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

Good afternoon, everyone. My name is Brian Culley. I'm the Chief Executive Officer of Lineage Cell Therapeutics. I'd like to welcome you to a very special webinar today. Before I begin, I'll refer you all to our safe harbor clause as I or other Lineage executives may make some forward-looking statements today, and you can learn more about our risk factors through our filings with the Securities and Exchange Commission at sec.gov. Now I know many of you were expecting us to report our 6-month interim data for OpRegen, but we've moved that update to next month in order to make room for something far more exciting. As you all know, we have reported that an earlier observation of retinal tissue restoration has been repeated in 2 additional patients on the OpRegen clinical trial. So we believe this is much more than just an exciting clinical observation for these 3 individuals. We believe this first-of-its-kind data using a replace-and-restore approach represents a new paradigm for how the biotechnology industry might finally be able to treat patients with dry AMD. The data are notable because we have a clear line of causality between our treatment and positive changes to a patient's anatomy. Human beings cannot restore retinal tissue the way that they can restore or repair skin or bone. The only way to achieve this effect in retinal tissue is through some sort of intervention, such as the transplant of new RPE cells. That makes this finding of restoration as robust as other binary measurements like enzyme replacement therapy. In the case of enzyme replacement therapy, the patient is biologically incapable of producing a certain enzyme. So if you detect that enzyme after treatment, you know for certain that the treatment is the source of that enzyme. We enjoy the same level of certainty here because retinal tissue does not spontaneously recover in humans, and no amount of positive thinking or placebo effect can change that biological fact. And because new tissue formation can only arise from interventional therapy, it should never occur on the control arm of a clinical trial, which we believe will be a significant positive contributor to our probability of clinical success in later trials. We're extremely fortunate to be in a position where we likely will be looking for evidence of a clinical effect from OpRegen against a background event rate of 0, providing significant statistical power to our studies. So we have good reasons to feel encouraged. But to cite Carl Sagan about extraordinary findings requiring extraordinary proof, there's always that possibility that there was some other potential explanation for the data, especially back when we initially only had a single case to point to. So maybe that patient was a genetic outlier in some way or there was some sort of administrative or transcriptional error. And even after we had asked several experts to thoroughly review and present the original case of restoration which we reported last year, everyone inside and outside of Lineage wanted to know if this was going to be a repeatable event. And as you'll hear today, we believe it not only has been repeated, but also can be shown to be reproducible, controllable and collectible in the context of a clinical trial. On a larger stage, we believe this finding is illustrative of something that we and many others have believed for a long time, and that is that the transplant of whole cells can be utilized in clinical settings to generate outcomes which are beyond the reach of traditional pharmaceutical approaches. This replace-and-restore approach is the core technology of Lineage Cell Therapeutics and underlies our long-term objective to become the leading cell transplant company. We're starting in areas such as dry or atrophic AMD and spinal cord injury, but we think there'll be additional places where cell therapy becomes a gold standard as the evidence to support this claim rises. And today, we look forward to providing you with another piece of that evidence. Six experts in the field of ophthalmology contributed to today's presentation. These all include clinical surgeons and leading academics. You will be hearing from 5 of these individuals today. They will share their independent views and perspectives on the data and these patients based on their first-hand experience and, in some cases, anonymized data samples. This webinar could easily fill an entire day, but we've tried hard to compress a lot of information into a digestible package, which can be appreciated by experts or generalists alike. We intend today to cover key aspects of safety and efficacy, structure and function and delivery and durability of our therapy. We believe our eagerness to provide this information in so much detail reflects our confidence and excitement in these findings. To kick things off, I will take just 2 slides to review the OpRegen program, and then we'll hear presentations from the experts before Dr. Gary Hogge leads an unscripted analyst and academic Q&A session with the speakers who are available today. With that, I will begin by reminding everyone that OpRegen is a transplanted suspension of allogeneic RPE cells. It is currently in a Phase I/IIa clinical trial for which we completed enrollment in November of 2020. We had 24 patients treated on that study. The clinical material is manufactured in-house at our facility. We have the ability to manufacture greater than 99% pure RPE cells. They are coming from an NIH-approved cell line. A single cell line produces all of the material, which we use. The cell line is established and extensively characterized decades ago. And importantly, we make no genetic modifications to these cells. We use a natural directed differentiation approach to convert pluripotent cells into RPE. And in fact, the levels of pluripotent cells in our clinical material are below the limits of detection. So we get complete differentiation. We have, in recent years, developed and deployed into the clinic a ready-to-use formulation. We do not have extensive dose preparation or handling or logistical issues. We have the ability to go from cells in a frozen state right into an injection device for the patient in about 5 minutes. And we are on a path to commercial production. There is no need for us to scale up beyond where we are currently because we already can manufacture the equivalent of 2,500 clinical doses in a single 3-liter bioreactor. And it would be relatively straightforward for us to scale up into multiple or larger bioreactors. By the way, I can tell you that, that reactor there can produce about 5 billion RPE cells, and we administer about 100,000 cells. As a reminder for the clinical design, it really had 2 halves. The first 3 cohorts, which had some dosing components, were all conducted in patients who are legally blind. After seeing that data collected and being comfortable with the safety profile and even seeing some anatomical -- encouraging anatomical evidence, we then moved into the second half of the study for Cohort 4 patients. These individuals had less advanced disease and smaller areas of atrophy on average, and they had better baseline vision. And we believe that this would be more typical of our intended patient population because these individuals would have more tissue available to be rescued. The highlighting, I just want to point out that the original case of retinal restoration was patient 14. That was, we believe, attributable to extensive coverage of the area of atrophy. There was a follow-up period identified by the arrow when this patient was first identified as having restoration. It was also commensurate with COVID. But at that point between patient 17 and 18, we then instructed the physicians to attempt to reach greater coverage of the area of atrophy in order to replicate the findings in patient 14. They were successful in 3 additional attempts to achieve extensive coverage. And as you can see in the final 2 attempts, they -- we have again observed retinal restoration. So among the 4 patients who received extensive coverage of our OpRegen cells across an area of atrophy, 3 of them have exhibited retinal restoration. Again, this is all done with a single treatment. We don't yet know how long a single treatment will last, but we certainly have had patients that have had retained these cells in their eyes for more than 5 years. So we next will proceed through a series of presentations from experts in the field. I'm very excited to get underway. And I think this is going to be a great session. Our first speaker today is Dr. Eyal Banin. Dr. Banin is a Professor of Ophthalmology and Director at the Center for Retinal and Macular Degeneration at the Department of Ophthalmology at Hadassah-Hebrew University Medical Center. More importantly, from my perspective, Dr. Banin is one of the pioneers of this technology, is involved in the very beginning, one of the first investigators. And his patient is one that will be featured today. So we'll begin with Dr. Banin, and please take it away, sir. We really look forward to hearing from you.

Brian, thank you very, very much. I'm very glad to be here today. And our novel treatment tries to address a very prevalent disease, age-related macular degeneration. It's the leading cause of blindness in people above the age of 50 years in the developed world and actually affects and impacts the quality of life of many of the elderly. This functional loss of retinal pigment epithelial cells plays an important role in the pathogenesis of AMD. The disease often starts in its dry or non-neovascular form as we see on the upper right picture here. And this may lead in time to loss of central acuity by progressive atrophy, and we'll see this a few slides down. In 10% of cases, the disease can transition to the wet or neovascular form of disease, in which abnormal vessels grow under the retina. And these vessels may leak or bleed, causing dramatic drop in vision, as shown here in the lower panel. While anti-vascular endothelial growth factor treatments have allowed better control of the neovascular form of disease, there is currently no effective treatment for the dry form except the traditional supplementation according to the AREDS trial, which provides marginal benefit. So there's a real unmet need here. This scheme will allow us to understand a little bit about the pathogenesis of the disease and also the way we propose to treat it. So on the left panel up here, you can see a scheme of the outer retina focusing on the choroidal vessels that are under the retina; the RP cells, which are the target of the treatment shown here with their purple nuclei; and above them, the photoreceptors. The RP cells are crucial to support the photoreceptors. And one of their main tasks is actually to take care of materials that form during metabolism of the photoreceptors, especially shut outer segments. And the RPE cells, when they fail to clear these materials, we begin to have accumulation of lipofuscin, as it's called, under and in the RPE. And this is what causes the formation of drusen, which are yellow spots that are seen in the fundus of AMD and are the hallmark of the disease and the way we diagnose it. Over time, this accumulation of debris and the failure of the RPE leads to the degeneration of RPE cells, as shown up here in the upper-right panel. And once the RPE degenerates, the photoreceptors secondarily degenerate. And this is a point where we want to intervene by introducing fresh and young RPE cells derived from pluripotent stem cells, which I will describe in a few minutes. This is to show you an example of progression of the dry form of the disease over time with expansion of atrophy. We see here in these yellow regions areas of atrophy. And on OCT scans that show the structure of the retina, you can see irregularity in the outer part of the retina, where the RPE lies and above it, the ONL. Here, we see enlargement of the areas of atrophy and more irregularity. And here on the right, after the span of 4 years, between these red bars, you can see that we lost RPE cells. Also the overlying photoreceptor layer, which is historically here, disappears. And this patient actually lost central visual acuity because this already involves the fovea, where our high resolution or fine resolution vision is present. This short movie shows the expansion of atrophy using another imaging modality for this autofluorescence, and you can see the expansion around the span of 2 years. And this growth of atrophy is accompanied by drop in vision, especially when the fovea is involved. And once the fovea is involved, we may drop to vision below 20/200, which is a threshold for legal blindness. And at this level of vision, even daily tasks like reading, recognizing faces, driving become very difficult to impossible. So how do we propose to intervene? So our proposal is to introduce via injection a suspension of cells that will hold young, healthy RPE cells. And this is the point to note that the retina, as an extension of the CNS, does not know how to renew itself. Many cells in our body have the capacity for self-renewal, but not so brain cells and retinal cells. What we're born with has to last us a lifetime. And in the diseases of aging, such as AMD, the processes that occur over time to these cells that are now 70 or 80 years old cause them to dysfunction, and we propose to introduce new and healthy cells. These cells, once in place, will help to recover perhaps the function of the photoreceptors that are still there that have not yet degenerated. And this is actually the point in time where we think treatment should be ultimately addressed when the process just begins to cause loss of photoreceptors. In 2003, we set out on a basic research mission to try to develop RPE cells from pluripotent cells. And by adding certain factors to the media in which these cells are growing in vitro, we found that we can actually enhance the differentiation of the cells into an RPE fate. And these cells are actually very similar to RPE cells in our eye in many ways, including expression of photo -- of RPE-specific factors and also functionality. When we transplanted these cells in animal models of disease, we saw that they can layer out in the proper niche under the retina and can survive. And when transplanted into an animal model of retinal degeneration that is secondary to RPE dysfunction, the presence of these healthy RPE cells allowed rescue in that area of transplant with better preservation of photoreceptors and also better preservation of vision as measured using the optomotor response. When these promising results were seen, the translational phase began, in which the technology was upscaled. And now we have a technology that allows the large-scale directed differentiation of the cells. And we have actually the ability to produce millions of doses of fresh RPE cells that are frozen and can be used as needed. FDA approval allowed us to embark on a Phase I/IIa trial, which includes 4 cohorts, a trial that was recently completed in terms of recruitment. The first 3 cohorts were dose escalation cohorts in which patients with very advanced disease were recruited in order to, first of all, examine the safety of the treatment. And once this was established, Cohort 4 allowed us to recruit patients at earlier stages of disease with better visual acuity and smaller areas of atrophy as shown here. So you can see here that the Cohort 4 patients had almost twice the resolution in terms of seeing letters on the ETDRS chart as compared to the first cohorts as well as a smaller area of atrophy. And this translates into a number of important measures, and one of them is the ability to actually transplant the cells efficiently under the whole macula. In the first cohort, as you can see here, the atrophy is quite advanced and the retina is very adherent as opposed to a Cohort 4 patient in which the process is still in the earlier phases. And then when you inject the suspension of cells, it can actually reach and expand across the macula. I would like to present the patient in which we first saw a very promising restoration of retinal structure. And this patient shows both the most common side effect of this treatment, namely epiretinal membrane formation, but also the promise of this treatment in terms of possible restoration if we treat the disease at the right phase. This is an 80-year-old female with a 20-year history of AMD. The treated eye was the left eye, which at baseline had 20-80 vision. The fellow eye had better vision. And this is -- these are images at baseline. This is the area of atrophy in her eye. The yellow dash lines denotes the area of the retinal blood that was formed during surgery when the suspension of cells was injected. And here, you see a photo taken from the video of the movie during surgery that shows this area in which the retina was elevated and the suspension of cells was delivered. We followed the patient. And 2 months out, we began to see formation of an epiretinal membrane that was pulling at the vessels. We'll see it better on the next slide on OCT. And this image is one month after this observation and 2 weeks after peeling of this membrane, which is the way we treat this complication. Here, you see the retinal structure at baseline. This is 2 months after transplant. We have this very thick membrane that's distorting the retina. But 2 weeks after peeling, the retina actually is able to restore its structure and the complication can be well treated. When we see -- look at the visual acuity over time, this patient has now been followed for close to 3 years. In the green line, we see the change in visual acuity in the treated eye, minus 4 letters, as opposed to the -- what was the better seeing eye originally, which dropped to a much greater extent. Then essentially, the worst eye now has become the better eye of this patient. This is -- these are images at baseline and 1 year out, where we can see this pigmentation that we think suggests the presence of the RPE cells that were transplanted, especially in the transition zone around the area of atrophy as well as outside. And the most promising and surprising result was when we looked at OCT scans in this patient. So what you see here are OCT scans 12 months apart, one of them at baseline and one of them 12 months after transplant. And usually, in the course of AMD, as we saw before, you would expect that a more normal healthy-looking retina here with good layering, good RPE, good photoreceptor layer would then turn over time into atrophy, as seen here. But actually, it's quite the opposite. So your baseline image is actually here on the bottom. And after 12 months, you see this restoration of better structure in an area that was previously atrophic. This specific scan was taken on the nasal border of the geographic atrophy in what we call the transition zone, where we think there is still capacity of photoreceptors to recover. And here again at baseline and 12 months out. And it's not an isolated scan that shows this. Anywhere you look around at the borders of the GA, you can see a similar effect. So this is at the temporal border, again, at baseline. Note this large area of irregularity and atrophy and much better structure 12 months out. This is at the superior border. Again, showing the same effect in the area with loss of RPE and photoreceptor layer and recovery of the layers here and also on the bottom and interior border of the GA. Again, an area of atrophy becoming much better structured retina. This has never been shown before. No treatment has shown reversal of such a process. And this gives us much hope that if we intervene at the right time, this treatment can perhaps address dry AMD progression. My friends and colleagues will present this data in a more quantified manner in additional patients. And I invite Dr. Monés, a good friend and a wonderful physician and scientist, to present further results of this trial. Thank you very much.

Dr. Banin, we're obviously very excited as the sponsor, but we also recognize this as a new technology. Perhaps you could share your thoughts on where this where this technology could go, patient profile, safety considerations and overall sort of gist of how you see this technology advancing.

Yes. Thank you very much for this question. I fully agree. I think that while there are promising results, it's still in a small number of patients, and I think we have to tread carefully. We need to expand the trial. We need to prove this happens in more patients. We have to look for possible side effects that may occur. I think that this trial has been conducted in the spirit of responsibility that we would like to continue. And while they're promising results, we should tread carefully and keep our eyes open for complications that may occur and hopefully, have more cases in which we can see these types of effects.

Do you have a perspective on whether earlier-stage disease could continue to show better outcomes? And is there a point at which going earlier might not be beneficial? Is there a ceiling to this admittedly early technology?

Right. Yes. I mean finding the correct time for intervention is going to be a bit tricky because, on the one hand, you don't want to take someone who has good functional vision and expose them to risks due to the surgery, due to your information, due to failure of treatment. On the other hand, if you wait too long and the atrophy becomes too established and too wide in its extent, you won't have these transition zones that are potentially reversible. I think that once we begin to see patches of atrophy that are growing and the vision hits something like 20/50 or 20/60, that would be the time to intervene. And I think that at the moment, going at earlier stages is a bit risky. But I think that if I were an AMD patient and I were hitting 20/50, 20/60 and I had small patches of atrophy, I would say, "At least treat me in one eye." And the other eye, maybe not initially. And we'll see the response and then decide on the other eye. But I think this is the point of intervention that we should go for. I mean even these patients in Cohort 4 are already a little bit too advance. So we see the effect in the periphery, but we're not able to have any recovery and the center of the GA is simply too large. So we have to start when the patches are still small and then transplant the cells. It'll take time to reach that point. I mean it's going to have to be a gradual path. But I think that as we see when we look at small patches of atrophy in patients that were treated, that completely closed, that's when we should intervene when it's possible to -- when all the -- when the whole lesion or these little lesions are all transition zones, are all like border zones that are still reversible.

Thank you, Dr. Banin. And just before this presentation, you had mentioned that there were some even more recent results observed in one of the patients. Would you like to share those thoughts with everyone?

Yes. So we -- actually, one of the last treated patients, which is now 7.5 months post-transplant, was just in for a visit a week ago. We didn't really have time to fully analyze the results. But it seems that over time, we are seeing better and better effect. There are many regions in which we can see restoration of retinal structure, and it's actually quite exciting.

That is wonderful. We'll look forward to seeing those data when they're available. And thank you so much.

Thank you very much.

Our next presentation will come from Dr. Jordi Monés. Dr. Monés is the Director of the Barcelona Macula Foundation. And Dr. Monés has the distinction of being the individual who originally identified these extraordinary findings. So I think you're really going to enjoy hearing from him. Dr. Monés, please initiate your presentation. Thank you.

Thank you, Brian, and it's a real pleasure. And it's -- I'm so excited because when I saw these signs of restoration, I truly thought I was wrong, that I was doing something incorrectly because this kind of myth that retina cannot be restored was so profound. So I'm quite amazed, and I truly believe we have something here. And I'll try to explain it, try to show it. And this probably will start a new era in the -- and a new paradigm, a shift in paradigm in thinking about geographic atrophy. First, I'd like to explain. I'd like to make an introduction on how we measure these things because the fact that we're introducing stem cells, RPE stem cells, the aborigines themselves into the retina, makes things a little bit different than just following or studying plain retina by natural history. So we need to deal with some specificities. Otherwise, we could not assess this benefit if we do things old fashion. So thank God we have a lot of kind of types of imaging for studying AMD, both exudative and trophic. And historically, we had color fundus photography, fundus autofluorescence, infrared imaging, optical coherence tomography, fluorescein angiography, Indocyanine Green Angiography and OCT angiography. The last 3 are mostly for exudative AMD we will not cover that. So we are not interested that much now with geographic atrophy. So we will stay on these 4. So color fundus photography is a historical standard. The old times, GA was measured by this. It has a lot of cons for detection of GA boundaries. It's good, yes, for detecting hemorrhages and pigment, but it's not precise at all for studying geographic atrophy. So it's by far not used nowadays for geographic atrophy. Fundus autofluorescence is a high contrast, has regulatory acceptance. Many trials have studied their primary end points measuring autofluorescence. It allows some phenotyping of the patients, but it's not precise at the fovea. It's very difficult to detect the foveal margins because of the change of field pigment in the fovea that interferes with lipofuscin. Therefore, it's not that precise. Then we have infrared imaging. It's never been used as a primary imaging. It has an auxiliary validity or health or systems for the FA -- for the autofluorescence to study the fovea. So we use infrared to guide us in the autofluorescence of the fovea. So it's just a complementary information. Then we have OCT, optical coherence tomography. This gives us an idea of the layers of the retina. And also the imaging, the projection of the OCT does an image that corresponds to the same as autofluorescence. So with OCT, with the hyper transmission, we can quantify boundaries and size as well as with autofluorescence. But in addition here, we're seeing the status of the retina. We have an anatomic tracking functions to do it always in the same time. It's not yet that being used for clinical trials. Automatic segmentation sometimes has to be human-guided, manually guided because sometimes it has some errors, but this is very interesting to me. So as we said before, fundus autofluorescence has been used to measure the primary end point in clinical trials, which is lesion size growth and progression. We have lampalizumab. We have Zimura from IVERIC. We have Apellis FILLY trial. And in lampalizumab, they were measuring lesion size in square millimeters. In Zimura and Apellis, they're already using the square root transformation, and we'll see afterwards that this is very important. The good thing of a square root transformation is that lesions that have different sizes can be compared because the distortion of the factor to dimension, it's solved by this transformation. So it's not anymore a problem to compare small and large lesions. And we will use that, and I'll explain to you why. But autofluorescence depends on the fluorescence of a natural pigment, which is like lipofuscin. And lipofuscin accumulates in life, age-related accumulation or in pathological states. So in very young cells, there is almost no lipofuscin. We see this graph here at the left. In the middle graph, we see how this is accumulated through age. And in our right, at the bottom, we have a 9-year-old specimen, a human, with no autofluorescence. So all people have autofluorescence. And what autofluorescence detects is absence. When we have absence, then we interfere, we don't have RPE there, and then we have atrophy. So absence of autofluorescence means atrophy. Let's see what happens without autofluorescence when we use OpRegen cells transplanted into a patient. Here, we have a scan going through a very dark area. This patient was already transplanted. So this dark area conventionally should correspond to an area of atrophy. But if you see the scan, all the layers of the retina there, there is no hyper transmission. There is no atrophy. So dark autofluorescence or absence of autofluorescence here do not correspond to atrophy. And this is because the OpRegen cells are very young because they are stem cell-derived so they're extremely young. And therefore, they have not accumulated any lipofuscin. So we cannot use autofluorescence to validate GA when we use OpRegen cells because they look like those areas had no cells, which is no sense. So autofluorescence doesn't work when we transplant stem cells. And when we see this scan going through the colored picture, we see this hyperpigmented area that corresponds to the cell. So the color imaging in our case helped us to see the pigmented cells. It does not give us an idea if these cells are viable, if they're just junk or debris, but we see hyperpigmented cells where we transplanted. So let's see with OCT. En-face OCT has been proven to be as valid as autofluorescence to measure lesion sizes. Here, we have this study for Yehoshua and a group of Philip Rosenfeld. The column in the middle is autofluorescence. The column on the right is the projection of the hyper transmission of the OCT. The images are very similar. So it -- OCT is as valid as autofluorescence. But in addition, we have all the layer details. And we depend to make these images in the hyper transmission of the sign out here at our lab. We see how the absence of RPE causes a hyper transmission of the signal, and this hyper transmission makes these en-face images. So OCT works to measure lesions. But what happens again in our case? When we put something extra under the retina, we are interfering with the hyper transmission. See the image below. The image above is baseline. The image below, we have an extra material that we don't know if these are viable cells, if this is inflammation, if this is dead cells. Whatever they are, they interfere the hyper transmission. So if we say that when we don't have hyper transmission, we have viable retina, that's probably overestimating. It's a false positive. So we cannot rely in hyper transmission or in its absence to say that the retina is atrophy or it's good, it's healthy. So hyper transmission doesn't help us when we put something under the retina. So we cannot rely on hyper transmission. So what would be the ideal end point to assess geographic atrophy when we use stem cells? FAF doesn't work. We've already seen why because these very young cells do not have lipofuscin. They do not autofluoresce. Hyper transmission reveals atrophy. However, absence of hyper transmission do not necessarily correspond to healthy viable retina. So the ideal end point should reflect directly the status of the retina. Therefore, the best end point would be an in vivo histological-like end point. An end point that would say, here you have healthy retina. Here, you have not healthy retina. That would be ideal. So then we go to histology, lessons from histology. As a long time ago as in 1976, Sarks already pointed out, suggested that the external limiting membrane could be the frontier between healthy retina and atrophy retina. And later on, more recently, Christine Curcio, she's an enormous export in histology in AMD, probably the best one, in 2016, she claimed that ELM comprises junctional complexes between Müller cells, photoreceptors and RPE, which means that the ELM presence means RPE and photoreceptor interaction. So if we have ELM, we have photoreceptors and RPE interacting. And also stated that a border of atrophy that can be precisely delimited is the ELM descent as opposed to the termination of RPE layer itself. Because of dissociated RPE in the atrophic area. As we said before, we may have RPE remnants, RPE debride that looks like RPE, but they're not. So whatever is the true border of the healthy and atrophy retina is the ELM border. And in a more recent paper 2018, Christine Curcio group stated again, the ELM border descend is accepted as the delimitation of the area with near-total photoreceptor depletion. And therefore, the boundary of the atrophy in cRORA, complete retinal, outer retinal atrophy. So the ELM histologically is accepted -- its border as the border of the atrophy. So nowadays, we have the OCT, and OCT has almost histological resolution. We don't see the cells themselves, but we see the layers. As per the layers, it's like histology. We can identify very beautifully all the layers, and we can identify very well the ELM. So that's why we use ELM in this study to measure the lesions, to know where we have atrophy or where we have viable retina -- true viable retina. We did not rely on RPE layer. We did not rely on the ONL. We rely on the ELM. Look here. This is the RPE. This is the -- sorry, this is the ONL. Okay. It's good to know that these layers are here, but this is the ELM. And despite that the ONL and RPE gets more to the center, we take the age of the lesion, the border of the ELM. That's where we put the borders of the lesion to measure our patients. So after this explanation, let me show you what we found, what we found in some of these patients. And these pictures are really impressive and almost as magical. So let's see this -- the first patient we saw these changes. As I said, we use the ELM border to measure the lesion. And here in this trial, we did something that is quite unique and it's really important. We had historical growth. We did not put cells in patients that we did not have previous information. So we wanted to know how this lesion had grown for at least the last 6 months. If we knew the historical growth and we do the square root transformation, then we -- the growth becomes linear, and we can predict at any point in the future how it could be the growth. So that's very important. So in orange, we have the historical image. In red, the baseline. We see that from historical to the red the lesion growth pretty much. In blue, it's 9 months after, much smaller than the red. And in green and in yellow are close to the month 9. And this is 2 years later. So 2 years later, the lesion is smaller than baseline. This is -- if this is true, and I do believe it's true, this is a complete new paradigm. The current trials, they're happy having a 25% reduction of growth in 1 year. And here, we have no growth for 2 years. So it's a complete shift. So let me explain you this graph. This is a very important graph. These dotted lines are the predicted growth. Yellow is the fellow eye. So when we had the historical from minus 14 months to baseline, we could from there predict the growth at 3 years. And at 3 years, the dotted line is a calculated predicted theoretical growth. The bold yellow, it's the actual growth, how this lesion grows, and it's pretty close to what we estimate, what we predicted. So that was a fellow eye. So it worked for the fellow eye pretty close. Let's see what happened with the treated eye. The blue dotted line is a predicted growth. The blue bar is the actual growth, a tremendous difference from what it was predicted. And in fact, this patient at 3 years had the same lesion size than at baseline. So these lesions did not grow at 3 years at all. In fact, in previous visits, even the lesion diminished, decreased, then it grew a little bit and grew back to the baseline. 3 years and no growth, no one has seen this before in any of the current trials. So that's the beautiful part. That -- this is the new thing. And it's the imaging that tell us that we are having restoration. So as we said, we're relying on the ELM. So here, in the upper lesion, if you could follow my arrow, I'm not sure of that. The ELM seems down the border that we saw at histology at the borders of the atrophy in both sides. In the image below, the ELM is continuous from one side to the other. So we have ELM. We have new ONL. We have new RPE. So in an area that was devastated, we have new retina. So the first thought you could say is, oh, this is quite up -- in the upper part of the lesion. Maybe you have a misalignment of the OCTs and you're then measuring the [ stem ] place. Okay, that's what I thought at the beginning. And then start looking all around, and this happened all around the lesion. So it could not be possible that 360 degrees images where all misaligned. So this was not only here at the border, but in other places. So let me show it to you. This is the SCAN 34. That's not at the border. That's quite within the lesion. And direct arrows show the edge of the ELM, above its baseline below its 35 months. So the red arrow has really gone into the center. So we have had this area of not only ELM but ellipsoid, RPE, ONL, plexiform doesn't subside that much so that plexiform also it's visible in the blue arrows. And this happens in both sides. And that's not at the border of the lesion, that's well within the lesion. So that's not possible because of a misalignment at all. And this growth already happened earlier. So we show first 35 months, but we have here 9 months and 23 months. And we see how this ONL continues to the center, but specifically the border we chose was ELM much inside the center of the lesion. So another scan much below. That's a Scan 20. On the upper image baseline, the inferior image at 3 months already -- 3 months already, we see the ELM going to the center with new RPE, with new ONL, with new altered plexiform, not sinking down, not subsiding. And this is at month 33. At month 33 in the right side, we still have new retina regenerated 3 years later, almost 3 years later. And this is for -- [ ninth line ] in 23. We see the progression of this restoration of these borders. This is Scan 16, another place. Again, especially in the left side, we see how the ELM goes to the center with a new beautiful layer of RPe, thinner RP, thinner ellipsoid, thinner ONL, but they're all present. We have new ONL, new ellipsoid, new ELM and new RPE. That's new retina in an area that there was no layer at all. That was completely atrophied. So this is a visual function. That's not the most important thing because this could be anecdotical, however, it has a trend. The treated eye after 3 years, lose no layers and the fellow eye loses a lot of layers. As we know, these patients in relatively short number of years, they lose a lot of vision. So there is a trend that the visual function was preserved and compared to the fellow eye. And we don't have microperimeters as a baseline, but if we can say something of this microperimeter, we see that at 3 years, the fixation is much more stable. And probably, there are areas in the center that the function is still better. Still, this is very preliminary, but the functional makes sense what we are seeing anatomically. What we are seeing at anatomically means new interacting photoreceptors with RPEs, so they must function. So let's show you another case. That could be just one. And when we saw the first scale, we thought maybe this is a miracle or something but, no, we had other patients that did the same. And restoring retina, it's something unique. And it doesn't matter if it happened just in 3 cases. This -- if you allow me to make a comparison, you have 20 people who are dead. You resuscitate 3 and you say, "Oh, it was only 3." You'd said, "Oh my God, we resuscitated 3 people from death." That's unique by itself, no matter if it's 3 out of 20. So this is tremendous information. And so it was not just only one, let me show you this second patient. For example, this very tiny area of atrophy disappeared. The layers where the RPE was restored, the ELM was restored, the ONS was continuous. Let me show you more scans. This is very beautiful. Baseline, we see a complete atrophy, complete iRORA, no [ co axons ], there is no layer. See the image below. We have in thinner, everything, new RP, new ELM, new RNL, the outer plexiform that it doesn't subside to the Bruch's membrane. In thinner, we have all the layers again. Here is these very thin homogeneous RPE, ELM, everything else that was not before. This other scan, the outer plexiform gets more into the center, the ONL, the RPE. Again, OPL, ONL, RPE getting closer to the center. And let me show you about the third case. This is just 3 months of follow-up. But as soon as 3 months of follow-up, The ELM in blue arrows has gone to the center. We have new RPE. The outer plexiform in green do not subside. It keeps up. It keeps this up because the ONL has recovered. And of course, we have less hypertransmission. Although we said we don't care about the hypertransmission, we care about the ELM. But everything else supports the feature that we have new tissue and new tissue that interacts, that RPE and photoreceptors talk to each other and connect. So this is another scan, new ELM, new RPE. And when we measured this area, it is just 3 months. It's -- but there was a decrease in the size of the lesion. So if we make the annual rate in square millimeters that we don't care about, it's minus 3.48%, but in a square root, it's 0.9 minus. If this 3 months rate would be done at 1 year theoretically, that would be 0.9 minus. That's huge. In the reverse, it would be a huge growth. Imagine how it is as ingrowth, 0.9% regression, it's huge regression. So thank you very much. I hope you enjoyed these images. I'm really impressed and astonished that some myths sometimes are no longer true, and restoring retina is possible. Thank you very much.

Thank you, Dr. Monés. That's wonderful. We're indebted to you not only for the finding, but your ability to make it so understandable. One of the challenges, of course, of new findings and new technologies. So Thank you again, and we look forward to having questions asked about this in the question-and-answer session. Well, to continue with our theme of seeing is believing. It's my pleasure to introduce Dr. Brandon Lujan. Dr. Brandon Lujan is the Assistant Professor at the KCI Institute at OHSU and Medical Director at the Casey Reading Center, and he is one of the premier experts in retinal imaging. Dr. Lujan, thank you very much for being available today, and we look forward to hearing your presentation.

Thanks, Brian. It's my pleasure to present some of the patients' experiences through January of 2021. The first is #21 in the right eye, and we'll be looking at some of the images of the retina, starting with the baseline images. Here, it's showing geographic atrophy centrally with expected drusen and RPE changes. After treatment, there's some postoperative changes, but we can already see that there's less choroidal detail centrally apparent. And that goes to the last image that we have, which doesn't exactly register with the priors, but does show these extensive RPE changes and some postoperative changes in this right eye. The fundus autofluorescence that picks up lipo fusion from the RPE shows the baseline image here and then that change over time, that there's an apparent increase in the FAF at the second time point. And then at the final time point in January. But the OCT, optical coherence tomography, is really the best way to get an understanding of what's happening in this eye over time. So what I've done is identified key cross-sectional landmarks and looked at the process of change over time at those positions. So in the upper left, we can see a cross-section through the retina, the location shown by the green line in the overlaid infrared image on the photograph from October. And in that upper left image, we see several important features. First of all, we know all of these images at different time points are well registered by looking at the choroidal vasculature. So I'm just illustrating this here with the blue lines. This is a quality control check just to make sure that we can actually look at change and it's meaningful, and that's the case in all these images. But what we see at baseline is that there's a loss of the ellipsoid zone. This is the critical point where the inner segments and outer segments of the photoreceptors interface. And there's also a loss of the overlying external limiting membrane, which is a key structural element in the retina where photoreceptors and Müller cells joined to form lateral stability. And both of those are lost as we see in atrophy. However -- and there's actually some additional features there in October. So there's a descent of the overlying retina. This is indicating that there's outer nuclear layer or ONL loss, the ONL are the photoreceptor nuclei. And as this reflectivity that you see kind of just falling into that pit, it's telling you that there's some cell loss that's occurred. Furthermore, there's a loss of the RPE. There's only visibility of Bruch's membrane, but the retinal pigment epithelium that nourishes the photoreceptors is absent. That's seen directly and also by the increased hypertransmission that's apparent down into the choroid. So that's all baseline that we might expect with atrophy. We can see some changes in those areas at this location over time. So when we look at the November 8 time point, we can actually see that there does appear to be a reformed ellipsoid zone as well as that external limiting membrane, and maybe even some formation of the RPE deeper to that. We still do see some of the Bruch's membrane, that discrete thin band at the bottom present, but there's some material that appears to be filling in above it. We do see a decrease in the hypertransmission. So where the RPE is normally reflecting light back and when it's absent, light is continuing into the choroid, causing that hypertransmission. That's now decreased, telling us that there's maybe some material that is now present that's reflecting or absorbing light. So that's a change. As we move on to December, we can see that, that ellipsoid zone has become irregular. There is still decreased hypertransmission of light, indicating that there are deeper changes. So there's 2 additional time points that we'll look at, this bottom one from December and on all subsequent slides, will carry over to the top. So now in this top slide, we're seeing the same time point. And then following on to the next, we see that, that area that had looked like ellipsoid zone becomes slightly more irregular and that there is an increase in hypertransmission, though not as much as there was at baseline. And at the final time point, there is a more discrete appearance of the external limiting membrane and what is also consistent with being an ellipsoid zone. And there is an RPE like structure that is present and continuous with the RPE that's intact and Bruch's is visible beneath it. So there is some change back to a more normal appearing anatomy at this location. If we move on now to the next retinal location of interest, we can see a broader area of geographic atrophy, where we see the edges of what's intact external limiting membrane and ellipsoid zone. There is this loss of the RPE centrally and increased hypertransmission. And again, this more light penetrating to the choroid. And there's also some features of retinal abnormalities or photoreceptor abnormalities, which are these outer retinal tubulations. There's actually one here and one more temporal to it as well. Very interestingly, at the second time point, in November, we do see what a reformed external limiting membrane that bridges that entire area. And again, these are registered images that I feel confident are in the same location. So that is very interesting. There's now this hyperreflective band that's contiguous with the ellipsoid zone that's present early on. And there's this hyperreflective amorphous subretinal material that's present. There's not any discrete banding but there's a presence of a lot of material that we wouldn't normally expect. As we move further on, that external limiting membrane becomes less visible and that amorphous material remains. There are discontinuities in that new band that was contiguous with the EZ that starts to develop. And again, that's carried over onto the next slide showing the further progression at this location, where we now see that the external limiting membrane is not visible and but that amorphous material remains. However, at the last time point, there is a more defined band that is starting to become present. And within this structure that's more central, there is the appearance of that external limiting membrane or hyperreflective band that does appear to be continuous of that, and that has evolved over this last 1.5 months. A similar appearance at baseline, a little further down in the image, but there's some important additional findings. So we still see these edges of intact ELM in the ellipsoid zone and that loss of RPE with hypertransmission. But here, just 3 weeks after baseline, we do see that there's a reformed band that's contiguous with the ELM. Again, the same location and now showing very different anatomical picture that we would not expect in the natural history of this condition. There's amorphous hyperreflective material again at the edge. And here a thickened ellipsoid zone. So the significance of this is unclear, but the ellipsoid zone is markedly thickened compared to baseline even away from that central area. As we move on, we see some discontinuity in the band contiguous with the ELM. We see a small area of subretinal fluid. And an interesting finding that I'll -- really becomes apparent as there's a thickening of Bruch's and the RPE that begins to be present at this location. And as we continue throughout the time course, we'll see that continue. So it further thickens as time moves on. And there is an advancement of the RPE edge over the last 2 time points. And a possible area where the ELM is overlying this new area. But in that center area, the ELM remains. So from the 3 weeks after to the final time point, that stays present and is indicative that there are photoreceptors and Müller cells that may be causing that reflection. We move a little bit further down. Here, we see at baseline, again, these edges that are intact, some degenerating drusen as we'd expect in dry-AMD and essentially a loss of the RPE with hypertransmission. Again, we see that thickened ellipsoid zone 3 weeks after, and some reformation of the ELM that wasn't present initially. So dramatic changes in the retina. We see that amorphous hyperreflective material present deep. We're seeing disrupted ellipsoid zone, however, in the beginning of December, that, that area of thickening appears to not be present centrally. We can see these changes also in the inner retina that I'm not focusing on, but we do see prominent membrane present there. We see that amorphous hyperreflective material deep. And again, this increased thickening of the Bruch's and RPE. So that becomes increasingly so as time moves on. We see that the Bruch's and RPE continue to thicken. We see this persistence of this material that's present at the base of this lesion. We do see some pigmentation type changes present there temporarily as well. And then interestingly, we do see that there's an overlying external limiting membrane that becomes really quite apparent at the final time point and even the appearance of perhaps of RPE that's present that wasn't as well defined earlier on. Again, the thickening of Bruch's and RPE. So that is a cross-sectional analysis. Another way to get a sense of what's happened to this eye over time is looking just at the edges of the ellipsoid zone. And what I've done and showing an example of it here is I've looked at each of the cross sections of this eye at baseline and then the final time point, and I've identified the unambiguous edge of the ellipsoid zone. So I'm showing that here with this green line, and that's making a point that I'll mark it red at that edge. Importantly, when I say unambiguous, hat I mean is that it needs to really look just like in ellipsoid zone would be expected to look like on OCT. Sometimes there is some further changes in the image with decreased reflectivity, but I'm not considering that. But I'm taking the most conservative approach possible to identify those edges. And so I'm marking one edge here and then I go through each of the B scans to identify both edges of the lesion on each side and then fill it in to create an area of that unambiguous EZ loss at baseline. When we look at that at the final time point in January, we do see that the -- this area of unambiguous EZ loss has increased. So there have been some changes to that anatomy over that period of time. Another way to look at that is to compare the ellipsoid zone map with the infrared image. So that's shown here in October and then in January. And what's very interesting is the changes, and Jordi talked about this, too, the infrared image that we're seeing. And that may give us some clues of what's happening anatomically. The final observation and way to look at this case has to do with the RPE and gross thickening at the multiple time points that are present. And what I've done is chosen one representative slice and location here and looked at it at each of these time points. And what we see is interesting, that there's clear thickening of that Bruch's and RPE. So this is definitely showing activity. This is not expected or what we would see in atrophy. So this is the same location at each time point, and it's very obvious how much change there has been. So these are very interesting observations, and this will continue as we move from January. When we summarize the cross-sectional findings and these other findings, I think what we can say is that baseline does show this geographic atrophy with loss of external limiting membrane, ellipsoid zone in the locations we expect. That at 3 weeks, there's actually significant outer retinal changes, including partial reformation of the ELM and ellipsoid zone. But there's diffuse thickening of the ellipsoid zone and amorphous hyperreflective subretinal material that becomes present. At 6 weeks, some EZ changes persist, but EZ loss is also occurring. There is some thickening of RPE in Bruch's that becomes apparent. By 3 months, the thickening of RPE, Bruch's continues. The external limiting membrane is more visible and continuous over multiple locations in the study eye. So the easy area in toto shows a loss of unambiguous EZ from baseline to 3 months. Again, this is a conservative estimate based on grading the edge of the EZ only where these characteristic anatomical findings were no longer present. It does need to be interpreted in context of these changes with ELM and the RPE, Bruch's. And it's really creating an interesting story about what's changing in this eye. Okay. We'll move on to the second eye. This is #22 in the right eye. This is the baseline image from October 5. We can see a central area of atrophy with increased choroidal vascular markings present with some surrounding hyperpigmentation and drusen, as we would expect in this diagnosis. And then the final time point, 3 months later, we see the choroid not as clearly. We still see RPE-type changes in drusen and some postoperative changes present as well with small amounts of hemorrhage and some choroidal changes superiorly. The autofluorescence from baseline as shown here. And then at follow-up, we can see that there is an increase in the area of hypo autofluorescence present. Here, we are looking at 4 different dates from these critical cross-sectional locations. So at baseline, and through the other 3 time points, again, I've looked at the choroidal markings to ensure that we're in the same place. I will note at the second time point and probably due to the timing of it, after surgery, there's some difference in its registration from others. So we can't be totally positive we're in exactly the same spot. But the first, third and fourth time point are all locked in and we can believe change is there. So starting from the October time point, we see the edge of the external limiting membrane quite clearly, that we go on to develop some residual subretinal fluid, again, after surgery in November and a PED that's present with some hyperreflective material internal to it. But that later goes away, the PED is not apparent at the next time point, and there is this now new subretinal material present. There is some reformation of that external limiting membrane. The edge that was visible at the first time point is -- it's now quite a bit extended beyond that. And it begins to go up that amount of the increased subretinal material that's present. At the next location, we see this sharp hypertransmission. Again, these are boundaries around atrophy where light that would reflect back from the RPE is continuing deeper into the choroid. We see that residual subretinal fluid and thickened outer segments, which are consistent with that. And then we do see some structure that's overlying Bruch's that we really didn't get a hint of from the baseline. And then that does appear to go into this persistent subretinal material that's present later on. We see this new large subretinal deposit that's present that wasn't there previously and it looks to be continuous with the RPE on the nasal edge. And then at the final time point, there is clearly an extension of the ELM where there was a gap early on. There is -- this subretinal deposit remains. There's no overlying outer retinal structures that are obvious, there's no ELM or EZ that's present, and it does look like it's pushing up into the synaptic outer plexiform layer above. So it's unclear exactly what that represents. I will say that the -- there's still a sharp temporal hypertransmission that's apparent again, temporarily, but not nasally. So there was a more clear nasal boundary before the reflectivity, more nasal hasn't changed. So that is interesting that it's less visible, implying that there is something reflecting or absorbing light that's present now. At the final location here, there's, again, areas of an edge of the external limiting membrane. There is a descent, which is telling us that there's atrophy -- is where the photoreceptors, cell bodies in the ONL are now falling into that pit of atrophy. And there's hypertransmission again because the RPE is absent after surgery and after the second time point, we do see this new PED and this subretinal material that's present along with residual subretinal fluid. That subretinal material remains. And then at the last time point, we do see some extension of the external limiting membrane that is now moving to more central from where it had ended at the baseline images. There is still persistent hypertransmission that's apparent here. So this isa -- as an earlier case, but there's a lot of interesting findings. Again, there's baseline central geographic atrophy. There's other satellite areas as well. There's the expected loss of ellipsoid zone, ELM and hypertransmission. At 4 weeks, there was this macular hole formation and a large subretinal fluid collection. But at 6 weeks, there was really just residual subretinal fluid present and new material apparent on the surface of the RPE. And by 3 months, all the subretinal fluid had resolved. There was the remaining subretinal material present and this formation of a large central subretinal deposit. And at 4 months, there was this extension of external limiting membrane at multiple locations across the OCT volume and increased subretinal material. So an eye that's definitely in flux, and we'll continue to monitor and look at these locations to see how things are changing.

Dr. Lujan, it's Brian Culley again. You mentioned about -- when talking about the Bruch's membrane, of the thickening that that's not normally observed in the setting of atrophic AMD. I'm wondering if these structural changes are things that you've seen with any intervention, not just naturally, but interventionally.

Thanks, Brian. No, I haven't seen that. The -- both the change and the speed of change is surprising to me, and it's not something I've observed with other treatments or in other situations.

Okay. Thank you. The next presentation will be from Dr. Christopher Riemann. Dr. Riemann is a Vitreoretinal Surgeon and Fellowship Director at the Cincinnati Eye Institute and University of Cincinnati School of Medicine. Dr. Riemann will discuss OpRegen safety as well as findings of retinal restoration in one of the patients which he treated, of course, is also one of our primary investigators. Dr. Riemann, please take it away.

A very good day, and thank you for tuning in. Here's my contribution to this presentation. I'd like to give a little bit of an overview of where we're at with the OpRegen project and the fully enrolled cohort 1, 2, 3 and 4 patients. I will also talk a little bit about a patient of mine that made it into the local news headlines with some exciting visual results. So as you know, the Cohorts 1 through 3 and Cohorts 4 are fully enrolled. Cohorts 1 through 3 were legally blind patients with poor visual acuity in huge areas of geographic atrophy. Those are the early cohort patients. And in Cohorts 4 had better visual acuity in the -- on the order of 21/25 and smaller areas of geographic atrophy. Follow-up has been multiple years for Cohorts 1 through 3 and also a significant amount of years for most of the Cohort 4 -- for many of the Cohort 4 patients. The primary endpoint was systemic ocular and safety intolerability. We didn't have any drama in terms of unexpected adverse events or serious adverse events. The OpRegen cells appear well tolerated in the subretinal space. Cohorts 1 through 3 had some improvements in some patients. But these were end-stage eyes with terrible disease, and most of them ended up losing vision because of progressive end-stage geographic atrophy. Cohort 4, on the other hand, had eyes that weren't end stage and 83% of these eyes had either sustained or improved vision from baseline, which is a pretty impressive result that we haven't seen in any dry macular degeneration treatment to date. There was no delayed inflammation, no IOP issues, no uveitis, no detritus. And most of the adverse events were typical post-surgical events that are fairly underwhelming. Taking a deeper dive at the actual ocular adverse events. About half of the patients had subretinal pigmentation, which we attribute to -- likely that the actual pigmented cells that we injected into the subretinal space. So it doesn't surprise us that there's some subretinal pigmentation. We view this as potentially a positive finding. In terms of negative adverse effects, there was significant epiretinal membrane formation in about 2/3 of the patients. And although a majority of these were mild to moderate, 3 of them required -- were severe enough to require surgical removal, and there were 2 retinal detachments. There was some CNV formation in 4 patients, all of which responded well to an injection or 2 of anti-VEGF. And 3 of the 4 of these were in the Orbit Subretinal Delivery System operated eyes. In terms of adverse effects, the -- 3 of the epiretinal membranes required reoperation and membrane stripping, membrane peeling. And 2 patients developed retinal detachment. Both approximately 2 weeks post procedure, one, both of which were felt to be related to the surgical vitrectomy procedure. These were both in the eyes -- both in eyes operated with vitrectomy retinotomy. One was successfully repaired and did well. The other one was not successfully repaired because the patient developed Stage IV lung cancer and withdrew early from the trial and did poorly medically for reasons unrelated to the OpRegen cells. Let's take a dive -- a deeper dive into one of my patients. This is the young lady that made it into the local news, the scripts and the Ivanhoe pieces that are available on the Internet. And it represents -- she represents the third compelling case of clear cut improvement of vision and retinal restoration, especially 65 years old and started off at 2100 with a moderate size geographic atrophy lesion in the study eye and had excellent vision in her fellow eye. We operated her after which she was promptly diagnosed with COVID, with mild to moderate symptoms. We stopped her immunosuppression until she recovered from the COVID. She recovered without incidents from the COVID. And even without the -- without the full regimen of systemic immunosuppression, she actually had no inflammation or signs of rejection of the OpRegen cells. So let's take a look at the history of her geographic atrophy progression. So here she is on the left, 12 months preoperatively and then at the screening visit on the right. And we can see that there is an unequivocal growth in the size of her geographic atrophy lesion on these Heidelberg red free images. You can see this on color vision as well. Here, you see the preoperative baseline visual -- vision that's fairly large. And then the interesting thing that you see here on the postoperative color photo at 3 months after delivery of the Orbit SDS -- of the OpRegen cells using the orbit Subretinal Delivery System is you see this fine pigmentary modeling that we think probably represents the OpRegen cells. You see a little bit of choroidal blanching in the area where the superchoroidal cannula was advanced. You see these tiny little subretinal hemorrhages, and we'll get to those in just a jiffy. Looking at the red freeze at baseline, that we've already seen. And then at 3 months postoperatively, we can see that this inferior border of the geographic atrophy is clearly less well defined. So that's an interesting thing. Here's the OCTs. You see very bright and nearly complete retinal transillumination defects through the -- at baseline preoperatively with some vitreomacular adhesion syndrome and a very thin central retina. We created a subretinal bleb [ and a sub ] that was subfoveal in this eye. And on post update 7, there was this kind of funny partial lamellar incomplete macular hole with this intact hyaloid and ILM bridge. And the interesting thing is you can see the cells kind of layering out here, and you can see that the transillumination of the retinal pigment epithelium is much less notable. Here, on post update 7, on post update 14, the subretinal bleb is going away. The macular hole appears to be auto-resolving. And then here, 2 months postoperatively, this funny subretinal bleb with the hyaloid ILM bridge has auto-resolved. There's minimal to no residual epiretinal membrane. And you see that there is this kind of thickened layer of RPE that's present here with much less retinal transillumination or transmission defect, OCT optical transmission defect, at 2 months compared to at baseline. And now in the area of the subretinal hemorrhage that we saw in the color photograph, she did develop a choroidal neovascular membrane, and that's very close to the area of choroidal puncture by the Orbit SDS needles. So at 2 months, she had a little bit of squishy edema. We didn't treat her at this point. She was seeing well, and I'll show you the visual data in just a minute. At 3 months, she got bad enough that we decided, okay, let's go ahead and treat her. And -- but despite having a little bit of a squishy choroidal neovascular membrane, here we see what her vision did. At 1 month, she was stable. The green lines here represent visual acuity changes in the treated eye. And here are -- and the orange line represents visual acuity changes in the untreated control eye. And you see that the treated eye had 13, 11, 12 letters of visual gain that were sustained out to 6 months. That's very impressive data that I've never seen in a dry macular degeneration before. In terms of geographic atrophy, reading center measurements after the treatment, the geographic atrophy was measured as smaller as in the treated eye versus stable in the untreated. Here's the visual acuity data that shows from 2100 to 21/25 at baseline and are staying fairly stable out to about a month. And then have 2 months, 3 months, 4.5 and 6 months, clearly improving, basically doubling her vision. This -- and here's the visual acuity and in the letter is red. In the right eye and the left, things remained remarkably stable. So again, a compelling example of improvement in retinal function. Looking at this women's -- this patient's microperimetry. You see the microperimetry initially was larger defects as opposed to a smaller number of defects. So again, compelling evidence that maybe the cells and the surgical procedure using the Orbit SDS are doing something despite a small extrafoveal choroidal neovascular membrane that was successfully treated with 2 anti-VEGF injections. So are these findings generalizable to the entire Cohort 4 subgroup? Well, let's look at kind of the pool data for the Cohort 4 patients. These are 12 eyes, 5 of which were operated with vitrectomy retinotomy and 7 of which were operated with Orbit SDS. So the pool data is not statistically significant, but we think it looks like there is perhaps stable and then declining vision in the untreated eyes and improved vision, and we'll see this is -- these later data points only have 1 or an end of 1 or 2 of those patients have gone out far enough. So we'll have to see what happens with longer follow-up for the full cohort of patients. But this is exciting. It's interesting. And if these differences in visual acuity end up being statistically significant, the important thing to note here is that these are of a magnitude, of a clinical magnitude that's clinically relevant and important. A 1.5 to maybe 2 line ETDRS line gain in visual acuity is something we've never seen before in a treatment for dry macular degeneration. So when we -- we looked at visual acuity, we looked at geographic atrophy. What about reading speed? This data is a little bit more muddled. If you're optimistic and you look at these graphs, the data points don't need to be filled in. Maybe the reading speed in the fellow eye is just getting a little bit worse over time, maybe it's staying the same. Maybe it's getting a little bit better in the treated eyes. It needs to -- we have to see how this pans out when a greater number of these Cohort 4 eyes make it out to the to the later time points. There are some -- we did National Institute of Visual Function questionnaires and the patients reported improvement in 9 out of 11 categories. I'm not sure we can make too much out of this. It's certainly exciting data, but this is a nonrandomized, non-masked trial and the patients all were really excited to be in this trial. So it's not clear whether or not this is hope and wishful thinking or this or whether or not this is something real. That also remains to be seen. So to kind of wrap up here, the previously reported observations that we've been talking about for the past several years continue to hold true. The OpRegen continues to be well tolerated in treated patients, even in patients where medical problems and COVID caused us to modulate the immunosuppression. And sustained subretinal pigmentation may suggest OpRegen durability, visual acuity improvements will suggest that even more so. But it's interesting that we see the pigmentation in the areas where we injected the pigment itself. Improved anatomy and function continue to be observed in terms of reduction in drusen. And OCT evidence of restoration -- and red free and geographic atrophy area measurements, restoration of photoreceptor RPE layers in some patients. And a better visual acuity, reading speed and visual function questionnaires have been observed in some early cohort patients and most, 83% of the Cohort 4 patients, which lead us to believe that earlier intervention in less severely affected eyes and more central placement of the transplanted OpRegen cells probably -- it may increase the likelihood of a clinically beneficial effect. So cohort 4 enrollment is complete and long-term follow-up is ongoing. And we're going to be taking very granular detailed dives into the OCTs and FAF measurements to try to -- try to piece -- try to tease out what's really going on here. This is a slowly progressive disease, the natural history of which. So we're going to need longer follow-up to really figure out what's going on here. But we're excited about the prospects of this data panning out to be very positive. I thank you very much, and I'll be happy to take any kind of questions.

All right. Thank you, everyone. It's my pleasure to now introduce Dr. Michael Ip. Dr. Ip is a Professor of Ophthalmology at UCLA. He has multiple professional roles including at the UCLA Stein Eye Institute. Today, he's joining us mostly in his capacity as the Medical Director at the Doheny Image Reading Center at the Doheny Eye Institute. Michael, we really appreciate you joining us today. Thank you. And please, the floor is yours.

Thank you, Brian. It's a real pleasure to present this imaging analysis that we performed at the Doheny Eye Institute on Lineage Cell Therapeutics Phase I/IIa clinical trial of transplanted allogeneic retinal pigmented epithelial cells in advanced dry age-related macular degeneration. This analysis utilized Petrel's, spectral domain OCT images that were captured at the clinical sites. These images were macular volumes consisting of 5 12 by 49 equally spaced B scanned within a 20/20-degree field centered on the fovea. The cross-sectional B scans, which I'll show you on the next slide, were manually segmented using a 3D ocular software tool developed at the Doheny Eye Institute. This tool is a validated Part 11 compliant software tool, whereby the graders were able to segment all the structures of interest to gather quantitative information from these images. And this slide shows on the top an example of an unannotated cross-sectional B scan. You can see the various striations that correspond to the different retinal layers. The middle image shows the annotations that were then placed by the graders that outline the boundaries of the different retinal layers. And at the bottom, you can see that the annotation fills in the thickness of each of these specific layers. What would be germane to this talk would be the outer nuclear layer that you can see in purple, and then the photoreceptor inner and outer segments which corresponds to the ellipsoid zone. And then finally, the RPE-drusen complex that you can see annotated at the bottom part of this slide. So this slide shows the thickness and area maps that are generated from [ en faus ] projections of the segmentation from all of the B scans in a volume scan. So you can see here on the 3 images on the right-hand side of the screen, you see 3 circles that have black areas and white areas. The areas in white represent an absence or loss of the retinal tissue that's being studied, whereas the gray or black area represents preservation of that particular layer of retina that's being studied. So you can see here, I'm showing the outer nuclear layer, the photoreceptor outer segments or the EZ. And then on the far right, the RPE-drusen complex. With that in mind, I'm going to show you some images from patient #14 in the study, which is really the first case of potential restoration of some of these retinal layers. So this slide shows an analysis of the outer nuclear layer, ONL. And it shows the preserved areas in millimeters squared. So what you can see on the top 2 figures, this represents the study eye. And what you can see in the study eye is that at baseline, the area measured was 36.14 square millimeters, which increased from baseline to month 12 to 36.59 square millimeters. In contrast, what happened in the fellow eye is at baseline, we measured 31.11 square millimeters of preserved ONL at baseline, and this decreased out to month 12 to 30.09 millimeters squared. This next slide shows a similar situation. Patient #14 with respect to the RPE-drusen complex. So if you look at the top 2 figures in the study eye, what happened is at baseline, we measured 31.85 square millimeters of preserved RPE-drusen complex area, which increased to 37.56 square millimeters at month 12. In contrast, in the fellow eye, there was a reduction in the RPE-drusen complex area, where we measured 28.66 square millimeters at baseline, which reduced -- which was reduced to 26.26 square millimeters by month 12. We had a slightly different situation for the EZ or outer receptor -- photoreceptor outer segments in patient #14. Both the study eye and the fellow eye had a reduction from baseline out to month 12, both again in the study eye as well as in the fellow eye. We also looked at an entity that's being studied quite extensively recently, and it's an entity called iRORA or incomplete RPE and outer retinal atrophy. This lesion is thought to be a potential precursor to frank geographic atrophy. And so if you look at this slide, in the middle part of the slide, on the top middle part of the slide, you'll see a large area of geographic atrophy with hypertransmission. This was at baseline. But if you note to the left of the area of frank geographic atrophy, there's a yellow arrow, and that points to some attenuation of the outer retinal layers with an area of hypertransmission beneath it, which meets the definition of iRORA. In this patient #14, in the same area which was registered -- which was registered to the same exact area at month 12, you can see that there is now a lack of hypertransmission beneath the yellow arrow, and there seems to be some restoration of the outer retina and RPE above it. So the next 2 slides are going to show summary data from Cohort 4, the cohort with better seeing visual acuity. And this slide shows a fellow eye analysis of multiple spectral domain OCT parameters in Cohort #4. And there are RPE values ascribed to all of these OCT parameters comparing and contrasting baseline to month 12. And at the level of significance of 0.05, you can see that there are statistically significant reductions in the ellipsoid zone area and the RPE-drusen complex area in these fellow eyes. So to be specific for the EZ area, fellow eye baseline was reduced from 26.13 to 24.85 square millimeters at month 12. And again, a similar reduction for the RPE-drusen complex area between baseline and month 12. This slide shows again for Cohort 4, those eyes with better seeing visual acuity. This time, an analysis of OCT parameters for the study eye. And what you can see here is that there are no P values that are statistically significant. So specifically, for the EZ area in the study eye, there was no reduction that we saw here from baseline to month 12. And again, this is in contrast to what I just showed you for the fellow eye, where there was a reduction in the EZ area from baseline to month 12. In a similar situation here for the RPE-drusen complex area, which showed no reduction that was statistically significant between baseline and month 12. So to conclude, outer nuclear layer preserved area in patient #14, increased in the study eye from baseline to month 12. And the fellow eye, in contrast, showed a decrease from baseline to month 12. Similarly, the RPE-drusen complex area increased out to month 12 when compared to baseline, whereas the fellow eye showed a decrease. With respect to the EZ or outer segments, the loss was persistent from baseline to month 12 in both the study eye and the fellow eye. And perhaps this may be ascribed to more difficulty with grading the outer segments than the other 2 parameters of RPE-drusen complex and outer nuclear layer. I also showed some interesting findings from an iRORA lesion analysis, where we saw resolution of a number of iRORA lesions in study subjects that were treated. I showed also the summary findings from Cohort 4, the better visual acuity group. And these summary findings showed that fellow eyes had a statistically significant reduction in the EZ and RPE-drusen area out to month 12. And in contrast, the study eyes had a stabilization of EZ and RPE-drusen area from baseline to month 12. These are just some early preliminary findings, but they look very interesting and quite exciting. Certainly, we wait longer-term data and complete follow-up from Cohort #4. I also think additional analyses such as the iRORA lesion assessment and count will be critical going forward as well. So I thank you very much for your attention.

Thank you very much for that presentation, Dr. Ip. And you can rest assured that you will be receiving more images for us as we continue to follow these patients. I did have a question for you. In speaking about the precursor lesions, are those fairly common? And do they typically progress to larger areas? Or do they maintain some small level of stability in patients typically?

Yes. That's a good question. This whole concept of iRORA was started by my colleague [ Voz Odda ], where he worked with a collaborative group, the TAM group where they finalized the definition of iRORA. And since then, we've really done a number of analyses in different clinical trials, mostly unpublished at this point, but what I can tell you is that these lesions are not uncommon in eyes that have -- already have central geographic atrophy, such as the ones that are being studied here. And so they appear to range somewhere -- some eyes have just a few, maybe 3 or 4 or 5, whereas some can have multiple iRORA lesions. And to answer your question, a fairly significant number of these lesions do convert over time into full-blown, what we would call, geographic atrophy.

That's wonderful. Thank you. Yes, to be consistent with our view that getting to patients earlier and maybe stopping these before they develop or advance could be beneficial. Great. Thank you. I'm sure we'll get some more questions on that later on the call. Well, thank you very much, Dr. Ip and thank you to all of the speakers of the primary portion of today's webinar. We are going to, in just a moment head to Q&A, but I want to have this one slide to sum up that we're very encouraged by the promising results, which we have continued to collect in these categories' structure. Obviously, everyone heard a lot today about anatomical changes to the structure of the retina, the evidence for retinal restoration. In addition, we've seen reductions in drusen in some patients. We have evidence now also for functional changes. The majority, high majority of our Cohort 4 or better vision patients experienced an increase in their BCVA. The majority of their untreated or contralateral eyes exhibited a decline in best corrected visual acuity, and we have some directionally positive data on other functional attributes, including patient-reported outcomes, reading speed and quite notably, microperimetry. In addition to these positive changes in both structure and function, we also have seen encouraging safety and tolerability. The OpRegen transplants have been well tolerated. There have been 0 unexpected AEs or SAEs. And this is a new technology which we think we can continue to improve and make an increasingly attractive safety and tolerability profile. And then the last category and that of durability, the earliest graphs have persisted for more than 5 years with no cases of rejection across 24 treated patients. And we've been able to reduce the immunosuppressive regimen down to about 90 days. In fact, we've had a couple of case studies where it's been reduced even further in time or amount. So overall, we're really encouraged by the findings of structure, function, safety and durability highlighting this program. I'm sure you have questions. So the question-and-answer portion is going to be led by Dr. Gary Hogge. Gary is our Senior Vice President of Clinical and Medical Affairs at Lineage, and Dr. Hogge will be receiving and directing the questions for the expert panel. Dr. Hogge, please take it away.

Thank you, Brian. I'd also like to thank the speakers as well. There's a significant amount of work that went into these analyses. So thank you. So we're fortunate to be joined today by Dr. Monés, Lujan and Riemann. And unfortunately, Dr. Banin and Dr. Ip had prior commitments. So we've had several questions, too, as to whether or not we hope to submit these data to publication. And we definitely intend to submit these data as part of a peer reviewed publication in the near future, particularly now that we've reproduced the findings. So we'll openly let everyone know once those data are accepted, hopefully at some point. So with that, operator, we are ready for questions. Would you please provide any additional instructions and we can begin. Thank you.

[Operator Instructions] Our first question from the phone is from Kristen Kluska.

Congrats on the findings from this trial and appreciate the level of detail provided behind the trial and your insights today. The first question I have is in terms of looking at the success at attempts to achieve greater coverage, if OpRegen were to be commercialized, do you believe this is something that could be improved upon as more surgical procedures and practice are conducted? And what are some of the key retinal imaging or other measures you might look at to conduct in determining who might be an eligible candidate?

Dr. Riemann, would you like to take the surgical coverage aspect? And then Dr. Lujan and Monés can go into the ideal patient perhaps?

So I think that we're definitely still in an early phase learning curve of how to best do this surgery. I think that if you look at the Cohort 4 data, they asked us to cover the macula about halfway through Cohort 4, and we were able to do that in 4 patients. So I think that there are all sorts of strategies that we can implement. I don't think there's going to be any issue or problem or difficulty successfully covering the macula and getting good coverage in these patients urgently going forward. There'll be a learning curve and there'll be some 2 steps forward, 1 step back, 1 step forward, 2 steps back. But I think we will get there, and it will be -- and there's already some work being done and some thoughts that many of us have of how to do that.

All right. Dr. Monés, what do you think might be the ideal patients and how to -- [ follow ] them over time?

Yes. I think that this has evolved since we started with the trial. At the beginning when we designed the trial, our endpoint was to prevent progression. At that time, I don't think we dreamed about restoring retina. That's been a great surprise. So when we designed the trial, we designed it in order to prove nonprogression. So we designed a trial in order to have fast progress in patients. That was one of the entry criteria, to have fast-progressing patients. Otherwise, a slow progressing, we could not tell a difference with a short period of time. But we also have -- we have learned a lot. And some of our prejudgments have turned to be, let's say, wrong, especially when we entered into this restoration area. And patient #22 is a very slow progressing eye. And the fellow eye hasn't changed much. So if we would just try to determine if we can prevent progression, this especially will be very difficult because the fellow eye almost did not grow in the short period that we have. But in the treated eye, we had restoration. So it means that now the slow progressing eyes become candidates to -- become candidates because we can restore retina. And if we restore retina -- and when we identify ELM, when we identify ellipsoid, when we identify ONL and RPE, if all these are together, they're very likely that they work. It's not just RPE alone. So if they work, eventually when we will intervene in earlier patients, we will have improvements in vision, significant and coherent improvement in vision. So fast-progressing cases for sure are candidates, but also slow progressing candidates -- sorry, as low progressing patients are also candidates. And so -- and I want to say it again, the intention was to us in all the trials, the intention was to prevent progression or to have less progression. But we enter into a complete new era of having restoration, which is completely a different galaxy.

Okay. And Dr. Lujan, how do you think it would be best to follow these patients up in both the short and long-term period of time?

Thanks. I think that the OCT, or optical coherence tomography, is really the cornerstone to the multimodal imaging approach that we have. I think we're learning a lot about just incredibly minutes, but very meaningful changes in structures that we just don't expect to go in the direction that we're seeing. So great observations from Jordi and on the external limiting membrane, and I found that independently as well. And it's very exciting. It's not kind of the direction that we expect. So using that technology, being as precise as we can to monitor changes and try to infer what we can about what's the actual underlying anatomy will be important getting forward, and we can detect very small changes that way.

I also wanted to ask which time points do you believe are most critical to evaluate across some of these key measures in a trial? And of the cases of retinal restoration, I know for one of them, you have some good longer-term follow-up. But in particular, what will be the key focus in looking at these 3 patients over time in addition to the potential for others that demonstrate this?

Okay. Dr. Monés, would you like to take that from the perspective of visualization and then Dr. Riemann from the perspective of patient outcome?

Yes. On the first cohort, the very worst cases we had, we saw some patients having RPE nesting in the retina, but it was a transient effect. And at that time, those cases we did not see -- besides RPE, we did not see retinal restoration. So early changes probably would not suffice because if we have something very transient, who cares? And also when immune supression is stopped, if the events would not stay, they would not be very meaningful. So having changes at 1 year or even at 2 years, like we have had here, and we have like 3, one of our patients has reached already 3 years. This is amazing. We still don't know if these changes will last 5 years. We've seen in patient -- in the first patient that there was a decrease of the lesion and then there was some sort of minimal growth. And at 3 years, the lesion was the same as baseline, but this is extremely meaningful. We have -- we've been able to have a lesion in a, let's say, 80-year-old person and we saved 3 years of none growing. That's extremely significant because they are not 20-year old. So maybe 3 years, 4, 5 years in their span of life, it's most of the life they have. So we are saving their sight for life if we are saving 3 years, 4 years, 5 years. Of course, if we save 10, that's better. And at this point, we don't know. And we don't know if the cells should be reintervened at some -- that's not the question now. The question now and the magic thing is that cells can restore retina, it's not a transient thing. It may last 1 year, 2 years, 3 years, of full interconnecting layers of retina. And that's the unique thing that OCT does, as all my friends and colleagues accept and agree and have shown. OCT is a 3-dimensional assessment of all the layers. It's not like 2-dimensional like color picture out of fluorescent. So we see all the layers and they're interconnected, they're working. So having this restoration for more than 1, 2 years, 3 years, that's an amazing thing.

So from the clinical perspective, I'm going to completely agree with what Jordi just said. I think that it starts to get meaningful at 6 months. And anything beyond 6 months, if you start thinking about an area under the curve, if you ask a patient who's losing vision, would you have a surgery to gain some vision for a span of 6 months? Most people would say, "Sure, sign me up," if the alternative is to lose vision. If you go out to a year, that's obviously even better, 2 years, even better, 3 years, even better. But I think it's becoming meaningful to the patient at the 6- to 12-month time frame. And it's really exciting to see that we've got that we have 3 different reading centers in Barcelona, in -- at Casey and at Doheny, that have all shown the same thing independently in the setting of really promising clinical results. Improved anatomy is one thing, but improved anatomy plus improved vision and hopefully reading speed, is the holy grail and really exciting here.

Our next question comes from Keay Nakae.

Two questions. First, in terms of areas of the GA where we might see improvement, are these transition zones always located on the perimeter, and that's where we should expect to see the improvements?

Dr. Lujan, do you want to take that one?

Sure. Well, I've only reviewed several of these with this in-depth level of analysis. And they -- I would say that they don't tend to exclusively on the edges. There are certainly changes that were more internal like what I showed in my presentation earlier today. So I think that they can be more prominent out toward the edge, but certainly can include the interior as well.

Okay. And second question, patient 14. We're seeing the results out to 3 years, which is very impressive. How should we interpret the BCVA increasing a little bit, then kind of going back to baseline at 3 years? How do we correlate the maintenance of the retinal improvement with any further expected improvement in vision, although certainly maintaining what they have would be grade as well?

Dr. Monés?

Sorry, I couldn't get exactly the question. Can you repeat it, please?

Yes. For patient 14, foreseeing the retinal restoration maintained at 3 years, should we also expect to see improvement in vision? Or is best case just maintaining what they had at baseline, so we saw that the BCVA and the treated kind of go back to baseline after some improvements from months 9 to 24?

Well, that patient was a very long-standing and a very large lesion. So if we restore anatomy, all layers, the first goal in GA is to prevent further loss. And that's already really a tremendous goal. So if we enter into -- we do treatment in an eye who has lost a lot, it's going to be very difficult to gain because the devastated area is very large. Whenever we get into earlier cases or cases that may still have some kind of remaining because many patients still have eye lens [indiscernible] remaining than those, let's say, a relatively small -- rational restorations will be very meaningful functionally. If we restore a small area in the center, that's going to translate into improvement of patients. So restoring anatomy, first, we'll prevent loss, which is already amazing because if we catch a patient, let's say, 20 50, 20 60, and we keep that, that's extremely meaningful. But in addition to that, this will translate to improvement in vision, whenever we get into earlier cases. I don't think there is any doubt in that.

the I can jump in here, too. That patient, patient 14, you have to take that in context with what's going on in the other eye. So the other eye of that patient lost a huge amount of vision. And so that the area under the curve of treated eye versus the untreated eye is unequivocally massively visually clinically significant to the quality of life of that patient.

There are no further questions on the phone at this time. I'd like to turn the floor over to Gary for our web Q&A portion.

All right. Thank you, Victor. We've got a number of written submissions. The first is from Mayank Mamtani from B. Riley Fin. Dr. Lujan, perhaps you could expand on this a little bit. So if you see a favorable reduction in the progression of atrophy and reduction in number and types of drusen, could you expand a little bit more on that? And why do you think that might be occurring? And where would the ideal area to be for opportunity to be delivered to be?

Well, so we're still used to the mindset of this relentless, progressive, devastating loss of the outer retina that we see. So we're having an effect with these treatments that is really interesting. And I mean, just the idea of some anatomy being restored, the presence of ELM and this thickening that we're seeing of Brooks and reflective lines that are present that weren't there before is pretty amazing. So it's clearly not the atrophy that we're used to seeing in the natural history or with any other treatments that I've seen. Where it's delivered is a little bit beyond my scope. I think we do need to be very specific about that moving forward about identifying exactly where delivery is occurring. There's a lot of ways we can do that via imaging and close analysis. But the -- yes, the kind of change of kind of the expected loss and atrophy and ultimately, visual function is pretty remarkable.

Dr. Riemann, your thoughts as far as the surgical perspective, can you speak a little bit about the recovery time line? And whether or not you would consider additional therapy at some future time point as being necessary? And what would drive you to that consideration?

I think those are important unanswered questions that I can make up an answer to make myself sound smarter than I am, but we just don't know, Gary, we don't know. I think that whether retreatment makes sense -- whether retreatment would work is the first question, and we don't know the answer to that because we've given a second OpRegen dose to exactly 0 eyes. And at what point of time that makes sense, those are really important questions that remain to be answered.

Fair enough. Dr. Monés, you first noticed this in patient 14, this effect, but there's a question as to whether or not we observed in any of the previous 1, 2, 3 was there evidence of any type of similar alterations in the area of atrophy? Or were those patients just simply too far progressed?

Probably, they were too far progressed. We saw survival and areas of pigmented cells by Color Fundus Photography and also by OCT. But as we said, we don't have areas above of the retina, which shows signs of restoration. These RPA, we don't know if they're just clams of pigment, really viable cells or dead cells or nonviable cells. So in those cases, we saw pigment there. We thought they were sales, but we could not prove it. Now we can prove. We have viable RP cells because of the effect they cause on the above retina. And that's a unique thing. And as Brandon said, there is some sort of a law or a myth that retina is not restorable. So -- and we never thought we could see this. What we thought is that by implanting the cells at the margins, we could keep those margins like stable and not progressing. But having new cells into the center -- brand-new layers into their center, honestly, we did not expect it. So this has been a very beautiful surprise that -- so we have defeated a myth, absolutely.

All right. The next written questions come from Joe Pantginis at H.C. Wainwright. Again, a question to you, Dr. Riemann. Do you think that from a surgical coverage perspective, that -- again, the earlier patient may be easier to separate and administer sub-rental space and also easier to visualize via intraoperative OCT or other imaging tool to facilitate that.

I think that's a great comment. And I think that also the earlier patient is likely to have less diffuse spinning. When you have really thin retina and you're separating the macula, you can generate iatrogenic macular holes, like we almost did in patient 22, that was one of my patients. And when I saw those early phase OCTs, I've had a heart attack. But fortunately, everything settled down, I think that smaller lesions will be more easily treatable subfoveally parafoveally, and I think that, that treatment is likely to be more efficacious because when you have these huge areas of atrophy, where there's been years and years of of apoptosis and dead cells and retinal regression, all the way up, sometimes even to the nerve fiber layer, what are you hoping to regain there? If there is some semblance of -- you could almost think of it. I understand that this isn't a perfusional problem, but you think of almost like a watershed zone in part with a stroke, there might be purely dead lost material, but it's that watershed zone that you can still get function out of. And if that watershed zone extends into the center of the fovea because it's an early lesion, that's the hope here that treating these eyes earlier, will get you a better function and better vision.

All right. Fair enough. To Dr. Lujan and Dr. Monés. Dr. Lujan, what -- so obviously the number is small. We're talking about 3 patients here, although the fundings are unique. Can you say anything just based on your observations of the phenotypical presentation of the GA or the patient's age? Or is there -- are there any commonalities in the 3 patients observed to date? Or is this something we just see more data?

Need more data.

All right, short and sweet to the point. Dr. Monés, would you agree or are there -- is there anything particular?

Yes. As I said, we wanted to have patients like the first one. And the first patient is a predominantly reticular drusen GA phenotype. And that's a very fast-growing, and we knew that, that was a very fast-growing patient. And at the beginning, we wanted to have very fast-growing patients. 122, it's not that case. It's soft phenotype, and that's a slow progress in case and I think there was another one like that. And those were included at the end of the trial and also to explore if those patients could get some benefit. But we anticipated or we thought that those patients would not be ideal because the phenotype is very different. Of course, the numbers are very small, but -- so this case encourages us that we don't need to discriminate this, let's say, low-growing phenotypes. So there are also candidates. But yes, the question is very appropriate because GA is very erogenous where a lot of different phenotypes could exist depending on the kind of stuff that accumulates drusen. We have patients that are purely reticular drusen. They behave very differently from those who are pure self-drusen. And then we have mix types that we have soft and reticular. So -- but this is encouraging what we saw with this last patient that also the slow progressing soft drusen-associated GA also gets benefits. So these are good news.

[indiscernible] need more data.

All right. I definitely agree with that. So next question comes from Dhesh Govender, Terra Capital Group. And the question to Dr. Lujan. So you've seen the improvements in the transition zone in the area of atrophy. What about the choriocapillaris? And do you see changes in that in the neural retina as well?

It's a good question about the choriocapillaris That can I don't think be very well assessed with structural OCT. There is -- you can visualize the [ core eye ] corneal architecture doesn't really seem to change in the qualitative analysis that I've done. The choriocapillaris itself is a very thin layer on structural OCTs. There are other technologies like OCT and geography that may be able to visualize that and then maybe considered moving forward for -- however, it's a difficult test to get and someone that can't fixate well. So I think that's something that does need to be continued to have continued study.

Okay. The next question comes from Dane Leone of Raymond James. Dr. Riemann, what do you think -- or a percentage of your atrophic AMD patients would qualify for this treatment? And what visual acute in might -- or disease history might represent a sweet spot?

I think most of our atrophic macular degeneration patients, if you catch them early enough, would qualify. So if I take a snapshot of all comers, although we certainly have a lot of patients with very advanced disease. But if you look at the time course of the development of their disease, they weren't always advanced. And if you look at -- I think, a vast majority of patients that will go on to develop age-related macular degeneration, if they're established in the clinic, some of them are going to be operable in terms of net risk. Probably 2/3 to 0.75 I think is a reasonable guess as long as you get them early enough. If I look at a set of all dry macular degeneration it's a guess because remember, as a retinal specialist, I don't really see a lot of end-stage dry macular degeneration patients those back to the referring optometrists oftentimes. So I don't see those. But I would I guess, probably half of all dry age-related macular degeneration patients with geographic atrophy would probably fall into the treatable. I agree with what the [indiscernible] 20 40, might be a little ambitious, but 20 60, when you lose your ability to drive. In the state of Ohio are practice, if your vision drops below 20 60, you lose your driving privileges, even daytime only, it's 20 40 for daytime, nighttime unrestricted vision. When you drop to less than 20 60, that's a pretty cataclysmic event for most seniors they can't drive. So I like the 20 60 threshold as a sweet spot.

Okay. Thank you. So there are additional questions, but we are out of time. So we will address all of them in over time and either by the experts today or the medical person group. But we do thank everyone for sending questions. We will get them answered. And with that, I'd like to turn it over to Brian Culley to wrap up.

Yes. Thank you, Gary, and thank you to our experts, both present and virtual because this was really great. You didn't hear much from me today, and that's by design. I don't know if anyone on the call is a historian of [indiscernible] but the process which and the principles that underlie the broad adoption of new technologies, and in this case, scientific revolutions or new paradigms, it really begins with the experts, and then over time, it becomes more of a generalized. And so eventually, we accept it as fact. And so this has been a wonderful opportunity to initiate that process. This is also a call that certainly does have investors associated with it. And so I just want to assure everyone that we are working on the basic science. We covered very technical topics today but overall, we also have interest in addressing and reaching into a -- what is clearly a very large commercial opportunity with this technology. But today was about seeing is believing. We really want people to see the images and understand that these changes are -- they just cannot be denied. There are actual anatomical changes, which do not happen naturally. So it's an early technology. We think it's going to keep getting better. You heard that theme today. And I really appreciate the very large number of people who participate on this call as presenters and as listeners. So thank you, everybody. Thank you to all of the patients, all the investigators, all the other professionals who are associated with it. And we look forward to helping everyone understand while we also responsibly treat this incredible discovery and try and advance it further. The good of everyone who suffered from dry AMD. Thank you all, and have a good evening.

Bye-bye.