Lineage Cell Therapeutics, Inc. (LCTX) Earnings Call Transcript & Summary

Good afternoon, everyone. My name is Jason McCarthy. I am the Head of Biotechnology Equity Research with Maxim Group. And it is with great pleasure to welcome you to today's virtual event, featuring Lineage Cell Therapeutics and an in-depth discussion on the company's allogeneic cell therapy program, OPC1, for treating spinal cord injury. As a research analyst, as many of my colleagues in the business would tell you, there are any number of therapeutic categories to cover, each with exciting companies and science and medicine that could be and often is transformative. And you could look at oncology, inflammatory disease, gene therapy, NASH. And what about Alzheimer's disease? It's been a pretty hot-button topic just in the last couple of weeks alone. And these are just a handful of spaces, and all are different. But what links them is that each has had its areas of tremendous success. And with it sometimes comes parabolic-like rises in valuations. So my question is what about cell therapy? Sure, we can always point to CAR-T and TILs and other oncology-related cell therapies. They are, after all, cell therapies but -- in and of themselves. But I'm talking about pure regenerative medicine. Stem cells, both autologous and allogeneic, untouched by gene manipulation, yet able to be driven to certain cell fates and differentiated paths to target specific diseases, rebuild tissues and transform clinical outcomes. The pure-play regenerative medicine space, which is gaining traction with larger players with the likes of Vertex and Bayer making acquisitions to move into this space, and high-profile IPOs like Sana Biotech, is finally, in my view, bringing cell therapy into the mainstream or more into the mainstream. However, while this is all exciting for the cell therapy space, understand and appreciate how this space, what's attracted these larger players, and the inflection point the space finds itself in now has come to be? And it's really the efforts and the successes and even some fails, both past and present, of many others before, including Lineage, that have positioned cell therapy at this inflection point where it is right now today. A combination of a shift in cell therapy space, finding its kind of niches, where it could be most effective, most notably in the integrating areas of cell therapy versus signaling types of cell therapies like MSCs, of course, manufacturing technology improvements and among other shifts have been driven by companies like Lineage. My coverage, as an analyst of Lineage, and the focus of the investment community has really primarily been on OpRegen, the company's allogeneic cell therapy, for the treatment of dry age-related macular degeneration or dry AMD. While it's not the subject of this virtual event, I would encourage you to have a look at the prior events hosted by Lineage and their work in dry AMD, for which the appropriate word to describe it may be transformative, which is probably the right word, with signals of actual retinal restoration and vision improvements. In other words, regeneration cell therapy, which is why we're here. However, Lineage also has another program which is coming into focus, and that's the OPC1 allogeneic cell therapy for spinal cord injury, or SCI, and the reason that we're here today. Spinal cord injury doesn't really need an introduction at all. It's devastating. Everyone listening or watching this event knows it. Perhaps you even know somebody who's unfortunately had an SCI. I happen to know 2 people in the course of my lifetime that have had one. The OPC1 cell therapy program came into Lineage -- into the Lineage story via its strategic acquisition of Asterias in 2019. OPC1 is an allogeneic cell therapy which uses oligodendrocyte progenitor cells, or OPCs, derived from a well-characterized and self-renewing pluripotent cell line, a line which was first established more than 20 years ago. They can provide essentially unlimited amount of material for the company's clinical programs and commercial supply, the latter, of course, if it's approved. Since it can address complex pathologies which do involve demyelination, OPCs have opportunities not just in SCI but also other neurological disorders, including multiple sclerosis and others. OPCs are a subtype of glial cells in the central nervous system, which have the ability to differentiate into oligodendrocytes. Essentially, it's rewiring the system. So the goal in SCI is to stimulate growth by rewiring the spinal cord so that it could fire correctly. It was actually based on a very simple hypothesis called the Hebbian theory of synaptic plasticity, and this goes back to the 1940s. And it says, neurons that fire together, wire together. The rationale is that when neurons fire or deliver their electrical signaling correctly and with the correct power and strength, there is a positive feedback that acts to reinforce the neuronal wiring. The efficiency of the system increases. This is what is needed to reverse the damage in SCI and where OPC is aiming, with positive signals of efficacy so far, too, which you're going to hear a lot about in just a minute. So this area is also of important interest, of note to the California Institute of Regenerative Medicine, or CIRM. CIRM is a key supporter of these therapeutic areas, including neuroscience, which has about $1.5 billion of the recently renewed $4 billion-plus budget. The OPC1 program already received more than $14 million from CIRM, and I expect that the company will be eligible for more funding if they choose to go that route. The next chapter, though, but more -- this is the most important part, is right now. This is what's coming for OPCs and Lineage. And here to discuss it are CEO, Brian Culley; and Dr. Edward Wirth, III, MD, Ph.D, currently serving as Chief Medical Officer of Aspen Biosciences, which is a group pioneering autologous-based cell therapies for neurological diseases. Dr. Wirth is a key opinion leader in this space with expertise in clinical trials, translational research, stem cells, MRI, spinal cord injury and neurological disorders. And with that long-winded introduction, I would like to welcome everyone to the Lineage Cell Therapeutics event on spinal cord injury and OPC1 cell therapy. It should be very exciting to hear all about it right now. So I will stop there and turn it over to Brian Culley.

Thank you very much, Dr. McCarthy. I appreciate people being able to join us today. One of the questions I received in advance of this event is why now? Like what is the point of your R&D? Why are you choosing to do one now? Multiple answers there. One is that we do have an opportunity to hear from Dr. Ed Wirth, who is a pioneer in this space and a global expert in the transplant of cells for spinal cord injury. But to build on what you're saying, we're seeing a lot of excitement around cell therapy. Companies like Sana and Fate and BlueRock, which is a Bayer subsidiary. Some of these programs aren't even in the clinic yet, while Lineage has 3 clinical programs. So we really wanted to make sure there is high awareness about the work that we're doing. We're certainly increasingly well-known for our work in dry age-related macular degeneration, but we're not an ophthalmology company. We're not an asset company even. We are a technology platform, and we'd like to say that just like Amazon started with books, before now selling everything under the sun, we'd like to demonstrate that the achievements we make with our lead program in dry-AMD can be applied to the rest of our pipeline and then some on to new opportunities beyond what we're just doing today. And that's the power of using pluripotent cells, to differentiate into specific cell types. And as an example of this, we didn't really say much about our SCI program after we acquired it. It had some deficiencies, and we didn't know if we could fix them. But things have gone very well, as you're going to hear today, and we thought that an R&D event dedicated solely to our SCI program was maybe overdue and would help people learn about the goals that we have, which go far beyond 2021 and dry-AMD. So thank you again for being interested in hearing about what we're doing in spinal cord injury. The agenda today is pretty straightforward. I'll do a brief interview, then Dr. Wirth will walk through the results of the clinical study. We'll address a couple other items, and then we will handle some Q&A. As we are a publicly traded company, I'll refer you first to our safe harbor clauses. I'm sure I'll be making a few forward-looking statements, and you can view more about us through our filings at the sec.gov. All right. So Lineage Cell Therapeutics is working very hard to pioneer this new branch of medicine, which I described, and that is transplanting specific cell types into the body. Why are we looking at doing this with spinal cord injury? It's individuals like Lucas Lindner who truly inspire us. Lucas, a very true story, was out picking up donuts for his grandmother. He swerved his truck to avoid a deer and lost control of the vehicle. And he was ejected from the vehicle, and he became paralyzed. He couldn't move his shoulders, his arms, his legs. But obviously, this is a very moving image, you see him throwing a baseball at an opening day of a Major League game. But I think there's something more important than the baseball. I think it's the water bottle. Lucas' ability to have a drink of water whenever he wants, is the compelling part of the story. Lucas' ability to move his wheelchair, that single knob there, gives him mobility and independence that he didn't have shortly after his accident. So it's fun to think about baseballs and typing, but the quality of life here is really about independence and the changes that we may be able to give to individuals who suffer from an SCI. And one of the things that's particularly notable for me is that no one expects they're going to get an SCI. There are some people who have behaviors or habits or genetic proclivities that may give them a reason to fear certain conditions. But nobody thinks they're going to hit the bottom of the beach when they come off of their surf board or the bottom of the pool off of a diving board or suffer from an error of an epidural procedure, or all the different reasons that people have spinal cord injuries. So it robs people of what they expect from their lives. And many of them, they expect this happens young. You can see here that we have about 18,000 new cases every year. There are at least 0.25 million people in the U.S. who suffer from spinal cord injuries. And as you might expect, vehicles, accidents, falls, those are the categories. And so very often, it's younger individuals. And the care, because these are younger individuals with their whole lives in front of them, can run as much as $5 million. All the associated care for a lifetime that is robbed of these individuals can get very expensive and create a big burden on the system as well. So notably, the majority of individuals, even 10 years after their injury, are still unemployed. The effects, the impairments of the individual go far beyond mobility. You're talking about pain and rehospitalization, risk of infections. COVID has been a horrifically frightening experience for people who may be on supplemental respiration. Depression and social challenges are significant and even shortened life expectancy. And I thought this figure was quite relevant. For some, it's Mount Everest. We just see a stairway, but for these individuals who are paralyzed, it may as well be Mount Everest. So what are the objectives for spinal cord injury? Of course, regaining some mobility. These higher-level injuries, as you go higher up the cervical nerves, they lead to more serious deficiencies in your ability to move. So the goal of our cell therapy, really the goal of anyone's cell therapy is to provide additional hand, wrist, arm, finger function, thus increasing the patient's independence and increasing their quality of life. For purposes of this program, we largely focus on the cervical injuries because the C4 to C7 injuries, that's where the control of the upper extremities is principally located. So it is wonderful to think about getting people out of wheelchairs and walking. But even if we can get some upper extremity mobility, that is where the highest quality of life is achievable in terms of things like interacting digitally with the world around you or being able to be mobile. So how we do this is we manufacture what we call OPC1 cells. So these are oligodendrocyte progenitors. So this is a type of cell that are involved with providing the insulation to the nerve axons. So if you think of -- as often described, nerves are like electrical wiring. Well, wiring doesn't work well if it's not insulated. It's very inefficient. So oligodendrocytes, as you can see by this illustration in blue, oligodendrocyte is responsible for providing that insulation around the axon, which helps it function correctly. And these cells are manufactured from a single cell line, and then they are injected directly into the spinal cord. We're able to do this because the platform, which I described at the beginning of the call, takes advantage of undifferentiated stem cells. These are cells which can divide without differentiating. So we can manufacture essentially an unlimited supply of these cells. And then we run them through a protocol, and we ask them to become specific cell types. That's called directed differentiation. So if we want to manufacture retina cells or RPE cells, we have protocols, and we have certain proprietary activities which we do in order to manufacture just retina cells. If we want to do immune cells, like dendritic cells for cancer, we can do that as well. But for this program, we manufacture oligodendrocyte progenitors. The cells themselves have the ability to become any of the 200-plus cell types in your body. They harbor that knowledge within them. The key is to unlock them and to know the recipe in order to manufacture a specific and discrete cell type. We do that, notably without altering the cellular DNA. We do not manipulate the genome of our cells. So we avoid the risks which are associated with genomic manipulation. And we can reach commercial production from a single vial of cells. Dr. McCarthy said at the beginning of the call, this is a cell line that was established more than 20 years ago, and it continues to provide all of the material we will ever need because of the feature of self-renewing pluripotent stem cells. These cells are -- and the processes that we have over many years are covered by a number of issued patents and pending patents. This program has RMAT designation, it has orphan drug designation. It has received, to date, $14 million in support from the California stem cell agency, for which we greatly appreciate their support. And we think that OPC1 is not a treatment for spinal cord injury, we think of it as a treatment for demyelinating conditions. So it could have application in other diseases. So with that introduction of the basic technology and Lineage business, I'm going to now turn it over to Dr. Wirth to talk about the program specifically in greater detail and the clinical data.

Thanks, Brian. So as Brian just mentioned, OPC1 addresses the complex pathology of spinal cord injury. And importantly, these cells function to support and myelinate neurons, and they have multiple potential mechanisms of action that we believe are acting in concert to really mediate the repair of these denuded axons as well as the restoration of function. You can see some of the activities down here at the bottom: remyelination; promoting the formation of new blood vessels into the newly formed tissue in the lesion cavity; and in fact, preventing cavitation itself, which can potentially prevent some long-term complications of spinal cord injury. Through these graphs, we've seen robust extension of the neurites, and we see this in vitro as well. And of course, we've seen dramatic improvements in motor function. And again, we've got a slide which shows some of the examples of some of these features. Next slide. So these are some examples of some of the effects of OPC1 that we've seen in our preclinical studies. So at the top of the left figure here, you see a spinal cord injury and what happens if you don't do any intervention at all, which is basically you get complete and permanent destruction of the spinal cord tissue in that lesion, leading to a lesion cavity. If you instead, you inject OPC1 into this lesion cavity within the first few weeks after injury, what you find is that the cells will proliferate and will completely fill that lesion -- what would have been a lesion cavity. And at higher magnification, and you can see in virtually every animal, you'll see new nerve fibers growing through the cells that are in the center of that green circle on the upper-right panel. We've done other in vitro studies to look at the functions of OPC1. So in the bottom-left figure, we've injected OPC1 into a mouse model that is incapable of forming compact myelin, which is important for proper nerve impulse conduction. And what you find in that -- where the red arrow is under the shi mouse plus OPC1 in these shiverer mice, you can see that they now have compact myelin around a number of these axons. And this is definitely human-related because, again, these mice, due to their genetic mutation, are incapable of forming that. So a good proof-of-concept that we can get compact myelin formation. In addition, and we published on this in the past, we found, per the bottom-right panel, that OPC1 does, in fact, secrete a number of important neurotrophic factors as well as other important molecules associated with neural tissue and repair. And one of the key features you see is that these neurotrophic factors are very permissive of extension or regrowth of nerve fibers from neurons that are surviving in and around the lesion. So again, we believe that OPC1 has multiple mechanisms of action that are acting in concert to support repair of the spinal cord lesion, promotion of new axon and nerve fiber growth and remyelination of axons, all leading to functional recovery. Next slide. So this is OPC1. Again, as Brian mentioned, these cells are derived from an NIH-registered cell line, in fact, the first in the world to be developed roughly 20 -- a little over 20 years ago now. These cells are allogeneic, and so they're off the shelf. And this is important for indications where the optimal time period to administer these cells is soon after the indication, such as spinal cord injury, where what we found to date is the optimal time window to administer these cells appears to be around 3 to 6 weeks post injury. Now we do administer a short course of a low dose of immunosuppression. And again, our immunological monitoring data suggests that this is sufficient to promote survival of these cells for as long as we've looked by a variety of means, including MRI scans and immunological analyses of the blood and the CSF, up to as long as 5 years after administration with no evidence of an immune response. So very encouraging data. And again, these cells are cryopreserved. And with the new process that's been developed to manufacture them, they now are in a what's called a thaw-and-inject formulation, which means they literally can be thawed out and pulled into the syringe right in the operating room. So there's no additional preparation needed, which is very advantageous for rolling this out to a much larger number of clinical sites. Next slide. So again, in several different animal models, starting with animals with a thoracic spinal cord injury, so this in a human would be where one has preserved arm and hand function but is paralyzed from the chest down. So in this animal model, what we found using the standard scale called the BBB scale looking at functional recovery in these animals, what we found consistently is that OPC1 administration leads to improved weight bearing; improved coordination between the hindlimbs and forelimbs; improved hind paw clearance, in other words, they're not dragging the paw as they walk; improved stability of their trunk; and decreased tail drag. These are all numerical features that are read out as part of this BBB scale. And what you see is it does take time for the function to manifest. So it doesn't manifest immediately after the cells are administered. It takes time in the order of around 6 to 7 weeks, give or take. And this is expected because the OPC1 cells are in an immature state when they're administered, and as they grow and survive in the spinal cord, they actually mature and then perform all of the functions that I mentioned earlier. So this time course is what you would expect to see. Next slide. We subsequently repeated these studies in an animal model of cervical spinal cord injury. So again, in a human, this would be someone who now is paralyzed from the neck down and is paralyzed both in the arms and hands as well as the legs. This particular functional readout was done in an even more rigorous way than what I showed you in the previous slide. The BBB scale is actually a subjective scale that's performed by a trained assessor. So it's very robust and widely used. For the cervical studies, we actually did this by what's called an unbiased kinematic analysis, where the animals are videotaped running on a treadmill with multiple video cameras, and all that raw data gets completely fed into an unbiased computer algorithm and analyzes their kinematics for very much the same types of things we saw for the thoracic study. So what you see in this unbiased readout is that over time, if you look at the OPC1 animals in the red line there with the squares, you can see that beginning by 2 months post injection and more so by 4 months, there's a very robust improvement compared to injured controls in their running speed, their forelimb stride length, their forelimb maximal longitudinal deviation and their rear right stride frequency. All of these things are pointing to improved function now -- if you notice everything here says improvement on the right side, that's because the most severe lesion that we were able to make in these animals was a lesion on the right side of the spinal cord. We wanted to go as high as we could in the neck, but we had to stay to one side for this particular model. And what's nice to see is, again, all that robust recovery was associated with the side where the cells were injected. Next slide. So all of that animal data then led into a clinical development program at Asterias and now part of Lineage, in which we conducted a dose escalation study. It was an open-label Phase I/IIa. So Phase I being predominantly around safety, IIa being to look for initial evidence of biological activity and potential efficacy of these cells. We -- at FDA's request, started in only the most severe patients. They -- or Grade A on the ASIA Impairment Scale, ASIA being the American Spinal Injury Association. So this is the most widely used scale, and it's now a global scale that's been re-termed the ISNCSCI exam, which is the International Standards for -- International Standards for Spinal Cord Injury Neurological Evaluation. Once we got initial safety data in the ASIA A's, we actually got improvement to go to the ASIA B's. And the difference between these 2 groups of patients, just so everyone knows, is ASIA A's have complete loss of both motor function and sensory function below their lesion, whereas the B's have some preservation of sensory function, but they do still have complete loss of motor function. So they're very close to one another with regard to loss in motor function. Now, as everyone knows, FDA requires you to establish safety, so we had to start with a low dose of 2 million cells. This is a dose that had previously been done in the Phase I safety study in patients with thoracic spinal cord injuries at an earlier stage of this program at Geron Corporation. So we started with 2 million cells, demonstrated that we could administer these cells safely with no adverse complications related to the injection procedure or the injection itself or the device. We then were able to move on to the doses where we had always estimated would bracket the human equivalent dose of the best efficacious dose we saw in nonclinical studies, which we'd always estimated was in the range of 10 million to 20 million cells. So this is very much in line with what we had predicted many years ago. So the plan was to dose patients initially with 10 million cells and then upon showing safety of the administration procedure with these higher doses, we then were able to go up to the maximum planned dose of 20 million cells. These patients all had traumatic cervical spinal cord injuries with a lowest preserved neurological level of C4 to C7, and we have a diagram showing you what that means for the individual. Again, the cells were administered 21 to 42 days, so roughly, again, 3 to 6 weeks post injury. These were all adults. And then we had a variety of clinical assessments, foremost being safety at this early-stage trial; but then also looking primarily at recovery of neurological function, again, using the standardized exam called the ISNCSCI that I mentioned; as well as some newer exploratory assessments, such as the Spinal Cord Independence Measure or SCIM and also an assessment of grasp function, which the acronym actually is GRASSP. The next slide. So this is a schematic of the trial study design. Initially, we only had permission from FDA to do cohorts 1, 2 and 3. So this was -- started as a straight dose escalation study with these first 3 cohorts going from 2 million cells up to 20 million cells, and you see the number of subjects here. As we started to gain safety data from cohort 2, we did obtain permission from FDA to add cohorts 4 and 5, which are, again, these slightly less severely injured patients, with the ASIA B's, again, but looking only at the higher doses of 10 million and 20 million cells. So toward the end of the latter part of the study, we were actually enrolling these cohorts concurrently, especially cohorts 3 and 4, which is going to be really important for being able to accelerate the enrollment in a subsequent randomized controlled trial. Next slide. So this is another look at the schema in terms of time as an individual participant in the study would go. So again, there's extensive screening and baseline assessments to make sure they meet eligibility, as well as a baseline MRI scan to establish where the lesion is and the target for administering the cells. Cells were injected on this time scale, as you see, on day 0. They were given a short course of immunosuppression, as I mentioned, for 60 days. This was extremely well tolerated. There were no serious adverse events of any consequence due to the immunosuppression. And again, our best immunological monitoring data suggests that this short regimen was sufficient to get long-term engraftment in virtually every patient for up to 5 years, which is the longest we've looked so far. The primary follow-up period was out to 1 year, again, with multiple neurological exams and MRI scans, as you see here. Then you can see there's a long-term follow-up program. This is something stipulated by the FDA to make sure there aren't any delayed problems. And that extends out to 15 years, but with only the first 5 years or up to 5 years of follow-up being in-person, the last 10 years being just by annual phone visits. Next slide. So in terms of these 25 patients, again, the focus was on safety. We had a very good safety readout from this, and we presented it to the FDA in an RMAT meeting around this and discussing next steps for the clinical program. We have very good evidence by MRI of successfully preventing cavity formation by virtue of having successful engraftment of the cells. As you'll see, we had some very encouraging signs of efficacy as it related to motor recovery. And you'll see there's some additional notable findings as well that we believe are important that will inform upon the design of, again, of a randomized controlled trial, which will likely be the next step in the clinical program. Next slide. This is just a brief summary of the adverse events. Again, the overwhelming majority of the adverse events in the study were mild to moderate in severity. We did have one adverse event related to OPC1, which is an episode of dysesthesia or neuropathic pain, if you will. This is something that's very, very common after spinal cord injury itself. And to see this in only one subject, we think, is actually encouraging rather than discouraging. As I mentioned, the injection procedure went really, really well. We only had one SAE related to the injection procedure. But again, no serious or long-lasting complications due to that. And we did have one serious adverse event, again, related to the immunosuppression, which again, resolved quite quickly. So overall, the injection procedure, the cells and the brief immunosuppression all had a very favorable safety profile that leads us to believe that this program is ready to advance further in the clinic. Next slide. So we've done, as I mentioned, multiple MRI scans on these individuals. These are all read out primarily by a study, a dedicated neuroradiologist in Denver, who had prior very extensive experience on these kinds of MRI readouts and spinal cord injury -- I apologize for the background noise. One moment. Apologize for the brief background noise there. So again, the 12- and 24-month MRI scans indicate durable engraftment of these cells. And you can see an example of that. So on this image, I don't know if my cursor is visible, maybe Brian's is, but the -- in the spinal cord coming down from the brain, you can see this area that's slightly brighter than the rest of the spinal cord. That's indicative in my experience of successful engraftment of the cells and actually have published on this previously. So this is indicative of a tissue formation, and we've seen this in 24 out of the 25 patients. And as you'll see, we had reason to expect even at baseline that one individual had such a severe lesion with spinal cord that it was possible that cells might not survive and might not be able to fill the lesion cavity. But these results overall were very, very encouraging. Next slide. So shifting for the moment to then looking at motor function recovery. Based on work that was done by investigators associated with the American Spinal Injury Association, there are -- what we saw was that, and again, apologize for some background noise here. There were 20 -- out of the 22 patients who received either 10 or 20 -- sorry, my apologies again, for the background noise here. So at 12 months, there were -- of the 22 patients who received either 10 million or 20 million cells, what we found is roughly 1/3 had 2 or more motor levels of recovery and 2/3 had had at least 1 motor level recovery, and only 1 patient, again, who showed no improvement in motor level recovery. And as you'll see why- you'll see in an upcoming slide, this is really meaningful because by definition, as an individual recovers a motor level, that allows them to regain function in their arms and then in their hands that allows them to do activities independently, such as Brian mentioned at the beginning of the presentation, which, for example, being able to grasp a bottle of water, lift it up, hold it to your mouth and drink independently without having someone to assist you with that. Next slide. So this is an example or illustration of what these motor levels mean. So again, each motor level in the cervical spinal cord corresponds to specific muscle group and a specific function. So starting at C5. The nerves from C5, or the neurons at C5, allow you to flex your arm at the elbow. C6 allows you to extend your wrist. C7 are your elbow extensors, which are your triceps muscles. That would, for example, allow you to push your own wheelchair. And then C8 starts getting into the muscles controlling your hands and your fingers. So again, as you regain each motor level, you regain additional functional ability. And as you'll see on another slide here coming up, additional degree of functional independence. Next slide. So and then again, talking about this recovery of motor function, okay? So the ISNCSCI motor score, so again, this is the International Standards for Neurological Classification of Spinal Cord Injury, it evaluates the strength in each of these key muscle groups on a scale of 0 to 5. So basically, there are 5 muscles that are graded on each side of the body. And so if we're talking about the arms and hands, for each of these 5 muscle groups, there's a maximum score of 25, and so therefore a maximum of 50 points per side. So any one of us, for example, who's not suffered a spinal cord injury and were to undergo this exam would receive a score of 50, and you'll see that's very important in terms of how much motor function some of these folks have recovered. The motor level score, again, is defined by the lowest level at which that key muscle function has a grade of at least 3, which means you can contract against gravity. So this becomes a functional useful amount as opposed to, say, a score of 1 or 2, where you have some contraction, but just a flicker, but not the ability to oppose gravity. Now Lineage and Asterias have been actively involved in an organization called SCOPE, the Spinal Cord Outcomes Partnership Endeavor, which is a formal working group of the American Spinal Injury Association, which has been working very hard to develop additional assessment tools that might then translate this motor recovery function into other types of readouts or combined with other types of readouts that would be deemed to be clinically meaningful by the patient community as well as the FDA. So for example, some of these additional tools have been the Spinal Cord Ability Ruler. You heard about the Spinal Cord Independence Measure. There's a new one that's been developed called the Capabilities of Upper Extremities Test and another new one called the Spinal Cord Injury Functional Index. So this is an area of very active research in the field, and it's very important because I think as many of you know, FDA requires a readout in a pivotal or a registrational trial to be "clinically meaningful." And so motor recovery, while intuitively is clinically meaningful, you have to be able to quantitate that in some way that the FDA would accept. So we're very involved in the field, and we've been incorporating and using some of these assessment tools as they've been coming out. Next slide. This is an example. It's a very detailed form, so I won't go through all the details today in the interest of time, obviously, but this is what the actual exam form looks like. Highlighted in the green box, as you can see, are the boxes where the motor function in each of these 5 key muscles on both the left side and the right side of the body are quantitated. These get tallied up on the bottom left of this form into what are called the motor subscores. So there's an upper extremity right score, upper extremity left score, and the total is the upper extremity motor score, or the UEMS. And that's important because we'll be talking about recovery in the UEMS. So this is a simple numerical additive. But again, what matters most to the patient is actually that plus recovery of motor levels. So in other words, if at baseline, your lowest level at which you're a grade 3 or better is C5, then you have very limited function in your arms and none in your hands. And what we're trying to do is push that motor function all the way down through the upper extremity through your arms and into your hands, which is what we were very gratified to see in some of the patients like Lucas Lindner, for example, that Brian mentioned. Next slide. And this is what a real-world benefit looks like. This actually comes out of -- this was actually derived from one of the core industry -- or the clinical guidelines for the standard of care for spinal cord injury. And it shows basically how much functional independence a person has dependent on their lowest intact motor level. So for example, at baseline, if someone starts out with a C4 neurological level. And by the way, C4 and C5 are, in fact, the most common neurological levels after an injury to the neck -- spinal cord in the neck. You can see if someone is a C4, they basically require nearly continuous assistance, 24/7, to perform all of these basic activities of daily living, such as bowel and bladder care, bed mobility transfers, eating, dressing, grooming, bathing and so forth. So you really -- you really have, relative to more independence, a pretty poor quality of life and a great need for an attendant, almost 24/7. If you can improve that individual by 2 levels, which I think if there's one more click, Brian, it will show an arrow going from C4 to C6. So again, we had 1/3 of our patients, which is probably an underestimate of the real signal, but to be conservative, we're reporting the data conservatively. So about 33% had 2 motor level improvement. You can see what a dramatic improvement in the functional independence a person has. Now they can do many activities of daily living completely independently and require only partial assistance for some of their other activities. So this allows a person to go back to school, to go back to work, to live more or less independently. And again, we were very gratified that this was exactly the case with a number of the subjects in the previous trials, such as Lucas. Next slide. So these are the numerical data. And again, we learned a number of important things in the study. So this study was primarily focused on safety, but we obviously wanted to take a very close look at the pattern and degree of motor recovery in these individuals, to see if, in fact, there was an encouragingly strong signal, which I believe there was. So if you look, again, at the 2 motor level of recovery, what we saw is that by 6 months, 4 out of these 22 individuals who got either 10 million or 20 million cells recovered 2 motor levels. That continued to improve further to 7 out of 22 by 12 months. So again, very, very encouraging data. And I believe by the 2-year readout, this was maintained, maybe even slightly improved by 1 patient further. So again, very encouraging signal overall. Likewise, the total upper extremity motor score, you can see, showed steady improvement to 6 months that was further improved by 12 months out. So this is very, very encouraging data. We did compare it against the best available comparable data out there, which is actually from Europe. We performed an internal analysis of data that we were able to obtain with permission from the European Multicenter Study of Spinal Cord Injury or EMSCI, which showed a 7.8 degree of motor score improvement. But there are some fundamental differences, just so everybody is aware, between the standard of care in Europe as it stands today and in the U.S. unfortunately, one of those being that in Europe, in these centers, the standard of care still calls for 5 to 6 months of inpatient care and rehab, and they're getting the very best of care in those hospitals. Whereas, unfortunately, in the U.S., due to economic pressures related to third-party payers and reimbursement, the standard of care is now that patients typically are getting pushed out of the hospital as early as 4 to 6 weeks after their injury. So there are some fundamental differences. The bottom line is what ultimately is going to be needed is a proper randomized, controlled -- prospectively controlled and blinded study to evaluate the magnitude of this recovery. But thus far, the data are very encouraging. Next slide. So looking in greater detail at some of the individuals who showed the least amount of recovery with OPC1, and by the way, I'd like to note that nobody in the study got worse. And that's important because actually, with spinal cord injury alone, some patients actually do have additional damage for reasons that aren't entirely clear, could be vascular, where they actually do, in fact, lose more function after their initial injury. So it can go the other way. What we found was in this -- if you look at the 2 -- the patients at the 2 bottom levels here, 2307 and 2303, who had the least recovery of all 22 patients who got the higher dose, in fact, both of these individuals were observed by MRI to have some compression of the spinal cord postoperatively. And as we'll show you on a subsequent slide, this was basically due to an entirely preventable problem that wasn't fully appreciated at the beginning of the study, which is simply that after you do surgery of any kind, there's typically swelling and fluid accumulation temporarily in the tissues. And it turns out, in talking with our surgeons, that we can prevent this in the future studies simply by asking all the surgeons to leave a drain tube in under the skin that would pull this fluid out for the first couple of days afterward, and this should be completely preventable. So that was definitely one lesson that we learned from the study, again, that we think would be -- will inform on the design of a subsequent trial and potentially lead to a greater overall response to OPC1. The other thing that was really interesting in this study was that if you notice, 3 of these patients in the red box here and the numbers coded in red started out with a neurological level of injury of C4. And this is important because, again, our study initially started with only C5 to C7 patients. And as we gained safety data, we wanted to look at C4 because, again, it's the second most common injury level. And in fact, as it turns out C4s, for reasons again that aren't well understood yet, don't respond as well to OPC1 as patients who have a C5 to C7 level of injury. And we've talked with a variety of experts in the spinal cord injury field, and interestingly, C4 patients also seem to have less spontaneous recovery than those who are C5 to C7. So really, what this means is that we need to look at C4s as potentially a separate group in future trials. We could either stratify them a priori or potentially look at them in a parallel arm. But again, this was another important lesson we learned from this open-label trial that will really inform well on the design of a randomized study and another important readout here. So again, if you think about the overall motor scores, some people looked at our data and thought, oh, it's not that great. But the reality is when you incorporate the lessons learned, it's actually very, very encouraging. Next slide. So this is that cord compression that we talked about. So if you look at day 30 here, if you look at the arrow, the tip, you can see the spinal cord is narrower than the spinal cord above and below. And just under the arrow, you can see that large bright area of signal. That's actually a signal of fluid that, again, normally accumulates after all surgical procedures, especially a spine surgery. And again, it turns out that many surgeons simply will prevent this from ever happening by putting a drain tube in for about a night or 2 and then pulling it out. And again, we've talked with all of our study surgeons, and none of them would have any reservations about doing this in a future trial. And in fact, the reason that we only had 2 with cord compression in this study was that our other neurosurgeons did, in fact, routinely put a drain tube in already. So it was something we weren't aware of when the study was initiated. Next slide. So if we take into account some of the lessons learned from this open-label study and then again, look at the overall upper extremity motor score gain, factoring in these lessons learned and how these could be managed or addressed proactively or prospectively in a randomized trial, in fact, what we saw was 17 of these patients would be included in the primary cohort in a randomized trial, and we'd be looking at a motor score gain upwards of 10 points, which, again, is very, very robust relative to what we see with regard to natural recovery. So we've modeled this out statistically with a biostatistician, and we think modeling it on this degree of gain actually would stand a very good chance of showing the clinical efficacy on motor score is potentially a primary endpoint in, say, a mid-stage trial, a Phase IIb, for example. Next slide. We also looked at whether any other factors had any impact on the degree of motor recovery. Again, this is really important to know going into a randomized trial, so you can determine whether you need to stratify or account prospectively for any of these other factors. And it turns out, you don't. So we saw no degree or no differential improvement with regard to age. In other words, older patients in the study did just as well as younger. No difference between men and women. No difference within C5 to C7. So again, they can be looked at as all one cohort. Importantly, no difference between 10 million or 20 million cells. And again, we predicted that the efficacious dose would be in that range, but not necessarily better with 20 million cells. And in fact, as it turns out, 10 million cells is just as good as 20 million cells. And then also no difference within our time window in terms of number of days from injury to injection. This is also important because we've been asked many times, are you sure you don't have to go in earlier than 3 weeks or later than 6 weeks. And within that time window, we see no impact on recovery. So again, this really informs very well, and we believe has already now helped solidify a number of the design elements of a randomized trial. Next slide. So again, all subject -- all 25 subjects now have been evaluated for at least 2 years, and the overall safety profile continues to be excellent. And again, these individuals get annual MRI scans and neurological exams out to year 5. We've seen no evidence of any adverse changes on the MRI scan, so very encouraging. We've seen no unexpected serious adverse events related to OPC1 cells, and nobody has worsened. And in fact, looking from year 1 to year 2, everybody has either maintained or obtained even a little bit of additional motor improvement, as is mentioned in the second half here. So again, the very first cohort, so these are the subjects that got the low dose of 2 million cells, they are now stable 2 to 4 years after dosing with OPC1. Now, 5 subjects in our second cohort have achieved at least 2 motor level improvement. It was 4 out of 6 at 1 year and now it's 5 out of 6 at 2 years, which is absolutely remarkable. And in fact, 1 subject in that cohort actually achieved 3 motor levels of improvement on 1 side, which is now maintained at 3 years. So these, in my opinion, are very, very encouraging data. Next slide. So just a quick summary on the takeaways then. Again, we have an excellent overall safety profile. We have a very high degree or rate of durable engraftment confirmed by MRI, with no evidence of adverse changes through 2 years. Nobody has gotten worse. 95% of these patients have had motor recovery in the upper extremities at 1 year. So we're very excited about that very high rate of response. We've had significant motor improvements achieved in 5 of 6 of the cohort 2 subjects. We know that the 2 worst-performing subjects had a very preventable postoperative complication. So again, that can be addressed in the next trial. And the results do, in fact, support further testing in a randomized, controlled clinical trial. So thank you, and I think we now go back to you, Brian -- no, on the device. My apologies, we still have a little more on me on the device. You want to go ahead to the next slide? So this is just the original device that I designed in conjunction with our lead neurosurgeon, Dr. Richard Fessler. So this device was designed to mimic the exact type of device that was used in all of our animal studies, but it was designed only in that vein for early-phase clinical trials. And while it worked very well, it had a number of design compromises. It's big and bulky. It has a lot of parts, as you can see here, requires multiple storage trays and supply kits. And in addition, it has a rigid needle that requires the ventilator to be stopped while the needle is in the spinal cord. And so because of all these limitations, I felt it was important for Lineage to move on with a more robust device. So here, you can see some of the experience with that device. So again, we have dosed successfully 5 thoracic and 25 cervical patients. These are the known challenges: large components, the flow variability with the manual syringe, it requires a lot of assembly at the support sites and a lot of support -- there's motion between unit sections, they're prone to wear and tear, and we have to provide 2 full sets at each of these sites. As I mentioned, it requires the ventilator to be stopped for -- which limits the injection time. And the ventilation limit is not compatible with the new thaw-and-inject formulation. So it's really important to get to a new device. So Lineage just announced a partnership with a company I believe called Neurgain that's developed a novel parenchymal delivery system, as you see here, which really addresses, I think, virtually all of the limitations of the earlier Asterias device. So the syringe is mounted on an infusion pump, which gives you much finer control over the delivery, flow rate and volume rate. The platform is much simpler and it mounts to the patient, so you eliminate all the bulkiness in the assembly. And the cannula itself can "float," if you will, so it doesn't require that the ventilator be stopped. And here's a summary of some of those features that I just mentioned. So again, it offers stability and control. Eliminates motion between the platform and the patient. The pump and the needle, the outside needle doesn't need to be in the sterile field, and it can be programmed to give you a very accurate dose rate. You don't have to stop the ventilation while you're injecting, so that's very encouraging. And it's much easier to use in a clinical setting. So there's again, it's smaller, there's fewer components, it's easy to assemble, it allows for single-hand operation for your XYZ positioning. It enables accurate needle depth penetration, it has straightforward cleaning and sterilization, and it's compatible with the new thaw-and-inject formulation. So this is all -- these are all very important devices -- this type of device could be used all the way through clinical trials and I believe even into commercialization. Next slide. I think now we're back to you, Brian. Yes.

Great. Thank you very much. So I just wanted to speak a little bit about the manufacturing improvements which have occurred. So in December, we -- Lineage announced that we had made some major improvements to the production and quality of these OPC1 cells. So you've heard plenty about the new ready-to-inject formulation. This helped get rid of the preparation of the cells the day prior. So this actually opens the door to being able to open a much larger number of clinical sites. Not every site is capable of manipulating the cells the day before, washing them, prepping them, et cetera, and then administering them the next day. So getting to a thaw-and-inject, ready-to-use formulation is far superior and a notable achievement for the team. They also increased the production scale by 10 to 20-fold. So previously, it was going to require a tremendous amount of effort to brute force our way to a larger study. Now that we can manufacture in the triple digits, that is enough clinical administrations in the low triple digits per batch that we manufacture, that, again, opens the door to larger clinical studies, a door which previously had been closed. We've had a significant reduction in the product impurities, which is very important. I'm going to show you a graphic version of that in just a moment. We also enhanced the functional activity of the cells while developing new methods, eliminating the animal-based production reagents and of course generated some new intellectual property to protect all of our inventions and advantages. This is something that we really want to make sure people understood. These bars in blue reflect the material that was used previously by a different sponsor. And you can see in the y-axis, the percent positive non-targeted cells. So one of the ways that you evaluate the cells is you look at the cell surface and identify the markers. And that can help tell you, am I looking at a brain cell, am I looking at a liver cell, am I looking at a skin cell? And you can see that there were very high levels of non-desirable or off-target cell types in the original material. So this, in my mind, reflects cell therapy 1.0, right? These were the early days of cell therapy. Now in Lineage's hands, using new technologies and better systems and processes and methods, we're able to develop what you can just barely see in orange, which is the Lineage method of making the cells. And you can see that those off-target or undesirable cell types are really minimal, just a couple of percent at most in the worst-case scenario. So it's a great achievement that the material that we are producing now is more consistent, which ultimately is the most important thing for the FDA and for interpreting clinical data. If you are constantly putting in some sort of mixture, and you're never quite sure exactly what it is each time, it's very difficult to make heads or tails of your clinical data. But if you have certainty and you have control over your processes, then you can interpret your data more easily, or you can run smaller studies in order to get your answers. This is again noting that these markers, which reflect potency and activity in different forms here, that the Lineage material was improved relative to the original material that was used in the clinic. So I'm very proud of our manufacturing achievements in this regard. So I just want to repeat that one of the questions we frequently get asked is whether or not we would be able to include things like physical therapy or electro stim in the context of a clinical study. And the answer is yes. We don't have any problem. In fact, we welcome that additive work. If we're going to give people the substrate for a benefit, any additional effort that they put in to try and achieve a higher degree of response, whether on control or on active study, we think is fantastic. So with that, I would only add that I think overall, OPC1 here offers a really compelling opportunity to deploy some of this next-generation technology in a space that doesn't have a lot of competition and yet has a very high unmet need. The clinical data is supportive of moving forward. Manufacturing issues have been addressed or improved. Delivery issues are ongoing, but we obviously have a very clear path for how we're going to do that. We have to talk to the FDA about a compatibility plan and next study design. But there's all sorts of new opportunities for partnering and maybe additional settings of demyelination. So thank you for all of that. And Dr. McCarthy, we would -- Dr. Wirth and I will be really delighted to do some Q&A with you at this time. Thank you.

Great, fantastic, great talks by both of you. There's a whole bunch of different areas that we could touch on, but I'll start with something very general, and I guess it will be for the both of you. Just talking about the spinal area. Overall, Brian, you mentioned early in your talk about the fellow in the wheelchair throwing the baseball, and it's about mobility in the arms and elbows, et cetera. And OPC1 is focused on the C4-C7 area, maybe narrow it down to C5-C7. But just in general, are there different sets of challenges in lumbar, thoracic? And we know there's problems in the upper cervical area that may preclude therapy. But is this kind of the sweet spot for a cell therapy to really see if it can make a difference, almost like a proverbial low-hanging fruit for regulators?

I think it's best for Dr. Wirth to answer it. He's the expert on that.

Yes, it's a great question, Jason. And there is a lot to that. So I'll try to be brief. So first, the thoracic spine is stabilized by our rib cage. And so the injuries tend to be either very mild or catastrophically severe and really almost -- really severely pulverizing the spinal cord at the level of injury. So in terms of going after that, is kind of a place where obviously, with very mild injuries, unlikely to warrant a surgical procedure to inject cells. On the flip side, you've got almost catastrophic damage. The one exception is in the low thoracic spinal cord. It is possible, where we're now getting down sort of in the T12-L1 region. It is possible that there can be damage that's sort of in between down there. And injecting OPC1 at that level is attractive in that you're much closer to the target neurons you want to reinnervate, the neurons that are going out to the muscles in your legs, for example, as well as contributing to bowel and bladder function. So very low lesions, as long as they're not too low where you're at the very bottom tip of the spinal cord, are very attractive. Now the thoracic spinal cord injury, as Brian mentioned, could be amenable to a combinatorial therapy. So maybe cells plus e-stim, for example, might be a good way to go because we're already seeing encouraging results from some academic groups with e-stim alone in even these very, very severe thoracic patients. One can't help but wonder if you were to put cells in and provide a tissue matrix in a more favorable environment for the e-stim, would you get an even better outcome? On the flip side of all of that is the cervical spinal cord, obviously, is really good place to start because, obviously, the functional deficits and the unmet need for these folks is really significant. And as I like to say, somewhat -- I'm not sure what the word is, tritely, if you will. If I can take someone who's a quadriplegic and make them a paraplegic, that's a good start, right? That gives them back a lot of functional independence. And then we want to build from there. So the question is, what else could we do that could eventually bring back some degree of leg function or bowel and bladder function, in addition to the arm and hand function. So there's a lot of work to be done there. But I think this -- obviously, the clinical readout is very straightforward. And the functional gains you're seeing and the impact on quality of life are very, very easy to get a read on in the cervical cord.

Right. So this is the sweet -- kind of the sweet spot area. Does this approach work in chronic patients or just subacute? Can it be for all of SCI in this region? Or how do you think you -- that has aspects of scientific and medical rationale, but also business?

Yes. So one of -- our early academic collaborator on this did look at in chronic spinal cord injuries, unfortunately, did not see good engraftment to the cells and did not see evidence of functional benefit. We think that the sweet spot time-wise after injury has to do with coming in after this initial very severe early inflammation has subsided. So over the first 2 to 3 weeks, but before the chronic scar tissue has really set it in a very permanent and difficult to penetrate way. Now the question would be in chronic spinal cord injury, could you perhaps go with a combinatorial approach that gives the cells a better foothold, for example, maybe seeding them on some type of scaffolding or maybe adding into the mix an agent that would break up some of that existing scar tissue. So I don't think that the chronic situation is hopeless. I think the data just suggests that it might require something in addition to the cells. Or there are groups, for example, that have looked at genetically modifying the cells to get them to secrete greater amounts of molecules that break up the chronic scar tissue. So that's another route that one could envision.

Yes. And Jason, one of the things that is interesting is a lot of things need to go right in order to repair the circuitry there. I know that there's an investigator at the Miami project who's already been looking at treating patients in the chronic setting using Schwann cells. But that's a different cell type, and the destination, the administration of those cells is a little different than what we're doing. And it kind of highlights one of the challenges in this space, is that a lot of aspects of it are not standardized. And so that's why we invested so much time and energy into our manufacturing, so that we could be able to interpret the data more clearly. But there are definitely some advantages to a chronic population. Certainly, if there's an effect, it's easier to see an effect in a chronic population because they tend to be -- they've plateaued or they're stable. And the area may be less inhospitable than in a subacute patient population. And certainly, there are probably 10x more potential patients to treat. So it's of great interest. But I think it's correct in your question that start where you think you can have a win. That should be the approach not just for cell therapy, but with drug development as a whole. Start where you think you can show an effect, demonstrate that you have something and then build upon there, and you can be more exploratory and start thinking about combinations like Dr. Wirth was just describing.

So what do you think the most important predictor of outcome is, whether it be from baseline motor level, I know you got the 2-point improvement, or timing of injection, number of cells that were deposited? Though I think I did hear the 10 million or 20 million cells didn't really make a difference. And kind of building on that question, that came from one of the viewers. There's been a lot of activity in the CNS and neurodegenerative diseases around biomarkers, right? You did have one slide with biomarkers on it. Is there a way to tie the biomarkers like growth factors back to what you're seeing with the cells that you've implanted? And how can you leverage that going forward?

Yes. It's a good question. And definitely, biomarkers can be really helpful. The challenge with cells that are administered into the -- directly into the spinal cord or the brain, for that matter, is that the biomarkers you're looking for are going to be present at really, really low levels in the peripheral blood, if they get out there at all. So there's limited detectability that might be an issue. You could potentially see them in doing spinal taps, to look at the cerebrospinal fluid. Unfortunately, that's a procedure that tends to have a lot of discomfort even in somebody who's paralyzed. You can get bad headaches, for example, and so you tend to be limited on the number of those spinal taps that a participant is willing to undergo. So biomarkers are a good way to look at it. MRI is really kind of a key readout for us, right? It's noninvasive, it lets us know how well the graft is done. I think the key things for us is that it turns out that, with the exception of this cord compression we saw in just a couple of patients, and the C4 patients who appear to be different in their ability to respond, really there are no other factors we see as being important predictors of a person being a responder to OPC1, which is the good news. So in my opinion, the overwhelming majority of the individuals that would be enrolled in a randomized trial are going to potentially be responders with the caveats I just mentioned.

Your expertise or one of your many expertise is in MRI, right? And you just mentioned MRI as part of that study. How long do you have to go out with the serial MRIs? Data out to 12 months, do you have to go beyond that to really show -- and a factor is 12 months sufficient? Is that what you can use in the next trial and then maybe have longer-term follow-up from there?

Yes. So currently, 5 years is, I would say, roughly a happy medium because again, with pluripotent stem cells, we're still at an early stage of the whole field, right? So the thoracic trial that was started at the previous sponsor, Geron, that was, in fact, the world's very first clinical trial of a cell therapy derived from pluripotent stem cells. So this program and the field in general are continually building a safety database, where we won't have to go out as far as we do now. But the agency is biased by the fact that with poorly sourced cell types, for example, there were trials done by academics with olfactory tissue and unfortunately, there have been reports after 5 years, 5 to 10 years, where a few patients have developed big masses in their spinal cord that required removal. So our safety data are really solid. And as the safety database builds for cells and for comparable cells, you'll see these follow-up periods get shorter. But right now we're in an early stage for the whole field.

Yes. Jason, I think that's such an important point to understand about Lineage is that -- Dr. Wirth was just describing that an investigator was using olfactory cells and putting them into the spinal cord. If your spinal cord was meant to smell, you'd have nostrils back there. It's core to our technology that we manufacture the cells that are dysfunctional or absent in the body, and we transplant those and replace those. And I think that that's really important aspect to the platform as a whole. We're not using undifferentiated cells. We don't put stem cells into patients. We manufacture the cells that are missing or dysfunctional. And we put those in place, and then we look for activity after the fact. So I'm glad that, that was brought up as a safety consideration because we think it'll be a lot -- it'll be tolerated much better to use the cells that actually belong there.

I think what you just said is actually important for the entire space as a whole, which we've been writing about, about a shifting. So I'll ask about that in a little bit and what we're seeing in cell therapy in general. But just in terms of what physicians might find clinically meaningful versus what regulators would accept, is a 2-point motor level of improvement sufficient? Kind of what's the natural progression of SCI severity over time? What's stable? Is 2 to 4 years, as you say, is -- Cohort 1 was stable. And then how much level of motor improvement can you expect spontaneously in some of these people? How do you get above the noise? What I'm really saying is how do you get above the noise? What's meaningful to you as a physician, Dr. Wirth? And what's going to be accepted by regulators?

Yes. So that's a great question, Jason. So the challenge for the field right now is there's no question -- there's no doubt for the experts in the field, the clinicians and the scientists that this motor recovery is clinically meaningful, because you've seen that. The pictures that we showed, it's almost by definition. The problem is, how does the agency view that? And again, the agency needs a numerical scale that clearly and unequivocally shows how this motor recovery translates into something quantifiable that is clinically meaningful to the patient. In other words, I can feed myself when I couldn't before, I can dress myself when I couldn't before. So this is where, again, this spinal cord outcomes partnership endeavor has been working very diligently on coming up with outcome measures that basically will get you to a numerical scale that is essentially driven from the motor scores but incorporates into it the recovery and the ability to do daily functional tasks that you couldn't do before. And that's actually tougher than one might think. Actually, there's been a lot of effort into it. They're making a lot of progress. But that's ultimately what's needed. Once we're there, once the field has developed that, and the agency has accepted it, we're going to have an endpoint everybody in the field could go to as, this is going to be our primary endpoint on a pivotal trial.

I think sometimes there can be a little bit of a difference, Jason, between what the scientists think is relevant and what the patients think is relevant. And it happens more frequently in diseases and conditions for which there aren't as many approved therapies, right? We don't have precedence, regulatory precedence for spinal cord injury. So it's really interesting, and I think it represents a big opportunity. When you talk with a patient and they explain to you that if I can curl this 1 finger a little bit, it might not hit in your clinical trial scale but it permits me to lock into the handle of a coffee cup or a mug. And so you can actually find some really interesting lessons, which may open up new opportunities and avenues and insights. And I think that's part of what SCOPE is doing, and that's what the field is doing as a whole. Just trying to figure out, how do we tether -- how do we minimize the gap between things you can measure and things that matter to the patient. And as soon as you get them to overlap, there's your endpoint.