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

Good day, ladies and gentlemen. Thank you for standing by. Welcome to the Lineage Cell Therapeutics Conference Call. [Operator Instructions] An audio webcast of this call is available on the Investors section of Lineage's website at www.lineagecell.com. [Operator Instructions] As a reminder, today's call is being recorded. A question-and-answer session will follow the formal presentation. All questions must be submitted electronically. On the left-hand side of your screen, you will see a question mark icon. To submit a question, click the question mark, type your question in the box and click send. I will now turn over the call to Brian Culley, Chief Executive Officer of Lineage Cell Therapeutics.

Well, thank you, everyone, and welcome to a very special event we have today. A therapeutic expert discussion where we will be reviewing a finding of retinal tissue restoration in a patient with dry-AMD with geographic atrophy. I will refer you first to our safe harbor clause as I and others may make forward-looking statements. Before I introduce today's speakers, we do have a lot of first-time listeners on the call, a lot of new folks. So I just want to remind everyone today about a few of the key attributes about OpRegen, our lead product candidate for the treatment of dry-AMD with geographic atrophy. The OpRegen product candidate is comprised of transplanted allogeneic RPE cells. This program is currently in a Phase I/IIA clinical trial with 17 patients treated to date. Lineage manufactures its own RPE cells. We do our own clinical trial material. We manufacture those cells from an established and NIH-approved and ethically sourced cell line. We manufacture 99% pure RPE cells from a line that was established more than 20 years ago and has been extensively characterized and no genetic modifications are made to these cells. These cells are prepared in a ready-to-use formulation. So there is no dose preparation or washing of the cells, and we were able to go from cells that are frozen right into an injection device in just 5 minutes. We had a commercial production path where we are already capable of producing more than 2,500 clinical doses from a single 3-liter bioreactor, and we have the ability to scale up to higher amounts in parallel or larger reactors. This clinical trial, as I mentioned, has enrolled 17 patients to date. Today, we're really going to focus almost exclusively on patient #14. Before we begin, I really want to orient everyone to the break in these -- in this trial, the first 3 cohorts, which were dose cohorts. Those individuals were all legally blind. They had very severely impaired vision, and they had very large areas of geographic atrophy. That makes identifying a clinical response very difficult because of the severity of their condition. However, more recently, we had moved into cohort 4. These are individuals whose vision could be as high as or as good as 20/65, and those individuals are where we're expecting to see better results. This represents more accurately our intended patient population. And although this is not the subject of today's call, I would just add that we are also in a subcohort in this larger cohort, in which we are exploring the use of a new subretinal delivery system called the Orbit SDS from Gyroscope. With that introduction underway, it is my pleasure to introduce today 2 experts in the field. Our first speaker will be Dr. Jordi Monés. Jordi Monés is the Director of the Institut de la Màcula and Director, Principal Investigator and one of the founding governors of the Barcelona Macula Foundation. Dr. Monés has published extensively and is one of just a dozen-or-so retina specialists belonging to all 4 of the major retinal societies. Dr. Monés made the original finding, which we will be discussing today. Also with us today is Dr. . Dr. Ip is the chief of the Vitreoretinal Surgery Service at the Doheny Eye Center at UCLA Stein Eye Institute and Medical Director of the Doheny Image Reading Center. Dr. Ip has authored hundreds of articles in the field, has vast clinical experience in ophthalmology and AMD in particular. And we are very fortunate to have both and Dr. Ip and Dr. Monés with us today. With that, it's my pleasure to give a presentation over to Dr. Monés to discuss OpRegen and in particular, patient 14. Dr. Monés, please begin.

Thank you very much, Brian. It's a real privilege to present today and share with you the results of subretinal RPE stem cell transplant OpRegen in this patient with atrophic AMD. For the last 10 years, my main focus of interest and research has been to study the dynamics and the pathology and very deeply involved in imaging of atrophic AMD. And I perfectly can say that I have never seen images that suggest retinal restoration or regeneration, as you will see in the next minutes. Atrophic AMD is a late-stage of AMD. No matter if a person has suffered exudative form or not, eventually all patients will end with atrophic AMD if they live long enough. The atrophic lesions consist in progressive retinal pigment epithelial death, which is the layer that supports and nourishes the photoreceptors and also contributes with them to the visual cycle. Therefore, the RPE dead cells lead to photoreceptor death and blindness where the atrophy appears. In this slide, these are fundus autofluorescence imaging that show how the areas of retinal death progressed within few years converting a normal seeing person into a legally blind in a relative short period of time. This person went from 20/20 into 20/200 in just 2 years. So this is a very fast progressing disease for the patients. The next one, please. And also, this currently a true epidemic in developed countries, especially now that the exudative form can be managed. And in some cohorts in some series, this can affect 1 out of 4 people of 80 years old or older. So -- and it's a lot of the biggest challenges and unmet need the ophthalmology committee have since this epidemic has no treatment. So nowadays the conventional wisdom is that regression or atrophy or retinal regeneration is not possible and the current investigation of clinical trials aim to slow down the progression of the disease, just to slow it down. And I have to tell you, many have failed even approaching different pathways. This is a very difficult endeavor. Next one, please. The next slide. Yes. In this optical coherence tomography scans we can see all the layers of the retina. And in the upper one, this dark -- the darkest layer at the bottom is the RPE plus the ellipsoid zone. This is supporting a layer for the ONL, which is the next layer of the photoreceptors. It's not that visible here, but now I will show you a better one. But in the second in 2013, there is a gap in the middle. This dark area is gone and when we color this, you can tell how this reddish layer, which is the RPE cells and a very fine blue line, which is ELM, the boundaries between the photoreceptors and the outer segments. And the light blue are the ONL. These layers just disappear. They disappear and with advance of years, we see the boundaries and how it progresses every year. So these layers die and the retinal within those margins is blind retina. There is no pigment epithelium, there is no photoreceptors, so this retina is blind. Next one, please. So the rationale of OpRegen transplant is to substitute or to replace these RPE dying cells or these RPEs who have died, by new RPE cells in order to prevent photoreceptor death subsequently in order to prevent progression of the atrophy, by restoring the RPE, which is probably the primary event in geographic atrophy. Next, please? So we will present -- we will focus today...

Ladies and gentlemen, please stand by for technical difficulties. Ladies and gentlemen, thank you for your patience. I do have Dr. Jordi Monés back on the line.

Okay. Thank you. Something was wrong with the connection. So we are focusing today in presenting the patient #14.

Ladies and gentlemen, apologies again. Okay. Sorry about that, guys. I'm trying to get doctor back on the line. I keep losing his connection. So Brian, I'll turn the call over to you.

Thank you. I know that Dr. Monés is calling in internationally. And so there may be a brief delay. If everyone will hang on the line for just another minute or 2, what we can do is see if Dr. Ip is available or if we'll be able to reestablish Dr. Monés' connection, just another minute or 2 of patience, and we'll try and solve this so that we can continue with the presentation. We do have a backup phone number that we're putting in place now is -- we've all experienced this where it just has to get e-mailed and reset and redialed and reconnected and brought it and ported into the connection. So we'll be able to -- I'm sure, I'm very confident we'll be able to restart this presentation very shortly. So thank you again for your patience.

Okay. Everyone, once again thank you for your patience. I do have Dr. Monés back on the line.

I'm sorry, I don't know what went on with the number. So we were focusing on presenting this patient #14. This is an 80-year-old female with no relevant past medical history. On her study eye, she had a visual acuity of 20/80, not reaching the legal blindness and the fellow eye at 20/63 and medium-sized GA lesions. Next, please. This is the overhang cells were transplanted in this patient through the retina with a very tiny thin cannula through this red spot. So a bleb with fluid and cells were injected under the retina and here as imaged at your right, you may see during the surgery how the retina has this bleb containing the fluid and the cells. Next one, please. One of the most frequent adverse events during this procedure is the formation of epiretinal membranes that most of the times are mild to moderate and clinically not relevant. But this patient developed a severe one, causing important distortion of the retina that required surgical intervention that was performed. And fortunately, after 3 months of surgery, the retinal structure was restored and compared to baseline. Those images that we have here at the right. Upper is baseline and inferior is after the surgery. So in green, we have the visual acuity of the study eye. The patient after surgery recovered the vision that was lost during the epiretinal membrane formation and even improved slightly vision at the end. The next one, please. Next slide, please. And let me show you now the results 9 months after the OpRegen transplant, and this is the slide. You -- in the upper, you see baseline. There is the atrophy in the center with this gap with the interruption of the outer retinal layer. You can pass me the next one, please. With color, we'll appreciate more the retinal restoration in the next slide. Now we have a continuous RPE double layer, which means RPE and ellipsoid zone. We have a restoration of the ELM, that's very important and also a restoration of the ONL. So having new RPE cell, it's important, but it's not a big deal. What is important is that over the RPE, you have signs of retinal restoration, which is ELM formation, ellipsoid zone and ONL. That's what is important. It means that this RPE is causing a benefit and it's causing -- or is making able that the retina can regenerate. That's what is important. Not the RPE presence, but the upper regeneration of the retinal cell. So this was so good to be true, that we were the first being skeptical. If that was an artifact if we had misalignment images because no one could expect such a restoration of the retina. That was very, very wishful thinking. So we reveal all the scans, and consistent findings were found no matter where the scans were. So as we saw, this was the upper part, in the upper rim, we had that findings. Next one. Next slide, please. The next. Yes. This is what we saw in the upper rim. The next slide -- and the next. Next, please. In the inferior rim, we had similar imaging and the vertical red line is where the original atrophy was. Inferior, we have the new rim of the atrophy. Both sides it was regeneration, not only RPE, ELM and ONL. And that was constant. The next slide showing a more inferior scan. Next. So it was not a matter of misalignment because the findings were symmetrical in both sides, no matter where we put the scan. The next slide. Here. Yes, again, the original boundaries of atrophy have moved to the center. So we have regeneration of the layers. Here, we can see that there is an area with RPE with no retinal signs of restoration above the retinal pigment epithelium, that's why we did not include it in retinal regeneration. We put the boundaries at the ELM, because those are the areas where in addition to RPE you have sign of restoration of ellipsoid zone and ONL. The next slide, please. So here are vertical scans. Again, next one, the same finding. So wherever we put the scans, wherever we had signs of recovery in both sides. So the misalignment was ruled out, and this was true restoration of areas of the retina. So then at the infrared, we realized that we had this kind of new grayish rim that we have never seen before, and that corresponded to the areas of new retina. And this thick rim grayish, which is here within the blue arrows, that's the area corresponding to the regenerated retina. And comparing to the fellow eye, the fellow eye has no gray rim. So these gray rim, 360 degrees in the lesion corresponds to the new areas of retina. The next one, please. So then, we calculated the boundaries of the atrophy and we did it with OCT-guided calculation. Usually, areas of atrophy are measured by autofluorescence imaging because when the cells that have accumulated -- the RPE accumulates pigment during light and when the RPE disappears, there is no autofluorescence and you got a dark image. However, these OpRegen cells, these are young RPE cells who have not had time to accumulate pigment, so they look dark. So they look like atrophy. So fundus autofluorescence imaging is not any more valid for this procedure. So that's why we use the OCT and we take the edges of the ELM to calculate the boundaries of the lesion over time. Next, please. This is a historical image. It is the image 1 year before baseline. We want to make sure that these lesions had shown growth previous to the entry into the study. So this patient had 4.2 square millimeter. However, nowadays, we use the square root transformation because we want a linear dimension to measure this lesion. Here is the baseline. The lesion is 7.90 square millimeters and the square root 2.8. Next one, please. This overlap shows between the historical baseline and the growth was 0.64 millimeters a square root per year. That's very fast. That's the lesion growing very fast. So that -- and this is 9 months post transplant. So now it's 2.39 square millimeters -- sorry, a square root transformation by millimeter. Next one. Now when we plot after transplant the lesion has decreased. So now we have the same speed of growth, but reverse of regression so minus 0.55. That's really very unique and completely unexpected. So the lesion was smaller 9 months after. Next one, please. Here, the gray rim we had at the infrared coincides with this area of new retina, regenerated retina or decrease area of atrophy and the color fundus photography corresponds to a brownish area, which is the color of the RPE. And we have clusters of RPE within the atrophy outside the retina, but what we care is that the boundaries where we also had the accompanying retinal signs of recovery. The next one. And finally, this historical of the lesion, from historical to baseline, a fast growth and then a fast regression from baseline to month 9, then certain growth to month 16, but much less than expected. And in any case, we have a lesion that 15 months after baseline, the lesion is smaller. And that's absolutely unexpected. As we said, the current trial, their objective is to get a 25% reduction of growth, not even 100% which we are stopping. And here, we have even regression. So is this something that is not in the aim of the current clinical trials, having a lesion smaller after 2 years, completely against the conventional wisdom. So what we are seeing today is a true milestone. It's going to be more or less difficult to reproduce it. We don't know. We have to work for that, but what this case tells us is that the biology of the eye makes this possible. It's possible to regenerate retina. So it's not true anymore that atrophy is irreversible and therefore the conventional wisdom will have to be updated. Thank you very much.

Thank you, Dr. Monés. That was terrific. And I think any time there's some research that indicates that maybe conventional wisdom was misplaced and that you are able to accomplish something is very exciting. But of course, you want to be sure. So we have with us today, Dr. Ip, who is an imaging expert and who would be able to talk about some additional analysis that was done on this finding. Dr. Ip, please begin. I'll just queue up your first slide.

Thank you, Brian. I just want to say I had some lag in terms of the slide progression from when Jordi was speaking. So I'm hoping that doesn't happen. If that does happen, I'm going to go to the PDF that we have and then just ask someone to advance the slides. The good news is I'm seeing my first slide here. I just want to say that Dr. Monés showed some very striking and convincing images with respect to the generation of the outer retinal layers as well as the RPE layer with this technology. And what we've done at the Doheny Image Reading Center is to do this in en face manner, as I will show you. And we have attempted to quantify the changes in the RPE as well as the outer retinal layer. So I will take you through that process, just by way of brief introduction at Doheny. We're an imaging laboratory. The images that were sent into us from this clinical trial were from Heidelberg's SPECTRALIS. And we have experienced graders who manually segmented all of the outer retinal layers and the RPE layers, and I will show you, we did this in a dual fashion. So this was done by multiple evaluators on each of the images. And the team here is shown on the third bullet on this slide. Next. And again, I don't know if that advanced or not. Can somebody tell me if it advanced, Brian?

Yes, Dr. Ip. The first slide is coloring of the layers, is it?

Yes. All right. Then I'll go on. I'm just going to go off my PDF and ask somebody to advance. So all right, as you can see here on this slide, various segmentation lines are drawn in a very detailed fashion. It's very meticulous and laborious work. But our folks are very well trained to do this, having a lot of experience doing this type of work. And what you can see here is that we are able to segment or separate out the different layers of the outer retina. You can see that at the bottom image where the different layers are represented in different colored band. Next. And from that assessment, we're able to do en face projection. So we're able to then now look at the area of these various outer retinal bands as well as the RPE layer in these maps as shown. So you can see 4 of them here just by way of representation on the left, there is the total retinal thickness. And we can represent the thickness of the retina in a variety of false color maps. And so what you're seeing here is that there's some thinning in the inner part of the image towards the central subfield and that's in blue, and then it's a little bit thicker in green in the outer band. And so what you can see on the second from left is a map of the outer nuclear layer. Second from right is the photoreceptor outer segments or the ellipsoid zone. And then on the far right is the RPE drusen complex. And so you'll be seeing these maps and what these maps mean is that what you see there in white in the center of those circles is the area of tissue loss of that particular layer. And what you're seeing in gray or black is the area where that particular layer of tissue is preserved. So keep that in mind as we go through the next several slides. So if we move to the next slide, the title here should say outer nuclear layer, area in square millimeters or the preserved area. And so the top row is the study eye. And what you can see from baseline to month 12 is that for the outer nuclear layer, the preserve area appears to increase slightly from 36.14 square millimeters to 36.59 square millimeters. So there is some improvement in the preservation of the area of the outer nuclear layer. So perhaps there's some regrowth of this particular layer of the retina. If you go to the bottom row in the fellow eye, over time from baseline to month 12, the opposite happens and there is less preservation of the outer nuclear layer area. And just to drive home a point that Dr. Monés made, this is not typically what you would expect to see that is a regeneration of some of the outer retinal bands. And so what we're seeing at least in this patient is a very encouraging response. Next slide. What you should see here is that this is entitled the photoreceptor outer segments in area of square millimeters, preserved area. Now the caveat is that this is a particularly difficult part of the outer retina to segment or identify. There's wide confidence intervals around segmentation of this particular area. And what we saw here is, again, the top row in the study eye at baseline, we had 28.47 square millimeters, which then reduced to 25.79 at month 12. And likewise, there was also a reduction in the preserved area in the fellow eye as well. So a little bit of an opposite response from what we saw in the outer nuclear layer. And again, this may be because of the greater uncertainty with respect to segmenting this particular layer. Next slide. And this slide is showing overall a dramatic increase in the RPE drusen complex over time. So on the top row, the study eye from baseline to month 12 went from 31.85 in terms of preserved area out to 37.59 square millimeters. And you can -- just eyeballing it, you can see that the dark area has increased quite a large amount from baseline out to month 12. And the opposite has happened to the fellow eye where there is a reduction in the preserved area of RPE drusen complex. Next slide. So I would summarize this for this 1 patient is that the RPE drusen complex area increased dramatically from baseline to month 12. Of course, we're very happy to be able to see that because that's exactly what this type of therapy should do, which is to regenerate at least an RPE layer, and we're able to quantify the increase in that RPE layer in this 1 particular patient. But what's really important that we really want to see is that there is an increase in the outer retinal band, and that's something that really hasn't been shown dramatically before and something we would definitely want to see because that is the functional part of the retina, if we are attempting to restore visual acuity in these patients. And indeed, we did see that in the outer nuclear layer, the area increased from baseline out to month 12. With respect to the ellipsoid zone or outer segment, the loss in that area does appear to persist at -- from baseline to month 12. But as I mentioned, this is a measurement that's very prone to subjective -- is a very subjective assessment and there's significant noise around this measurement. So we'll be looking forward to seeing more patients and doing this outer segment assessment to see if we're able to see some regeneration in this layer from baseline out to the various study endpoint. And so that completes my section. I will turn this back over to Brian. Thank you.

Thank you very much, Dr. Ip. Thanks, everyone. There is an opportunity for Q&A. If you see the tab, you can type in a question. As those questions are being submitted to today's speaker, I wanted to just summarize very briefly some of the overall findings from the study, not just patient 14. We're quite pleased to note that the transplant of RPE cells has been very well tolerated. There have been no marked sustained reduction in vision in any of the 17 patients who have been treated to date. And most of the better baseline patients, which I described at the outset of the call, those who have better vision at baseline, most of those have improved their visual acuity at their 1-year time point or whatever the last available visit is. Overall, we have seen some evidence of directionally positive signs in various patients, including aspects such as the reduced growth of GA, improved BCVA, improved reading speed, improved retina structure, as just described by Dr. Ip. We have seen, in some cases, significant reductions in drusen, the waste material. And we have seen very stable engraftment. We now have data of providing evidence of the cells being present for more than 48 months with no reports of either acute or delayed inflammation or rejection of the OpRegen cells. So as we get ready to receive questions, I'll add that OpRegen as an RPE transplant therapy is being positioned by Lineage to address a multibillion-dollar commercial opportunity in atrophic AMD. The transplanting of cells may be able to provide benefits, which are not able to be achieved by other approaches. We are pleased that the transplant of whole cells means that we are immune from some of the limitations of specific pathways. So we are able to treat problems that may involve more than one pathway, which is something which can be challenging for small molecules or antibodies. This treatment has been very well tolerated. We've seen some patients with changes consistent with a treatment effect. We have numerous patents covering many aspects, and we have exclusive rights to a unique delivery device, which, again, is not subject of today's call, but does provide some important competitive advantages as we try to deliver the best cells the best way for the best outcomes. I will turn it now to the moderator to set us up for Q&A.

[Operator Instructions]

All right. The first question comes from Jason McCarthy. The question is, can you discuss a little about the safety aspects of this type of therapy? Even though this cell therapy approach is inherently safe already, the idea of injecting into the eye, which is already an immune privileged site, making OpRegen even more safe. Folks, if you'd like to identify which speaker you want to answer the question. Otherwise, I will just alternate. So Dr. Monés, could you talk a little bit about the safety of this kind of therapy, maybe generally and specifically with OpRegen? And then the next time, I'll come back to you, Dr. Ip.

Yes. Cell therapy and RPE transplant has been done for a while. And whenever the cells are well produced and purified and follow a very strict manufacturing procedure, which is really an issue because it's very complicated. There are a lot of safety steps. These cells can be safe. They do not show tumor formation, they do not show inflammation. And most of the rate depends on the procedure itself, in the surgery, in the retinal bleb, et cetera. But this is accounting that the cells are produced following all the rules and doing exquisite work. When cells are produced less well and everyone has read reports in this regard, then the cells, which are not purified and they have fibroblasts or undifferentiated cells, et cetera, then these cells can be very, very dangerous. So the stem cell implementation is safe if the cells are exquisite and well produced and very purified and really well identified. Then the technique for the surgeons or retinal surgeon is not a big deal. We are quite used to put to remove -- to remove hemorrhages under the retina. We're using a very, very tiny hole, the risk of doing a retinal detachment with that kind of hole is minimal. So the complication of the surgery are, for example, for endophthalmitis are like any other surgery, 1 out of 3,000. For retinal detachment, probably 1 out of 100 and maybe the only complication that is more characteristic for this procedure is the epiretinal membrane formation, which is a wrinkling of the internal limiting membrane, the surface of the retina, maybe because of the position of cells over there. But most of the times these epiretinal membranes are clinically not significant. They're mild, moderate. They do not cause visual loss. And most of the times, they don't need to be a threat. This case was an exception, and she's -- this lady develop severe at epiretinal that could be intervened in a conventional epiretinal surgical removal. So it's not -- this surgery is not big deal. Because of the suspension, if we were trying to implant a platform as [ capital ] with cell, that's a big different thing. Then you need to do a big retinotomy, a big hole in the retina, put that platform under retina, that's much more iatrogenic. But implanting suspension of cells has the advantage as the technique is quite straightforward.

Terrific. The next question comes from Darius Moshfeghi from Stanford. Dr. Ip, I'll direct this to you. Is there a time limit beyond which RPE transplantation would not be expected to be useful? Or another way of thinking about it, does photoreceptor loss indicate poor candidacy for RPE transplant?

Darius, that's a good question. And I would have thought before the results that we had just seen, at least in this N of 1. I mean, that's the big caveat here is that we have an N of 1. But prior to seeing this patient, I would have thought kind of along the way, I think the question he's insinuating, which is at some point, you've got so much photoreceptor loss. You've got so much outer retinal layer loss that it may be futile to try this type of approach. But from what I have seen thus far, and I showed you sort of the en face quantification of the outer retinal bands and Jordi very nicely showed the cross-sectional images, which I think are very striking. If indeed we're able to regenerate outer retinal bands, I think that we can probably identify patients with more and more advanced stages of disease, i.e., more and more loss of photoreceptors and outer retinal bands and perhaps successfully try to target these patients for visual restoration.

Wonderful. Thank you. The next question comes from Joe Pantginis. Dr. Monés, the question is, since patient 14 received the cells using the standard delivery technique, what, if any, impact could the Orbit delivery system have on potential outcomes and reductions of adverse events, such as the peal you referenced?

Yes. The aim of the Orbit device is to avoid a transmeatal approach and to avoid the retinotomy and then to avoid potential retinal detachment and mainly to avoid epiretinal membrane. So the approach is different, and we don't know yet if that will make a difference between the chances of success of one technique or the other, but probably it's irrelevant. The approach probably is not the most important. It's just the delivery route. You can go to the one side, if you can go through the other side. But essentially, the action will take under the retina of the RPE viable cells there, integrating, restoring the retina. So probably that will not be -- the biological reaction will not depend that much on the approach. The approach is mainly to avoid the epiretinal membranes and to avoid entering to the transmeatal and breaking the retina.

Great. Dr. Ip, the next question now for you. Is there the potential to have multiple dosing with OpRegen, meaning could the dosing be optimized where a little bit of retinal tissue is restored each time with continuously building vision back or at least slowing and slowing deterioration to the point where vision loss may be completely halted?

I suppose a piecemeal approach could be done. I think that would be a less ideal approach because every time this is applied, the patient has to go to the operating room. So ideally, this is a one-and-done type of experience for the patient as well as the physician. I also think that a piecemeal approach, having more and more procedures just increases the risk of the epiretinal membrane formation and other surgical complications.

That's great. I'm going to add a follow-up question. If you had this kind of technology in practice and approved treatment and you performed procedure and you felt you got suboptimal results compared to your typical results, how long might you wait before considering re-treating a patient if you felt you didn't get enough regeneration or recovery or whatever your metric was?

Yes. I mean -- I think that's a good question. And that's very different than the initial question, which is, if you feel like you've got a suboptimal response, I mean that's our treatment goal really probably wouldn't want -- you really wouldn't want to have multiple planned treatments, I don't think. But yes, certainly, if you feel like you've gotten a suboptimal response, the ability to add to the initial therapy would make sense to give that a try. Now the answer to your question in terms of how long should you wait before you augment your initial therapy? I think it's hard to answer that right now without actually really conducting additional studies, which I know the company is doing, with respect to the durability of the initial therapy. So in other words, if it turns out that the therapy is extremely durable. I suppose one would be less likely to augment the initial treatment. But on the other hand, if the therapy doesn't quite seem as durable as we would hope initially, then perhaps that would lead one to consider augmenting the therapy sooner rather than later. But I think that depends on getting some more data to really fully adequately answer that question.

So that is a very nice segue into the next question for Dr. Monés. The question is, how many patient numbers would it take to show more regeneration to have the broader eye doc community believe it?

Yes. That's a good question because one case, even with such a breakthrough does not convinced to the community to jump into doing it. And I don't think we had an [ early ] part. I think what we have here is true and it's regeneration, I'm completely full convinced. What we need to identify is what happened differently in this patient or what that patient had differently? Or what we'll do differently that maybe did not realize? So that's why we need to do in order to try to replicate that. But if I could reproduce what we saw today in a few more patients, I would be more than convinced because it's like -- you resuscitate somewhat. It's such a big thing that you don't need to resuscitate many people to say that's a big thing. So when something is that big, you don't need thousands of numbers to tell this is true. So I would say that with few less than 10 patients, even less than 5, if we could reproduce that, I would say that that's convincing.

Terrific. I know we're getting to the bottom of the hour. I just want to squeeze in another question or 2. I'm going to keep this one confidential from the investment community. But the question is Dr. Monés to stay with you, RPE and drusen complex increased at month 12 when compared to baseline, while RPE outer segment is persistent, does that mean that drusen size has increased?

I don't think so. Because it's very difficult to identify what do we have in the RPE. So some of the new RPE has a double layer, which means the RPE, the interdigitation zone and the ellipsoid, but they are smaller. Also, we may have RPE viable and RPE debris. So we cannot be sure that these months of material, if there are any, they're really chosen or their months of death RPE or other kind of materials. And that's why I don't care that much if the RPE looks worse or better. If we have above signs of recovery, such ELM or ONL because if we have that, it means that this RPE is functional. When we have RPE and nothing above, that's not a big deal because RPE there without having a retinal restoration means nothing. But when we have RPE, no matter how is the shape. And we have ELM and ONL restoration, that's such a big deal. But also what I outlined in color are restore RPE almost all the times was a double layer. They were not months. They -- it was very irregular like when the RPE is sick in before and the RP dies in atrophy. So these were 2 layers, meaning the RPE itself and the ellipsoid. And if you have ellipsoid it means that the photoreceptors are interdigitating with the RPE. And that's the proof that you have this kind of genomics of this kind a couple working together, RPE plus photoreceptors. And that's the proof that it is working. So I would not make much speculation of drusen because the material we may have there maybe do not correspond to the conventional drusen.

Brian, can I follow-up on that just a bit?

Absolutely.

Yes. I mean overall, I would agree with Jordi, I wouldn't worry too much about the drusen. So when we show that the RPE drusen layer complex increase from baseline to 12 months, it's just how it was measured, how we decided to measure that at the reading center. Drusen generally don't increase that dramatically anyway over a 12-month period of time. But it's clear that the RPE model layer is -- has increased dramatically over that period of time. And those images that you can see from what Jordi showed in terms of what you can see in those color photographs, you can almost see the RPE model layer, pretty pigmented. It sort of repopulated the entire or most of that area of geographic atrophy. And if you look at those en face projections of the RPE drusen monolayer that I showed, you can see that there's quite a dramatic increase in that area. So it's very clear that the therapy is doing what we would hope, which is that you're repopulating a monolayer of RPE cells. And the thing that really is the most dramatic, again, that I would emphasize is it does look like there's some, at least, in this N of 1, that there is some restoration of the outer retinal layers. And Jordi showed that in the cross-section. I showed that with respect to the outer nuclear layer, having a larger area of preserved area over time. And to get back to the original question, what does that mean for the persistence of the ellipsoid zone defect? Well, yes, that's a little bit of euphemism for it didn't get -- the defect did not get smaller. But again, I would highlight the caveat that I mentioned several times during my part of the presentation that this is very subject to this particular measurement of the EZ as opposed to the outer nuclear layer, the EZ layer is more difficult to identify and a little less reproducible. And so again, more patients over time to assess this particular endpoint is going to be important. But what I'm encouraged by is in the outer nuclear layer, which is a little less subjective, at least again, in this N of 1, we did see an increase in the preserved area of the ONL.

Very good. Thank you. We started late, so I'm going to run just a little late. I want to get one more question in from Dr. Moshfeghi from Stanford, who asks the RPE and retina regrowth appear to be sparing the fovea. How would you correlate this with the observed improvement in visual acuity? And as a clarification to that question, he is specifically referring to the area of new gray. I suppose I'll direct that to Dr. Monés.

Yes, of course. Darius, thank you. When I made the calculation, I was very confident on the measurement or boundaries outside the external rim of the lesion. It was more difficult to calculate the remaining areas, the island in the middle. Those areas were more disorganized and more difficult to see the ellipsoid. If it was, it was less visible. So I would make a strong statement on the changes outwards on the external rim of the lesion because I'm very confident on that. But in the foveal island area, it was more difficult, and I would not make strong statements there. So if I had only those foveal changes, I would not be that strong with my statement. But considering the outer rim, yes, no question. But in the fovea, it was difficult and this question of vision, I don't think I can make any point to correlate what I saw in the anatomy with the vision.

Terrific. Thank you. I do want to add that we had a lot of questions this afternoon. Many of them did go beyond the scope of this call asking about other programs and share prices and things like that. I would just like everyone to know that company representatives are available. If you didn't have an opportunity to have your question asked and answered today, you can certainly reach out to myself and others at the company, we'll do our very best to get you answers. But I want to share my deep appreciation to Dr. Monés and Dr. Ip for taking the time to share all of this with everyone. It's our belief that this is the first of many examples of the power of cell therapy as it emerges, and we're delighted to be one of the first to be able to demonstrate this kind of effect in the patients. And we will be working very hard to demonstrate more examples of it as we continue on with this clinical trial. So with that, I will conclude the call, hand it back to the moderator and look forward to following up with everyone at their convenience. Thank you.

Thank you. This does conclude today's conference. Thank you for your participation. You may disconnect your lines at this time.