, and that NVG-291 demonstrated the ability of repairing the injured nervous system. The next slide, and I'm going to bring Marc back in for this one, is a second test that we showed, and we did on both the upper and lower extremities. In the upper extremity, we measured in the first dorsal interosseous. In the lower extremity, the tibialis anterior, which is the muscle adjacent to the shin bone. Marc, if you could explain the startle MEP for the audience, that would be helpful.
Sure. The previous test we did was investigating the corticospinal tract, which is involved in voluntary movement. When your brain says move your hands, the corticospinal tract then tells your hands to move. The pathway we're testing here is another motor tract, but it resides in the brain stem, as you can see in the figure on the left, where the reticular formation is, and then sends its axons down the spinal cord.
This motor pathway is involved in more gross motor movement and stability, and non-voluntary motor tone. What happens after spinal cord injury is the corticospinal tract that's involved in voluntary movement is oftentimes more severely damaged than the reticulospinal tract that we're looking at here. The reticulospinal tract becomes overexcited and overcompensates, causing an exacerbated and large response to an otherwise what would be a normal response.
What this ends up looking like is following spinal cord injury, when you interrogate the reticulospinal tract, there's actually an increase in this signal as opposed to a decrease like we saw in the corticospinal tract. The way we investigate this is very similar to how we investigated the previous corticospinal tract. We actually stimulate the same exact locations and record from the same muscles.
The only difference is that along with electrical stimulation in the spinal cord, we also provide an audio tone that causes a startle response in the individual. The audio tone goes through the ears and is integrated within the brain stem, and then it sends its axons down the spinal cord to modulate the response of the corticospinal tract.
In this case, the audio tone signal that is produced travels through the injury for both the upper and the lower limbs, as opposed to when we're just investigating the corticospinal tract by itself, the lower limbs were only stimulated below the level of injury. In this case, both upper and lower actually travel through the injury site, and then we measure the response in the muscle itself.
An expected response for this, as individuals recover and their corticospinal tract increases its contribution, you see a corresponding decrease in this reticulospinal startle reflex. What we expect to see is if we're improving individuals' repair and function is a decrease in this signal. On the next slide, we'll see what occurs in the upper and lower limbs.
Yeah. So thanks, Marc. That's what we saw in both the upper and lower extremities in the tibialis anterior and the first dorsal interosseous, which is we see a decrease in the startle motor evoked potential, which is what we wanted to, and these were both statistically significant. These two findings are really critical, as they support a normalization and a rebalancing of the corticospinal and the reticulospinal signaling pathways.
Together, these measures really provide evidence of changes in the motor pathway activity that are consistent with our biological rationale and the objective of treatment with NVG-291, which is what we're seeing is we're seeing evidence of repair of the injured nervous system here electrically. The next question is, how does this translate into functional impact?
As we get into the functional responses that we saw in this study, I'm now going to bring on Dr. Sukhvinder Kalsi-Ryan from Toronto, who's the lead developer of the GRASP test. GRASP, as we get into this RESTORE study that we've just kicked off, it's going to be our primary endpoint. So Dr. Kalsi-Ryan, it's a pleasure to have you on, and look forward to hearing about the GRASP study in more detail.
Okay. Well, thank you for the segue into my talk today. I am also very happy with some of the discussions that Dr. Abramoff and Dr. Warren have had already, really have set things up nicely. Good morning to everyone, and it is a pleasure for me to speak with you today. My goal today is to really provide you a clear understanding of the primary endpoint used in this phase III study, the quantitative prehension sub-test of the GRASP outcome measure. In addition to the tool, I will talk a little bit more about arm and hand function, its significance, and how meaningful this study really is to PLEX. PLEX stands for People with Lived Experience, so I will refer to people with spinal cord injury with that acronym. Next slide, please.
I am a physical therapist by training and began my career as a patient-facing therapist in the world's first surgical spine program based out of Toronto, Canada. Early on, I developed a strong passion for restoring function in people living with neurological deficits, and that interest naturally led me to focus on hand function, which quickly evolved into developing new assessment measures for spinal cord injury.
Because at the time, the field really lacked a sensitive tool. Two decades later, I remain a practicing physical therapist and now serve as a clinician scientist at the Kite Research Institute in Toronto, where I lead my Neurorestorative Upper Extremity Lab. I divide my time between studying new opportunities to restore function and continue to treat patients. Next slide, please. For any person, the hand is the primary means of interacting with the external environment. Our hands are essential to survival.
We use them to feed ourselves, care for ourselves and others, and perform our work. Therefore, hands are a profoundly important part of daily life. Next animation, please. If you take away the body's ability to do other things, such as walking, the hands and upper limbs become even more important. That is why it is widely recognized that for people with spinal cord injury, regaining upper extremity function is among the most important factors in improving quality of life after injury.
As a scientific community, we therefore view the restoration of hand and upper extremity function as a major challenge to address. It is also important to understand that hand function, even small neurological changes, can translate into meaningful functional improvement for PLEX. Subtle gains can still have real significance. Next slide.
This is the first drug that can be applied to a completely different cohort of PLEX than any previous compound studied to date. Drug development in spinal cord injury has focused for years on the acute population. This study is important for a few reasons. For the first time, the prevalence population can be offered a treatment, not just the incidence population.
In other words, this treatment has the potential to benefit people already living with spinal cord injury, not only future cases. Second, the treatment window is much broader, making it possible to intervene months to years after injury, whereas most drugs that have been studied are only available to the acute cohort. And third, because the drug is being studied in incomplete injuries, the potential for transferability to non-traumatic spinal cord injury is much more realistic. Next slide. Earlier I mentioned the gap.
Let me tell you about the gap. When I first set out to develop restorative treatments for spinal cord injury, I quickly shifted to developing an outcome measure because there was a critical gap. An upper extremity measure specific to tetraplegia that could capture subtle change did not exist. This became especially important because in 2006, as clinical trials began shifting from mostly thoracic and mixed injury levels to cervical levels, while drug companies were preparing to study therapies in the cervical subgroup, they did not have a sensitive outcome assessment to detect changes that might result from new treatments. Two clicks, please. Between 2006 and 2009, we developed a tool that was clinically feasible to administer, sensitive to subtle change, and appropriate for both acute and chronic spinal cord injury in the development of new therapies.
In 2009, we launched a validated version one, followed by version two in 2018, and the myelopathy version in 2020. GRASP version two will be used in this particular study. Two clicks, please. Although GRASP was launched in 2009, its use in clinical care, research, and R&D has contributed to it becoming a reliable gold standard. It has evolved from an exploratory outcome measure to a primary outcome in many rehab trials.
Today, not only is the research community interested in using it, but PLEX are as well because it helps them relate changes in the assessment to changes in their own function and capability, which is what matters most to them. Next slide. Before I go into more detail about the development of GRASP, I would like to acknowledge the research team that has supported me from the beginning.
Alongside the unwavering support of my colleagues, I also want to recognize the early funding that helped make GRASP possible. Next slide. Because a hand is such a complex organ, we created a multidimensional outcome measure and an underlying construct to define its functional state. That construct incorporates sensation, strength, and prehension.
For each of these domains, we use specific tests that generate a numeric score representing the deficit, with values closer to zero indicating greater impairment. To assess sensation, we use Semmes-Weinstein monofilaments at the three locations on the palmar surface of the hand, producing a score from zero to 12 for each hand. For motor function, we assess 10 muscles in the arm and hand, producing a score from zero to 50 per hand.
For prehension, we examine how well the individual can perform specific prehension patterns, and then assess how successfully they complete tasks using those same patterns. While both sensation and strength are important, today we will focus on the prehension domain because it is the primary endpoint of the study. Each subtest can be scored independently, or the subtests can be combined to generate a total GRASP score per hand.
Next slide, please. Prehension is defined as the act of holding or grasping an object. Dr. Christer Sollerman, a hand surgeon from Sweden, studied hand function in healthy controls and concluded that eight core prehension patterns account for 100% of daily hand use. We selected four of those eight patterns for inclusion in GRASP. Together, those four patterns account for 75% of daily functioning.
This is how we ensured that the test is both relevant and relatable to everyday function for PLEX. In quantitative prehension, each prehension pattern is paired with a task, and performance is rated based on completion, time, and quality. Each task is scored from zero to five, where zero indicates no hand activity and five indicates normal or near normal performance.
Scores of one and two reflect partial task completion, three reflects task completion with reduced movement quality, and three or five reflect completion with more normal hand movement. Higher scores indicate greater neurological recovery. As a person begins to use the prescribed prehension pattern to perform the task, this reflects gains in sensory motor function and improved hand control. At the subtest level, total scores range from zero to 20 per hand and zero to 40 bilaterally.
Scores between zero and 10 indicate little function and no task completion. Scores between 10 and 20 suggest that some tasks can be completed while others cannot. Scores from 20 to 30 indicate that most tasks are being completed, while scores from 30 to 40 indicate that all tasks are completed with near normal quality.
Overall functional gains are generally observed up to a score of 24, while scores above 25 suggest additional neurological recovery. Using prehension patterns to evaluate hand function is important for three reasons. First, by using the four selected patterns, we account for 75% of the activities a person performs on a daily basis, making the assessment relatable to everyday function. Second, the score structure for quantitative prehension allows us to capture changes that reflect neurological improvement. Third, next animation.
Because we evaluate both task completion and movement quality, we are able to detect more subtle changes. For example, a person using a pinch meter may show no increase in force over time, yet that same individual may be able to perform a task such as moving pegs. One form of assessment would suggest no change, while the other reveals meaningful subtle gains.
When I say that there was no measure available when we began developing GRASP, I meant that there was no robustly developed assessment with strong reliability and validity that was suitable for use in clinical trials. When GRASP was launched in 2009, the first measurement property we evaluated was reliability or reproducibility. This refers to the ability of the assessment to produce consistent results when administered by different raters or by the same rater over time. Next animation.
The second property we examined was its association with other established tools, and the findings showed that GRASP was strongly associated with upper limb function. Next animation. Third, we assessed its sensitivity and confirmed that it was more sensitive than the gold standard measures available at the time. These measurement properties were a key reason for the strong uptake of GRASP early in its development. Next slide, please. In multicenter clinical trials with multiple raters, several factors are essential to minimizing rater variability. The first important piece to the puzzle is to ensure that you have a reliability of your assessment tool that is greater than 0.80 or greater than 80%, and that we've done already with the GRASP.
We then should always implement a standardized education module, ensure that the training is led by content experts, and confirm that raters have the competency to deliver or to administer the test. We follow this with trial progression. As the trial progresses, ongoing support through post-training follow-up is also quite important. In this study, there is strong emphasis on consistent assessment procedures across all sites, as well as on having the same rater assess the same patient whenever possible. Next slide.
In summary, we have discussed the importance of upper extremity function and why it has become such a critical focus in spinal cord injury trials. We have also established why this clinical trial is so important to the community. It offers people with chronic incomplete spinal cord injury access to a potential new treatment with a broader application window than therapies studied in the past. Finally, we have confirmed that the selected primary endpoint, the quantitative prehension subtest of the GRASP, is a robust, reliable, and valid outcome measure that is sensitive to subtle yet meaningful changes in hand function in people with cervical spinal cord injury.
Thank you very much, Dr. Kalsi-Ryan. That was fabulous and really a very comprehensive review of GRASP, which it segues perfectly into what we're going to talk about next, which are the results that we saw at NervGen for GRASP quantitative prehension, and we're even going to get into the GRASP total scores. In the CONNECT study, we saw greater improvement in GRASP quantitative prehension with NVG-291 at week 12, most notably with both the placebo adjusted mean and the median change from baseline.
We exceeded the established minimally important difference, or MID, of two points. This two point level is important because at or above which individuals show clinically meaningful improvements, such as the ability to comb their hair, brush their teeth, or button their shirt, which as we'll see in a few slides, these are activities that individuals gained after treatment with NVG-291 therapy.
The average improvement that we saw, which you'll see on the left-hand side of the slide, was 3.7 points with NVG-291, compared with 0.4 points with the placebo, which is an observed difference of 3.3 points. The individuals are broken out as a waterfall on the right-hand side, and you'll see that six of 10 individuals were able to have a two point improvement or better, which is greater than or at the level of the minimally important difference compared to the placebo, which you can see. We reviewed this result as a positive signal of clinically meaningful improvement in functional hand use, and this warrants confirmation in a registrational setting. When we go to the next slide, we're going to look at week 16, which is we discontinued treatment at week 12.
We followed individuals again for another four weeks off treatment. Then we looked at GRASP quantitative prehension again. What we can see here on the left side of the slide in the bar graph is that the NVG-291 treatment arm obtained an improvement on average of 4.4 points above baseline, compared with 1.2 points for placebo. Again, at week 16, we are exceeding the minimally important difference of two points.
The maintenance of improvement that persisted after dosing ended is consistent with our hypothesis that NVG-291 is enhancing plasticity and reforming lost neural connections. Basically, when we discontinue NVG-291, very much as we saw in Dr. Warren's presentation, once we discontinue drug, we are not seeing the functional benefits they gained. We do not see these individuals falling off a cliff and losing the improvements that they gained during treatment.
Basically, once these neural connections are made, we are not losing them after drug is discontinued. Next slide, please. We also looked at GRASP total score at week 12 as a supportive assessment of really broader upper limb improvement. This composite brings together strength, sensation, and prehension, giving us additional context for the hand function changes that we just discussed with quantitative prehension.
At week 12, the mean improvement was 8.7 points with NVG-291 compared to 4.3 points with placebo. The median improvement was 10 points with NVG-291, compared with just 0.5 points in placebo. The importance of these findings in the GRASP Total Score is really just the consistency that we are seeing with the quantitative prehension results, and this just adds support to the overall pattern of functional improvement that we are seeing in these NVG-291 treated individuals.
You can see the waterfall results on the right. As we go to the next slide, in slide 75, you can compare both the graph on the left and the waterfall on the right. Just as we saw in the quantitative prehension, upper limb improvement that we see in GRASP Total Score was maintained four weeks after treatment discontinuation. We do not see a drop-off or loss of function after we discontinued the drug. The GRASP Total Score increases to 12 points with NVG-291, compared to 4.7 points for placebo. Again, you can see the waterfall, which actually becomes more robust in the NVG-291 group on the right. Next slide. We also looked at Patient Global Impression of Change, or PGIC. I will use these two terms interchangeably.
We asked participants, we wanted to know how they felt their overall condition change and what they perceive that benefit to be on a seven point scale from very much worse, which gives one point, up to very much improved, which is seven points. All of these assessments in both the NVG-291 and placebo arm took place a median of 296 days after study completion. This occurred during our blinded exit interviews.
Both the interviewer as well as the participant in the study were blinded to their treatment arm at this time. Among those participants providing response to PGIC, six of eight in the NVG-291 group, or 75%, described themselves as very much or much improved, compared with just three of nine in the placebo arm, or 33%, who only noted that they were much improved. This adds to the participant's own perspective.
It adds to the functional findings and really helps us understand that these individuals that are receiving NVG-291 perceived a meaningful difference in their overall condition. This is important. As we move forward and we had discussions with the FDA wanted to know not only what is the functional benefit, but how does an individual perceive this on a day-to-day basis?
In addition to the PGIC, if we could go to the next slide, please, we performed blinded exit interviews that were really performed to further contextualize the clinically meaningful results that we saw after 12 weeks of NVG-291 subcutaneous treatment. As you can see, 67% of the individuals reported improved bladder control. Bladder function is really a major issue with individuals that have spinal cord injury. What does this improvement mean? It means less catheterization.
These individuals experienced less leaking, and they had the confidence that they could perform activities such as driving in a car or sleeping in a bed, and they had the knowledge that they would know when they had to void. It really gave them much more confidence that they could do activities without having an embarrassing episode of leaking. 56% of these individuals reported reduction in muscle spasticity, which these are really painful muscle contractions that are seen after spinal cord injury, whether it is from minor trauma, you bump your leg on something or changes in temperature. If you look at the bottom, this is really from the blinded exit interviews and quotes from these individuals, and I think these are real-world improvements that we saw.
Ability to brush your teeth, comb your hair, button your clothes, prepare food, meaningful functions that can reduce an individual's reliance on a home health provider or a family member and really improve their independence. Next slide, please. I am going to bring Marc DePaul here in a second, but we also performed video analysis. All of the individuals, whether in the NVG-291 or the placebo arm, performed a 10 m walk test in the CONNECT study. What we wanted to do, we not only looked at time, but we wanted to really evaluate what was their improvement in walking function in treatment versus placebo. Before I hand this over to Marc, I am hoping these videos will run. If not, the gentleman on the left is one of two individuals that was unable to complete the 10 m walk test.
He was in the NVG-291 treatment arm, and both were able to complete it after 12 weeks of treatment. This is the same individual. He cut his hair. You will notice that he is wearing the same pants. Marc, I am going to hand this over to you to discuss the video analysis that we did. Just so everyone understands that the individuals doing the video analysis were blinded to the treatment of these patients. Marc?
Thanks, Adam. As Adam indicated, we observed improvements in the 10 m walk test in both groups. Both the placebo group and the NVG-291-treated group improved their speed. However, when reviewing these videos, there were two general parks that the individuals fell into. One looks like that they increased their speed through compensatory means by throwing their body forward, pressing against the floor in order to generate energy and throw their limbs forward in order to increase their speed. Then others, it looks like that they improved their speed and also improved the quality of their walk. It looks like that they had more control over their limbs and were able to move at a faster pace in a controlled manner. In reviewing the spinal cord injury literature, there are three metrics that should improve if you are improving neural control of your walking.
The first is coordination, and this is coordination between the joints, how well does the hip and knee work with each other, and how well does the knee and ankle work with each other. Joints that move together are coordinated. The second is mechanical effort. In order to increase your speed, the energy needs to come from somewhere. Where are these individuals generating their energy from?
Are they pushing off the ground and launching their limbs forward to increase their speed, or can they lift their limb off of the ground and then consciously think about it and use their muscles and their nervous system to increase their speed? The third is postural stability. As you improve your trunk stability and improve your walking, your posture also improves.
We investigated this, especially at the single stance when an individual has one leg off the ground and is advancing forward, we took a look at their postural stability. As Adam stated, we had two videos for each individual at baseline, and then at the end of treatment at week 12, we had these analyzed completely blind.
The group that analyzed the videos received the 40 videos and returned them back to us, and then we were able to divide them into the treatment groups. What we found, if we go to the next slide, is that across the three hallmarks of recovery, coordination, mechanical effort, and postural stability, the NVG-291 subject showed significant improvements in each individual test.
Now, when the nervous system is improving and repaired, you would expect improvements in all of these metrics, or at least have improvements in several metrics at the same time, versus potentially a single metric in which can be explained through compensation. What we next asked is, we see group wise differences across these three metrics, but as a whole, do the NVG-291 individuals improve across all three metrics when compared to the placebo? In order to do this, on the next slide, we ran the global statistical test, which incorporates all three assessments into a single data point. If you do well in one and bad in another, those will average out to about average and have no real movement.
If you do well in all three of them, you will get an increase in your score, or bad in all three, you will get a decrease. What we found at the group level across all three metrics is that the 291 subjects, again, significantly improved compared to the placebo subjects. Such that if you took any random 291 subject and compared them to any random placebo subject, there is a 73% chance that the 291 subject was outperforming the placebo subject. One thing to note is the treatment of benefit was quite large, and the 95% confidence interval was completely in the positive, suggesting that this is a true biological effect that we are observing and not due to chance. This table shows that we have a group wise difference across the three metrics.
The next question we asked, were there any individuals that were responders in these metrics, or is this sort of being driven by certain individuals? If we go to the next slide, we could see what the individual responder analysis looks like. Over on the right is the composite score across the three metrics. Each individual is represented in their own responder analysis.
The thing to note here is that every single 291 treated subject outperforms the majority of the placebo subjects. We could break this down into the individual subject scores across the metrics, which is the heat map on the left, where a plus one shows that an individual beat every single subject on the opposite treatment group, and a negative one shows that they lost to every single subject in the opposite treatment group in that assessment.
One thing to note here is that the green, the positive values, reside almost primarily in the 291 group. When an individual improves in one metric, they tended to improve in many of the metrics. This is a hallmark of neural repair. As opposed to the placebo subject, a few of the placebo subjects did improve in one metric or another, but it was typically in that single metric.
The gains are typically much smaller than the others. What this tells us is that we are not only seeing improvements in these individual metrics, but when taken together, we are getting a strong signal that our treatment is improving overall neural control of their locomotion. I will hand it back to Adam for any additional comments he would like to make on this data set. Adam, you are muted.
Thanks. I find this really interesting, Marc. Thank you very much. I think really when I look at this data, the walking data, and we could see this when we looked at all the individuals and the improvement in gait, especially in the 291 arm, but this really demonstrates the whole body effect that we are seeing from NVG-291, not just an improvement in the hand.
Let me switch gears for a little bit and let us just start to talk about the data from the CONNECT study. It really provided us with a strong foundation for advancing NVG-291 into the phase III RESTORE study here. This has basically propelled us to a point where we have the potential to become the first approved drug treatment for individuals living with spinal cord injury.
We have a mechanism of action supported by decades of target validation and preclinical research, alongside proof of concept efficacy in a chronic prevalent population that will not spontaneously recover, demonstrating objective evidence of improvement in motor signaling, enhanced function in key priority areas, and an increase in quality of life as reported by individuals treated with NVG-291 in the blinded exit interviews, as we saw compared with placebo.
In the CONNECT study, as well as in our phase I study, we saw that NVG-291 was safe and well tolerated. What gives us confidence as we move forward is that the RESTORE study builds directly on this foundation of neuro repair seen in the CONNECT study. We are bringing in a larger population focus, and we are focusing on functional hand use with GRASP. Next slide, please.
The next handful of slides are going to walk you through the RESTORE study, which is our phase III registrational study, and how we have translated our findings from the CONNECT and our discussions that we have had with FDA over the last year into its design. Next slide, please. We had a type C meeting in Q3 2025, and an end of phase II meeting in the first quarter of 2026 with FDA, and these meetings played a critical role in how we shape RESTORE's focus and endpoint framework as a single registrational directed study. The agency has been consistent in their guidance, and it is reflected by the three points on the slide.
FDA asked that we focus our primary endpoint on a functional measure that is clinically meaningful and a key recovery priority for the cervicomedullary motor incomplete SCI population, which is hand function, and we have discussed this for most of the morning. This is how we selected GRASP quantitative prehension as our primary endpoint.
FDA also requests that we support our primary endpoint by ensuring that individuals on treatment are reporting a perceived benefit, which we are measured by PGIC, along with the perceived benefit by their treating clinicians, which we will measure by CGIC or Clinician Global Impression of Change. Finally, FDA stressed the importance of blinded qualitative exit interviews to contextualize the observed results so that we understand the real-world impact of NVG-291 treatment on participants' everyday lives.
There is a functional benefit, and FDA wants to understand how does that translate into how the patient feels that they have done. Next slide, please. As you can see from this slide, RESTORE retains the core foundation of the CONNECT study while we increase the number of individuals to 150 participants. Just as in our previous I-B/II-A study, we will enroll individuals with chronic traumatic cervicomedullary motor incomplete spinal cord injury.
These individuals will be one to 10 years post-injury and randomized in a one-to-one pattern of NVG-291 with placebo. They will receive, again, daily subcutaneous injections of NVG-291 followed by four weeks of observation off treatment. There will be an optional 12-week open label extension that will follow the main study. Primary assessment is now GRASP quantitative prehension at week 12.
Key secondary endpoints focus on global assessments such as PGIC and CGIC, as well as additional measures of independence based on the blinded exit interviews, as I discussed on the last slide. This FDA-aligned phase III design allows us to evaluate hand function while assessing the broader impact of treatment. Next slide, please.
Successful execution of the core aspects of the RESTORE study is vital to our success. This includes rigorous oversight of the administration of GRASP. Quantitative prehension is our primary outcome to support consistent assessment across multiple sites. I think Dr. Kalsi-Ryan really discussed this eloquently, but I am going to go over here what we are doing. We have engaged a specialist vendor to ensure the GRASP training and that there will be ongoing certification independent of our CRO. Enrolled subjects will be assigned the same rater throughout the study.
We will maintain central video review with continuous quality checks throughout the study. These oversight measures are designed to ensure quality, consistency, and rigor of our primary endpoint data. Next slide, please. RESTORE is also designed to support at-home dosing, and this is an important aspect of RESTORE as we work to bring the study to the individual and remove any geographic barriers to entry.
This is a subcutaneous injection at the end of the day. To ensure competent at-home administration, we are also undertaking a number of steps to ensure success. The first dose of drug is going to be given at the study center with both training and observation by the site's principal investigator. On day two, a nurse at the study subject's home will demonstrate preparation and administration for both the participant and their caregiver.
On day three, the participant and the caregiver will perform all steps of administration of the drug under nurse observation to assess competency and ensure the study drug can be administered without any issues. We are also going to continue with the study team at each site. We are going to have them follow up on a weekly basis for the first month to review dosing, reinforce training, and address any questions or changes in the individual's health. We also have written and visual instructions, as well as an administration video showing how the subcutaneous injection is performed, and we are also providing a dosing journal. Additional support with the ultimate goal to ensure consistent administration of NVG-291 at home is what we are after here.
We feel that all of these steps that we put in place, we are very confident that this is going to ensure proper drug administration and adherence to the dosing. Next slide, please. RESTORE is 90% powered to show a 2.5 point treatment difference in GRASP quantitative prehension at 12 weeks, and this is considered to be clinically meaningful. At this point in time, I want to introduce Christine McSherry and Barry Munro and turn the presentation over to them. I think we are going to start with Christine first to discuss the community perspective and how individual and caregiver priorities inform the work that we are doing here at NervGen. Christine, thank you, and Barry, thank you as well.
Of course. Thank you, Adam. Hello, and thanks for letting me be here. Just a little bit about my background, so you understand why I am here and why that background brought me to NervGen. 25 years ago, in 2001, I founded an organization, Jett Foundation, for my son Jett, who lives with Duchenne muscular dystrophy. Jett Foundation went on to play a pivotal role in the advocacy surrounding the first drug approved in Duchenne.
I later co-founded something called Casimir, where we developed novel outcome measures for diseases with high unmet need. Today, I have the privilege of shaping patient advocacy and clinical affairs at NervGen. Those may sound like very different chapters in my career, but actually to me, they are the same story. In 2016, I sat on the sponsor side of an FDA advisory committee for the first Duchenne drug.
I bring that up because what I learned through that experience directly informs how I think about spinal cord injury today and some of the reasoning behind why we designed RESTORE. FDA was looking at the study data, including the 6-minute walk test for that drug in Duchenne, but families were seeing things that were not necessarily captured by that number.
The boys were not necessarily walking faster, but they were walking further. They were getting up off the floor after falling, not faster, but without any help. They could get themselves a snack independently. That might sound like small distinctions, but they were not in Duchenne. Walking further meant making it to more houses on Halloween. Getting off the floor independently meant a young man might safely be left home alone.
Getting a snack meant the difference between sitting at the table, at the lunch table with peers versus sitting alone with an adult who has to help them. The measurement told us something changed, but the person living with Duchenne told us what that change actually meant, and collectively, that helped inform the benefit-risk discussion at FDA.
We, the Duchenne community, had to bring much of that context forward after the fact, after the study. Today, we have the opportunity to do something different. We can think about meaningful benefit perspectively, and that is why I came to NervGen. As you have heard from all the speakers, spinal cord injury is extremely heterogeneous. Two people with what appears to be a very similar injury can experience very different functional consequences. In some ways, each person can almost look like their own rare disease.
Coming from rare disease, that felt very familiar to me. The challenge became: how do we design a study that measures function rigorously but also captures what that function actually means to the person experiencing it? Because when we listen to the SCI community, as you have heard over and over, we hear very clearly that hand function really matters, and bowel and bladder really matter, and less visible functions even matter. Sensation, blood pressure, temperature regulation, intimacy can all affect daily life profoundly. Every day, I hear things like, "People think the hardest thing about being in a chair is not being able to walk.
That is hard, but what is really hard is not being able to do the simplest things with my hands and always having to ask for help." One thing that stayed with me all these months since I have been here at NervGen is an older gentleman said to me, "I really miss the intimacy in my life. Just being able to hold my wife's hand or touching her knee and communicating that love and being so proud when we are watching our children raise children of their own." Those are not abstract concepts. They are function, independence, human connection, dignity. If I take what I learned in rare disease and apply it forward to spinal cord injury, it comes down to this: Listen to what matters, measure it rigorously, connect that measurement back to the life of the person experiencing it. That is the wonderful opportunity I see with RESTORE.
Importantly, of course, we have something in GRASP that allows us to measure that functional change. Following our end of phase II meeting, we achieved alignment with FDA on the RESTORE study parameters, including GRASP quantitative prehension as the primary endpoint, as you heard Adam Rogers talk about. We are not stopping at GRASP in whether or not the score changes.
We are also using patient and clinician global impressions and qualitative exit interviews to understand how those changes actually show up in everyday life. This is not just my view of where drug development should go. I recently heard Dr. Janet Woodcock, now retired Dr. Janet Woodcock, who spent decades at FDA, including as Director of CDER, Deputy Commissioner, and Acting Commissioner, make essentially the same point. Clinical trials have traditionally worked best in relatively homogeneous populations.
In heterogeneous populations like SCI, we have to think differently about endpoints, meaningful function, and what matters to the person. For me, that brings the story full circle. A decade ago in Duchenne, we brought those families into the room to help FDA understand what a measured change actually meant in someone's life. Today, that concept is actually embedded much more formally in FDA's patient-focused drug development framework.
Now, as of yesterday, SCI had its own patient-focused drug development meeting, creating that formal mechanism for this community to tell regulators what meaningful benefit looks like for them. We are fortunate. We are not blazing an entirely new regulatory trail. There is an understanding of importance of contextualizing that data of clinical benefit at FDA. Our challenge is the heterogeneity.
We still have to do the difficult scientific work of creating as comparable of a study population as possible so that we can see the treatment effect. If we see that treatment effect, RESTORE is now designed to help us understand what it means. That is the progression for me, from Jett Foundation to Duchenne, to Casimir, and now to NervGen. Listen to what matters, measure it rigorously, connect that measurement back to the life of the person experiencing it.
Because meaningful recovery is not just about a number changing, it is about what that change allows someone to do. Sometimes what it gives back is something even bigger: independence, human connection, and dignity. That is the perfect place for me to introduce Barry Munro. Barry Munro is an attorney and a tireless advocate for the spinal cord community.
He has served his community in numerous capacities. Yesterday, he helped lead the spinal cord injury patient-focused drug development meeting that brought the community together to tell FDA directly what it means to live with spinal cord injury and what that meaningful change actually looks like. Barry, please introduce yourself. You were in the room yesterday, tell us what FDA heard.
Thanks, Christine, and thank you for the opportunity of being here today. The joy of being in this conversation is something that we've been advocating for a while in what we call partnered research. The only way we're going to see genuine therapeutics that will help people with spinal cord injuries, especially in our field, is by partnering and working with companies like NervGen and the FDA and the community as a whole.
Only together will we get it done. I've been at this for 39 years, since my injury in 1987. I'm a C5 quadriplegic and have seen sort of the desert, and maybe now we're into the oasis, I'd like to think, going forward and seeing some actual applications of therapeutic things coming out that will genuinely help people with spinal cord injuries.
For decades, I've heard the community hearing from the outside world that, "Boy, wouldn't it be great if you could walk again?" But we've been told, and we've told others since 2004 in the seminal Kim Anderson paper, saying, "Those aren't our priorities. Our priorities are bowel, bladder, pain, and spasticity." These are the main things that really affect the daily living of people with spinal cord injuries.
Unless you live with someone with an SCI, you won't really know that or been around somebody like that. The PFDD opportunity that came along was such an enlightening aspect where we had finally a chance to put this in front of everybody. We were told yesterday that it was one of the most well-attended PFDDs ever done, which is great.
Over 1,000 people joining the call and countless submissions and phone-ins, as well as others who are genuinely galvanizing the community. It's trying to explain to the FDA, who are really listening, as to the other things that are important. Going back on the theme of today, I can't stress enough the comments we heard yesterday of just the mere fact that someone can gain fine motor skills in their hand and how that would change their life. I can say that personally, that I have met friends who have a higher level of injury as me, would just love to have somebody scratch their nose. Can you imagine that? Really, it's something in itself is a huge quality-of-life issue.
I think the best quote I heard yesterday was a quadriplegic saying, "There's regular time and there's quad time, or a quad second." Something that we all take for granted in picking something up would take maybe a matter of a second, could take us up to maybe a minute and a half, two minutes, if at all. If you imagine compounding that on every daily task you do throughout your day, you can think about what we go through with people with spinal cord injuries. It's really exciting.
What I also heard too was, this is coming from the community too, which really impacts all of us together, is looking at combinatorial therapies, and that the combination of different things that we know work, from electrical stem to therapeutics like NervGen, that these things combined can really make a difference. The FDA was listening.
We also heard from the community that we are a community that are not adverse to risk. We want things, and we're almost really, frankly, desperate. What people don't realize when they think of Parkinson's and MS, they know there's of a terminal nature, that there is a potential end coming based on a chronic injury or a chronic condition. It's like that with spinal cord injuries, too. Although we look stable, the secondary complications are killing us. Sepsis, bowel and bladder disease, these are things that are killing us right now. I've been saying this for a while, and I had a chance to say it 10 years ago in front of the NIH.
I said, "People are dying." At first, I was mocked for saying that, but now we're realizing that a generation of people with spinal cord injuries, as we do somewhat age, I can use the words of Christopher Reeve, that it's a form of benevolent torture. We have enough science and healthcare to keep us alive, but not enough to make us whole again or to cure us.
That's the part that we're all working on. I think the work that NervGen has done is exciting because you're addressing exactly what the community has been talking about, these incremental fine-tuning things. But the fact that you can affect bowel and bladder, it is life-changing. I know right now that the FDA is, their eyes are wide open, and they're listening to what we're saying, and this PFDD couldn't have come at a better time.
I know through my experience and leading up to this that in every case of a PFDD, exponentially afterwards, the investment and the approval of therapeutics and things that come afterwards are exponential because of the PFDD itself. These are good times, and we're excited about the future and how we're moving forward.
Thank you, Barry. That's fantastic, and I'm so glad it was a successful day. Thank you, everybody. I'm going to turn it back to Adam.
Barry, thank you very much. RESTORE is a real chance to change the trajectory of SCI treatment and improve function. I'm going to wrap this up before we go to the audience for questions. We are funded through phase III readout. We have a strong rationale for the RESTORE study, and we are a pipeline and a product, and we look forward to efficiently enrolling the study. I want to thank everyone for joining today, and let's turn it over for questions.
Thank you. We will now begin the question and answer section. As a reminder, if you have been provided with the link to participate in the Q&A, please use it to join and wait to be called on. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster.
While we-
Our first question-
Go ahead.
Comes from Marc Goodman with Leerink. Your line is open.
Yeah. Can you talk about the other potential indications that you were mentioning before and just which have the highest probability of success because they're the most related to, I guess, the good data that we saw in phase II? Just trying to think about that, maybe a question for the people who are not with the company as well as kind of a question for you, Adam. Thanks.
Thanks, Marc. Marc DePaul, do you want to answer that? I think it's based more on the scientific rationale, but do you want to take that to start?
Sure. Spinal cord injury is a monophasic injury. There's an event that happens, and then you're left with the aftermath events. My personal scientific belief is that we're likely to see better results in potentially monophasic injuries, where you're not fighting the biology in a degenerative condition. That's not to say that it wouldn't work in a degenerative condition either, because we have very strong preclinical studies to suggest that this does work in preclinical models.
In terms of next indication, there's a lot of factors that play. One of them is the scientific rationale. Others are the current landscape of that indication in terms of therapeutics. I think there's good scientific rationale to go into potentially any of the indications we showed in our slide at the end of the preclinical section. It's really going to come down to discussions we have with key opinion leaders within those areas, what the clinical landscape looks like, and what the actual development program would look like in order to address these other indications.
Marc, let me answer this. Marc, this is for you, Marc Goodman, as well. The way I look at it is indications such as stroke, multiple sclerosis, where we can show improvement in neuron regeneration. Those are the areas that we're thinking of at this point in time. I think we have another question.
Thank you. Our next question comes from Joseph Thome with TD Cowen. Your line is open.
Hi there. Good morning, and thank you for the presentation today. Just a few from me. It looks like for the clinical trial study, you're doing a lot to standardize in terms of rater reliability and rater competency. I guess even though these are chronic patients, is there an amount of learning on the GRASP scale that happens? I just know that there was one patient in the placebo arm that did perform kind of relatively outsized versus the others, and was just curious if there was any sort of learning component in GRASP over time that these patients see. Second, how do you think about potential redosing? Obviously, you're showing the longer-term follow-up data that patients continue to improve after the course that you looked at in the study, but do you think you could see even further improvement if you did redose? Thanks. Or dose for longer.
Dr. Kalsi-Ryan, do you want to answer the first question?
Sure. With respect to learning in general with any kind of assessment, particularly the GRASP, the GRASP is performed in one month intervals. So with respect to a patient being able to having learned the task and do better on it a second time is highly unlikely because of the time elapsed between assessment points. If there is some practicing of those specific tasks, they may show you a little bit of learning, but that is what you're looking for, is for them to develop a skill set. Sometimes that comes along with not just the drug, but also learning or practicing tasks with their hands.
I think, Joe, the second part of your question is would we expect improvement after a second dose. Is that correct?
Correct, yeah.
Okay. So what we saw clinically, obviously at 16 weeks shows we saw continued improvement. What individuals when they were in the blinded exit interviews, I don't think I touched on this enough today, even after the 12 weeks, those individuals that received drug noticed a stepwise improvement in their function that continued even up to the 296 days median after the study ended.
So they continued to see some improvement. Would a second dose help? Potentially, yes. I think that down the road, we look at this as a injury where individuals will receive multiple doses of drug. I don't look at it as a potential chronic use of a drug for the rest of their life. I think at a certain point, they will max out on their functional improvement, and then we'll stop treatment at that point.
Great. Thank you very much. Maybe just one more if I can. I guess on the outcomes on the GRASSP and the patients that you did treat, did you see any correlation to, I guess, localization of injury or time since injury? Or was it kind of, obviously, patients were doing well overall, but any sort of correlations that you were finding there?
We don't really have a profile at this time. That's a difficult question for us to answer at this point in time.
Okay, perfect. Thank you very much.
All right. Thank you very much.
Appreciated.
Can we take the next question, please?
Thank you. Our next question comes from Ami Fadia with Needham & Company. Your line is open.
Thank you for taking our question. I really enjoy the discussion today. Just the first question, for the phase III RESTORE study, are you planning any interim analysis to detect in case there's any sort of site variability, or if any particular site has drifted from the others during the study? Also, from the CONNECT study, did you see any relationship between the baseline GRASP severity and the treatment effect? Or is that something you might look at in the RESTORE study? Thank you.
Could you repeat the first question for me? I'm sorry. Let me answer the second question first. The second question, we didn't see much of a relationship between baseline GRASP. I think as we expand this to 150 individuals or 75 in the treatment arm, we probably will have a greater ability to evaluate that. Could you repeat the first part of your question for me, please?
Yeah. Sorry about that. Just wondering if you have any planned interim for the phase III.
Oh, the interim analysis. Yes.
To detect any kind of site variability or any kind of particular sites that might have a different scoring than the others?
No. We are working to maintain really a standardization of scoring, and that is through the teaching of it. There will not be an interim analysis. It is only a 12-week study, which is very brief. Despite the briefness of the study, even in the last study, we did see significant improvements in these individuals. But there is no interim analysis that is planned for this study.
Thank you so much.
Thank you.
Thank you. Our next question comes from Michael Freeman with Raymond James. Your line is open.
Yeah. Thanks for the presentation today, and I appreciate the work you're doing here, and the need you're trying to address. My questions today are on the upcoming phase III. While recruiting might be underway at the moment, I wonder how you are sensing the rate of recruitment following the evidence that you've yielded from your prior studies. It was a relatively long time to recruit your early studies, and I wonder how you're feeling about recruitment rates on phase III.
Sure. Michael, you were a little bit garbled, but I think the question was, what do we anticipate for recruitment rates?
Yeah, that's right.
Yeah. Okay, sorry. We anticipate pretty robust recruitment. We're dealing with the prevalent population. There is a pent-up demand of individuals that are looking for access. We are taking this study, instead of just one single site in Chicago, we are spreading it out over the United States and into five sites up in Canada. So we anticipate pretty robust enrollment.
We obviously just opened enrollment this week, as it's up on clinicaltrials.gov. We've done a few things to improve enrollment as well. We're no longer looking at motor evoked potential. We're really just dealing with GRASP quantitative prehension. I think some of the barriers that we had, which was, one, the geography of location, as well as the barrier of the MEP, and we're removing that, I think will aid us with the recruitment for this study.
All right. Thank you very much. [inaudible] [Another question. Potential CAD 350,000- CAD 500,000 for a one-week course. I wonder what understanding of the results of the phase III might steer the pricing of the drug within that range or potentially beyond that?]
I'm sorry. I wasn't able to hear it. That was a very garbled question. I apologize about that.
Yeah.
I heard about something about 150,000 individuals out there.
The question is on drug pricing.
Oh, drug pricing. I'm sorry. We've provided no guidance on pricing at this time. Okay, if we can go to the next question.
Thank you. Our next question comes from Andreas Argyrides with Chardan. Your line is open.
Thanks for taking my question, guys. Sorry if there's any background noise. I really appreciate this really thorough overview. Again, apologies if this question has been asked, but can you help us understand how the FDA and external clinicians view the clinical relevance of a 2.5 improvement in GRASP quantitative prehension, and what functional changes in patients' daily life does that represent?
Hey, Dr. Abramoff, I'm going to throw this question to you, if you don't mind.
Yeah. I think the important overview, in terms of the GRASP function is that even a small change can make a huge difference in people's quality of life. That can be better able to grip or be better able to extend their arms. That can help with things like transfer, catheterization, even doing things like putting their hair up in a ponytail. All those things can make a big difference, even with relatively small and modest apparent gains on GRASP function.
I think from a-
One follow-up. Oh, sorry.
Go ahead. I'm sorry. I didn't mean to cut you off.
No, no. I just wanted to ask a follow-up question, if you wanted to make some additional comments on that one. That's fine.
Yeah, I think the comment that I have is, FDA has been very explicit with the company that they want to see clinically meaningful improvement, and they want it supported by PGIC. Just so you understand, they really want to understand how does this drug functionally impact the individual's life, and how does the individual perceive that improvement? Those two really go hand in hand. Go ahead, you had one other question.
Yeah. Of all the findings from CONNECT, what do you see as the single most important observation that gives you confidence the efficacy signal will replicate in RESTORE?
Well, number one, we are recruiting a population that is almost identical to that study. We are going to have rigor over the GRASP quantitative prehension test. We are going to be monitoring very closely how these individuals administer the drug at home. We feel very confident based on the GRASP results that we got in the CONNECT study, that we are confident that we can succeed in the upcoming RESTORE study.
Also, looking at the walking data as well, I think gives us a lot of confidence. Really, actually, when you look at everything combined, whether it's the hand function, the walking data, and then you combined it with the individual's view of how they were doing in their blinded exit interviews. Truthfully, the blinded exit interviews gave us even more confidence of the results that we were seeing.
Those individuals were blinded, and it really shed so much light on the overall functional improvement that we were seeing with these individuals. That was really interesting to see how these individuals, and they were blinded to the fact whether they were getting drug or not, how their day-to-day life was improving. Thank you. We are out of time. I am going to hand it over to the moderator, but I want to thank everyone for their time today. I want to thank everyone that came on for NervGen here to speak today. Thank you very much for your time, I am going to hand it back to the moderator.
Thank you. That concludes our question and answer session and today's R&D Day. Thank you for joining. A replay will be available on the Events and Presentations section of NervGen's website. You may now disconnect.