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

Hello, and welcome, everybody, to today's call. My name is Brian Culley, and I'm the CEO at Lineage Cell Therapeutics. I'd like to thank you for joining today and learning more about the exciting work we're doing in cell therapy, and more specifically, our allogeneic cell transplant technology, which we believe can lead to clinical outcomes which are out of the reach of traditional therapeutic approaches. The reason for our call today is that thanks to an unexpected surge of 4 patients being treated in just 8 days, we recently completed enrollment of all 24 patients in a Phase I/IIa clinical trial and felt this is a great time to provide a more fulsome update. Before I introduce our therapeutic expert today, we have a lot of new followers, and I want to ensure that everyone is starting from the same baseline. So I'm going to present just 5 slides to remind you about our, work and then I will introduce Dr. Riemann, who will be able to do a deep dive into the data which we have generated to date. So as Lineage, of course, is a public company, I will be making some forward-looking statements, and I refer everyone to our safe harbor clause where they can learn more information about the risk factors. Lineage Cell Therapeutics has a really distinct and innovative approach to cell therapy. We transplant differentiated cells to the body. So we don't actually administer stem cells to any patients. What we do is we use stem cells as starting material. And from those stem cells, we manufacture differentiated cells. And it's those cells, those differentiated cells, which are transplanted to the body in order to rescue or restore what lost function. This includes some advantages, some notable advantages for us, not just hundreds and hundreds of cell therapy-related patents and patent applications, but we control our own manufacturing, and we have world-class know-how and intellectual property associated with these technologies. This approach has enabled us to advance 3 clinical stage programs: OpRegen, which we will talk about today, which is -- just completed enrollment in the Phase I/IIa study in dry age-related macular degeneration. Also, we have a Phase I clinical trial ongoing in non-small cell lung cancer with our VAC program where we manufacture dendritic cells. And we also have a completed Phase I/IIa clinical trial in spinal cord injury for which we manufacture oligodendrocyte and administer those to the spinal cord. What's really exciting about our approach is that there are things that we have observed that you typically cannot find with traditional approaches. So we've been able to show evidence in a patient of retinal tissue restoration. We've been able to eliminate the cavitation, which occurs with a spinal cord injury, and we've seen very high induction of the immune system using our dendritic cell approach. These programs, multibillion-dollar aggregated opportunities. So there's a great commercial potential for them. We have a lot of upcoming news. And the company has a strong financial position. As of September 30, we had $38 million of cash and marketable securities. The technological approach is capitalizing on the potential of pluripotent stem cells. These are the cells that can become any of the 200 cell types in your body. We focus down on retina program, spinal cord program and immune cells. But in theory, these cells that we begin with can be directed to become any other cell type that one might wish to make. That platform is quite powerful as we apply it in the setting of dry age-related macular degeneration, we think this is a promising place to go, because to date, there really -- there hasn't been nothing approved in the setting of dry-AMD, nothing approved by the FDA. And yet, there is a tremendous number of individuals who suffer from dry-AMD. Far more people suffer from dry-AMD then suffer from wet-AMD. But again, wet-AMD has very successful programs and treatments, but yet there's still nothing approved by FDA for dry-AMD. So there's a strong economic argument to go after this area. And notably, there have been some unsuccessful attempts by the traditional approaches. And we believe that, that's because those compounds are going after specific pathways. We're replacing the whole cell. We think that's what's required in an advanced condition like dry-AMD. There are a relative paucity of competitors in this space. Gene therapy is in here. Oxidative stress approaches are in here. But overall, only Lineage has shown retinal restoration. Only Lineage has access to the the Gyroscope SDS, which you will hear about on today's call. And really, only cell therapy offers the promise of being able to restore tissue with very infrequent dosing, maybe at 1 time, maybe at every few years. But certainly, nothing like what we see in wet AMD with monthly or quarterly injection. If we are successful, we need to be prepared to be able to address the market. We already can manufacture more than 5 billion RPE cells from a 3-liter bioreactor, and we can tether a bunch of these reactors together. So we already have a massive production in 3-dimensional scale, which we think, again, gives us a competitive advantage with this allogeneic approach. So these are not cells that come from a patient, these are established cell lines, 20 years older, been extensively characterized. And we just control them and drive them to become peer populations of retina cell. So with that, as an introduction, it will be my great pleasure to introduce Dr. Christopher Riemann. He is our therapeutic area expert for today. Dr. Riemann is a vitreoretinal surgeon and Fellowship Director at the Cincinnati Eye Institute and University of Cincinnati School of Medicine. Dr. Riemann has been a principal investigator or co-investigator for many Phase II and Phase III clinical trials. And he's a member of numerous professional associations, including the American Society of Retina Specialists, the American Academy of Ophthalmology and the Association for Research in Vision and Ophthalmology. His numerous original research works have been published in international peer-reviewed journals, and he has several patents for innovative surgical technologies. Dr. Riemann also is an adviser to a large number of pharmaceutical companies. So he has highly appropriate expertise on today's topic, which is the development of a new therapeutic for dry-AMD with geographic atrophy. We're extremely fortunate to have Dr. Riemann available today to provide you all with a more in-depth review of the updated OpRegen data, which he and, separately, Dr. Allen Ho from Wills Eye just this past weekend at the AAO Annual Medical conference. And with that, I am delighted to turn control of the presentation over to Dr. Riemann.

Brian, thank you so much for the opportunity to speak today and speak with the audience. This is a really exciting project, and it's -- I got to tell you, it's my favorite project that I'm involved in right now. So what I'd like to do is to kind of present the state of the union as far as the data goes for this Phase I/IIa clinical trial. We'll start off a little bit by talking about safety and tolerability, then we'll talk about survival and persistence. We'll talk about structure function effects. We'll talk about the safety of the thaw-and-inject formulation. That's a new formulation of the cells. And then we'll take a look at how we're doing with the Gyroscope Orbit sublet in the delivery system, how these surgeries are going and how the patients are doing. And then we'll take a little bit of a deeper dive into the cohort 4 patients, and remember, the cohort 4 patients are the ones that have a pretty good vision and where we're hoping to be able to see some favorable visual outcomes. So just as a matter of review, age-related macular degeneration can be dry or wet. In the wet form of disease, as Brian was saying, we inject monthly with anti-VEGF injections. It's the dry macular degeneration that doesn't have a good treatment. And the main common pathway by which dry macular degeneration can cause catastrophic visual loss is through this across the development of something called geographic atrophy. So if you look at these black and white photographs at the back of somebody's eye, these are the same eye of the same patient taken from 2012 to 2019. And you see the initial slight -- all the way on the left, the 2012 image, all the way on the left, you see some -- like a speculative pattern that's -- those are the drusen that we see in dry age-related macular degeneration in a small central dark spot. That's normal, that's the central fovea. As you go towards the right, over time, you see that around the fovea, you have these dark areas of retinal pigment epithelial loss that appear. And when those dark areas impact the central -- the central fovea, that's when the vision tanks. And you see in this patient, this patient started in 2012 with 2020 visual acuity and ended up more than 3x worse than a legally blind in 2019 because of this progressive area of geographic atrophy. So the issue with the geographic atrophy has to do with loss of retinal pigment epithelial cells. If you look at this left image, and I'm sorry, I don't have a pointer for you today. You can see that there's waste products, the yellow stuff, yellow clumping stuff on the dome. Those are the drusen that accumulate because the retinal pigment epithelium, which is a monolayer of pigmented cells that is absolutely crucial for retinal photoreceptor function, that dies off in those cells, wither away, causing loss of the overlying photoreceptor cells and subsequent visual loss. The OpRegen cells are transplanted into the subretinal space to replace these damaged, lost retinal pigment epithelial cells. And we hope and we believe with the resulting improvement in visual function. So the Phase I/IIa OpRegen trial has 3 -- has 4 cohorts. The safety cohort of eyes cohorts 1 through 3 that were all legally blind, and those eyes were all recruited a long time ago, and fully recruited the long time ago. What we're going to be talking about mainly today is cohort 4, which is the efficacy portion, kind of more the Ib/IIa element of this trial, which -- where we're happy to report that as of last week, we fully -- where we fully enrolled the additional patients. The primary objective, as with all early phase studies, is to evaluate the safety and tolerability of the subretinal transplanted OpRegen cells in patients with dry macular degeneration and progressing geographic atrophy. The secondary objective is to look at the survival and possible treatment effects. And then the exploratory objective is to -- in cohort 4 patients is to use the subretinal injection of the thaw-and-inject. It's a new formulation of the cells that's easier to transport and easier to prepare. And to also investigate an ultimate path -- an ultimate methodology for getting the cells where they need to be, that's usually the Gyroscope subretinal delivery system. And we'll talk about why we're doing that, [ interestingly, in a bit ]. So Lineage has exclusive rights to the Gyroscope subretinal delivery system technology for cell therapies or dry-age related macular degeneration. So that's really exciting. The typical way that we get these cells to the subretinal space is to do a vitrectomy, and you see that illustrated here on the left diagram, to do a vitrectomy surgery, removing the gelatinous material from the center of the eye. And then making a retinotomy, basically, poking a hole through the retina that then get a microneedle and injecting the cells under the retina. That's the vitrectomy-retinotomy approach. The Gyroscope system is a novel new way of doing it, where we actually inject the cells without into the subretinal space without feeling a vitrectomy and without making a retinotomy, were poking a hole in the retina. And we think that there are some advantages of doing it that way. And what I'll do is I'll play this next slide and show this video. So what we do is we make this a sclerotomy in the outside of the eye, we advanced the cannula in the suprachoroidal space, and then pushing needle through the suprachoroidal through the cohort into the subretinal space and inject the cells into the subretinal space. Creating a treatment led, again, without really entering the eye with a vitrectomy and without removing the vitreous material without -- most importantly, without making a hole in the retina. So the starting the population here. We already talked about the fact that there's 4 cohorts, cohorts 1-3. They're all legally blind eyes that were 2,200 or worse. Cohort 4, the inclusion criteria were 20/64 to 22/50 and had smaller areas of geographic atrophy. If we look at the baseline characteristics, as you would expect, these are all older folks. And the ages are pretty well-matched across the 3 -- the 3 columns here. The first column is cohorts 1 through 3; and the second 2 columns represent cohort 4, with 5 patients operated with vitrectomy, retinotomy and 7 patients operated with the Gyroscope subretinal delivery system. You see that the geographic area in the cohort 4 patients, the geographic atrophy area in the cohort 4 patients is significantly smaller, and the vision is significant. So in terms of important results, safety results, systemic and ocular safety and tolerability was excellent. There were no sustained reductions in visual acuity and in cohorts 1 through 3, where we really didn't expect to see an improvement because these were very advanced end-stage eyes. And in cohort 4, with better starting vision we saw either improved or sustained vision on baseline. In 6 of 8 patients, 2 patients were so recently treated that we're not reporting data because it's just -- they were just treated last -- in the past few weeks. There was -- most importantly here is there is no acuity delay information. There is no sympathetic ophthalmia. There is no uveitis. So the cells are well tolerated in the eyes. And the surgical -- the surgical adverse events are typical in what you would see in eyes after surgery. So nothing significant to report there. Looking at the ophthalmic safety inputs. There are some interesting and notable things to discuss, right? So a significant percentage of patients developed subretinal pigmentation. We view this as a positive finding. We are injecting pigmented cells into the subretinal space. And these pigmented cells are visible and that pigmentation persists, in some cases, out to 4 years of follow-up that we think is a positive finding because it implies, we think persistent survival of the cells. On the negative side, in vitrectomy-retinotomy patients. 13 of 16 patients developed significant macular pucker. 2 of them developed -- 2 of those macular pucker resulted in a retinal transformation and 1 developed retinoschisis, 1 patient developed a retinal detachment, and which we needed surgical repair. And 1 macular pucker, 1 smart tissue layer was so severe that it need to be removed surgically. And that was indeed vitrectomy-retinotomy patient. Looking at the Orbit subretinal delivery system patients. Of the 4 patients operated where we have data so far, none of those developed macular puckers, Lamellar hole, retinoschisis or retinal detachments. So that's exciting news. On the downside, 3 of the 4 orbit SDS-related patients developed very small, asymptomatic and subretinal hemorrhages. We don't think these are relevant, but these need to be watched over time. This phenomena needs to be watched over time. And then choroidal neovascular membrane formation, which is basically switching from the dry macular degeneration over to the more aggressive wet form of the disease, but you need the monthly injections for, happening in 1 patient in each group so far. So what are the treatment effects that we're seeing? This is patient #8, so this is a cohort 3 patient where we have very risk topography to show you. And one of the things that we're seeing is in areas where the OpRegen cells are transplanted, usually which is a sign of sick retina, sick with dry macular degeneration retina, they seem to regress. So if you look through on the top left corner, you see a little pigmented area right just above the area where the -- that little vessel traverses horizontally just above the center of the photograph. Those are the actual cells. And if you look at the baseline photograph, you can see the speckled yellow pattern, those are the drusen and then if you now go to the bottom right-hand photograph, you see those same dark cells that are there and the drusen in that area have gone away. Now this is something we've never seen with any kind pharmacological cell therapy for dry macular degeneration. And it's very, very exciting. Not only are these changes visible power form for this topography, but OCT, optical coherence tomography, it's another way that we look at people's retinas. And what these are, these are optical B scans. It's a fancy camera that we use to generate cross-sexual images using laser flight of time e-scan laser reflectivity. And you can see in the top left-hand corner here where it says baseline, you can see that kind of lumpy, bumpy layer at the bottom of the retina. Those are the drusen. And if you look at the 24-month picture, this is the exact same cut to that exact same eye, you see that the drusen have gone away. And again, that is new, that is novel, that is really, really exciting. So this is what one of these OpRegen surgeries looks like. We put a stitch in, [indiscernible] with a stitch in. And you can see the geographic atrophy there. We make the spirotomy. And this is -- and we -- it's a careful dissection, but we make -- we open it all the way up and that dark material that you see is the cohort. We dissect down to that and we insert the cannula into the sub-retina in the superchoroidal space, and you see centrally the little needle driving out that's poking through the retina and creating the bled right there of cells. So this is a patient that I operated a few months ago. And you see the retinal blood there that's been created and then we closed, and take 1 more look at the blood, and you see that the blood is beautifully maintained, it's not inflating, which is something that we can sometimes see when operating with vitrectomy [indiscernible]. And I'll ask you to just kind of look at this picture and look at the blood. Remember, this patient's lying on the back and up is the bottom of the screen grid, right? And you can see the blood kind of touching on the superior third or so of the geographic atrophy. And then extending in the photograph down from there, which in real life is actually up from there. If we now fast forward a few months, this patient is sitting up in a chair. So the picture here is actually upside down from what it was. What you see is you see the cells layering out right at the edge of where the blood goes. So these cells, the darker pigmented areas, they layer out with gravity. And when the patient sits up, which they do, to live their lives after surgery, the fluid -- the blood sits there and the cells kind of layer out by gravity. And they end up here under the retina at the edge of where the blood is, which is exciting. Here's optical coherence tomography, where you can see baseline and then post-op day 1, post-op day 7, post-op day 7, post-op day 14, 1 month, 2 months and 4 months, you can see the fluid, the blood absorbed. And most importantly, as the blood goes away, the cells remain. And you can see the cells here, all this kind of -- these currency things here that appear on optical coherence tomography. These are cells, and they are layering out and polarizing and forming, and hopefully, improving visual [indiscernible]. So let's talk about the function here, structured function relationships in the cohort 4 patients in a little bit more detail. So remember, these are patients that had 20/64 to 22/50 visual acuity at baseline, they had documented worsening geographic atrophy over time prior to being enrolled in the study for these eyes have been operated with vitrectomy-retinotomy and 4 of these eyes were operating with the Gyroscope subretinal delivery system and the thaw-and-inject formulation. If you look at the visual acuity signals, this is best-corrected visual acuity. You see what really appears to be an impressive visual acuity signal. So the left chart shows what the vision did over time in the pre device relative to the fellow entry device. And it's certainly, well, noisy data, as all data is, but there's clearly something going along that seems to be -- seems to suggest a significant visual acuity signal. And if you look at the magnitude of the visual acuity signal, some of these eyes have gained over 15 levels, and that's stuff that we've never seen before in treating dry age-related macular degeneration. Very, very exciting. If we pool the data and graph it, even though there's only 8 eyes and only 4 of them made it out -- have made it out 12 months so far. And despite how noisy it is -- green was the treated eyes and yellow was the untreated eyes -- we've actually reached statistical significance at the 9- and 12-month mark . So that's super exciting, super interesting. And we're very, very excited to see how this develops now that we have cohort 4 fully enrolled and progressive. Looking at the size of the geographic atrophy, this data is a little bit less bombastic-looking. It's a little bit more noisy. But there does seem to be, especially if you look at it, a subtle trend towards a slower progression in the treated eyes versus the untreated eyes. Whether or not this pans out, we'll just have to see as more patients make it out to longer periods of time. So another thing I just wanted to briefly touch on here is there's been a few eyes that have been, what I would call super responders, where we've seen what appears to be structural restoration of outer retinal and retinal pigment epithelial anatomy. Again, and that's new. So here's an 80-year-old woman with a greater than 20-year history of macular degeneration 20/80 visual acuity in the treated eye, 20/60 vision in the entry. This patient was operated at our Israel site and received a very large OpRegen thread that completely encompassed the entire retina. The little star here, the little red start, shows where the retinotomy was made, where the little puncture site was made in the retina, and the yellow -- dotted yellow line traces, the outline of where the blood was. And here over on the right, you can see a brain grab with the surgical video with a round blood that occupies the [indiscernible]. So looking at this patient's visual acuity, they did -- great initial. And then this was the patient that developed that formable macular pucker, which caused visual acuity reduction. You see the vision goes down at 2 months. And then in 3 months, they operated that patient and removed the macular pucker, and the vision jumped right back up, and the visual acuity improvement has maintained out to 24 months. So that's really exciting. Here, you see OCTs at baseline in the top right panel. And at 2 months where you see this white line at the top of the retina, that's the. Severe epithelial membrane and that's going to pucker that scar tissue that's formed. And you can see it kind of pulling up on the retina diffusely and stretching the retina up, that's what caused the visual loss. That macular pucker has been surgically removed and normal retinal anatomy was restored 2 weeks after the membrane filled. If we take a really close look at the OCT images, we can see that -- comparing baseline vision that's going in 20/80 in the baseline OCT, at month 9, the vision has improved from 20/80to 20/60, that's a significant jump. And if you look very carefully at these striations here, you can see that striations that kind of fade, they come back. And as they come back or restore rather, these striations that fade centrally and those striations are the normal retinal outer segment photoreceptor layers, they'll restore. You can see those striations rightly out of nuclear, you have a plexiform, the external limiting membrane, those are restored over time. And that's really exciting and new. And here's some more anatomy that shows external limiting membrane, an ellipsoid zone that is -- and even retinal pigment epithelium that seems to be restored in the area that receive OpRegen [ transplant ]. Right? This is, again, it's never been seen before. Actual reversal of the geographic atrophy and the micro [indiscernible] changes. And here's another one where you see a restored outer plexiform layer, and these cuts, these OCT cuts, are identical -- are in identical locations. So not only are we seeing structure improve, but we're seeing function improve, with the vision again, going from 20/80 to 20/63. So here's another way to look at this data. We super -- we didn't -- we had a outside reading center, superimposed. The area of the geographic atrophy by tracing it out. And I'll show you what I'm trying to -- what these color images are trying to demonstrate [ one by one ]. So the baseline visit was in July of 2018. From May of 2017 to July of 2018, over a year, this is prior to getting any kind of treatment, you see that the geographic atrophy grew from orange to red, growing -- lesion size is bad. And as we saw early on in the [ pad ], is associated with decreased visual function. So here, you see, without treatment, this patient is getting worse over time. Then we treat -- in July of 2018, the patient was treated with OpRegen, and in April of 2019, we redraw the trace and you see that the area of geographic atrophy appears have gotten smaller. That's exciting. Not only has it gotten smaller, but that reduction in size persists all the way out to 23 months of followup. So again, kind of to summarize, we have a compelling and hopeful story where geographic atrophy sized reduction seems to be in this 1 patient, may -- it seems to be demonstrated and maintained out to 2 years of followup. So what can we conclude? We can say that OpRegen appears well-tolerated in the 20 patients that -- where we've got data, and 4 recently treated patients, their surgeries went well. And so far, the patients are doing okay, but we don't really have real data to show you because it's too early. Reductions in drusen and restorations of photoreceptor and retinal nuclear layers were observed and have persisted in some patients, along with slowing geographic atrophy progression, and in some patients, even a reduction in geographic atrophy area. And with those structural improvements, we've seen better visual acuity and improved reading speed in some early cohort patients and most cohort 4 patients. We've seen sustained subretinal pigmentation of the treatment area that suggests durability of these transplants of OpRegen cells. In some cases, out to 4 years as a follow-up. And the epiretinal membrane problem in patients receiving the OpRegen with vitrectomy and retinotomy seems to have been resolved by switching to the Orbit, the Gyroscope subretinal delivery system, at least in the patients operated to date, and we're really, really excited about that. The OpRegen thaw-and-inject formulation has been utilized in 7 patients to date. We've only shown you data on 4 of them. 3 of them are recent and cooking and is exciting. My second patient, unfortunately, just got COVID. So that's a little bit of a needless drama, but she's doing well, and we anticipate we'll have data from her forthcoming coming soon. So the patient enrollment is now complete in all 4 cohorts of the study, and we'll see what the data shows. The key tool here is that -- I just want to give a shout out to the Gyroscope team, to the Lineage team, and to all of the study sites recruiting patients into a Phase I trial, where immunosuppression is needed. So all of these patients would be immunosuppressed in the setting of a COVID pandemic, is a tall order. And the fact that we've had this Herculean recruitment effort be successful is a testament to a phenomenal collaboration of very capable people. So with that, I think, Brian, you've got a few more points.

Yes. Thanks so much, Dr. Riemann. I tell the short version of the story all the time. And I got to say, it sounds a hell of a lot better when it comes from an expert like you. So thank you very much for that overview of the data today. We do have a number of research analysts who have joined the call. Also on the call is Thomas Hoffmann from Solebury Trout. So he has the Q&A, and he can direct those questions to you or I as needed. So Tommy, do you have questions in the queue for us today?

Yes, absolutely. And thank you, Brian. So the first question is from Joe Pantginis from H.C. Wainwright, and he was asking actually a couple of questions. The first one from him is, can you talk to your overall confidence that long-lasting pigmentation is from the RPE cells? And second, can you talk to your [ mentioning ] confidence regarding the bleeding events seen with Orbit-treated patients being transient and self-resolving.

So yes, I'm happy to take that one. The bleeding events -- the hemorrhages have gone away. There's been 1 extrafoveal choroidal neovascular membrane that was -- that formed 6 months after the surgery at the -- either at or very close to the needle puncture site, that's responded favorably to 1 anti-VEGF injection. We think that it's not surprising that there would be a tiny little speck of hemorrhage. When you puncture the most perfused structure of the human body, the core in terms of blood slope per cubic millimeter, the most perfused structure in the human body. It's not a surprise that we get a little speck of hemorrhage. And we know from experience now with the Lineage patients, 7 patients with the -- 7 Lineage patients. And we also know from the PRELUDE trial that was looking at a different cell line by Janssen, we know that the -- and had 21 eyes operated, that this methodology for getting cells or anything into the subretinal space works and it's safe. What was the second question? There were 2 questions.

Yes, that was a 2-part question. The second part was, can you talk to your mentioned confidence regarding the bleeding events seen with Orbit-treated patients being transient and self-resolving?

So that's true. And then the second -- I think the first part of that question -- I took the second part first, I'm sorry.

Yes. The first part was, can you talk to the overall confidence that long-lasting pigmentation is from the RPE cells?

So in the patients where we see the cells, where we see the pigmentation, we can see what looked like cells on the OCT. And we can see -- and we can see patient -- and we can see that those -- we could see treatment effect in terms of reduced drusen and better vision that's sustained in some patients out to 4 years. So do we know that for certain? No. This is an early phase trial. But we are hopeful that, that is what we're seeing, and that, that is a plausible explanation for the subretinal pigmentation that we're seeing.

Another question that came from Joe Pantginis of H.C. Wainwright is what would be the biological mechanism by which the trend for GA slowing could improve over time, if any?

The -- so there's 2 reasons why we might have a slowing of geographic atrophy progression, 2 theoretical reasons. So how do these cells work? Option 1 is a trophic effect. If you take -- so where the transplanted cells secrete cytokines and growth factors that are necessary for the health of photoreceptors and for the health of surrounding retinal -- native retinal pigment epithelial cells that prevents apoptosis. So that's the first option. The second option for why we think these cells work is that these cells might actually replace the actual photoreceptors. I'm sorry, the actual lost cells that are damaged by the geographic atrophy. So cell replacement versus trophic effects from cells that are nearby are the 2 things that we think are the potential reasons why this would work.

The last question from Joe is for this restoration patient. Can you talk to how you would never see this? And what number of patients further would you need to see to be fully confident in the OpRegen potential effect?

So I'm not a statistician, and I don't know what the beta error would be necessary. I think that, that's an excellent question. And I think that in order to really establish that, we probably would have to really come up with a good OCT metrics to quantify the health of these different layers that are in the retina. And then use either algorithms or blinded reading -- mask reading centers to try to trace out these different layers. So what number of patients do we need to tell more than just an anecdotal story? I'm not a statistician. And it's important that I tell you what I know. It's more important that I'm transparent about what I don't know. I would say Phase III kinds of numbers would be my guess. And -- Gary, Dr. Hogge, what do you think?

Yes. I would echo that as well, Chris, is that if we see multiple numbers in repeated dosing groups, I think that, that would encourage us. But I'll start with 1, and we'll build from there.

That's right.

Excellent. Our next question comes from Ahu Demir at NOBLE. Please, for the audience, remind that they can submit additional questions below the Zoom video where it says in the portal, Ask a Question. The question is, can you elaborate on the primary and secondary endpoint options for a registration study assessing OpRegen considerations that one, competitor landscape; two, yet insignificant improvement in GA; and three, comparing the measures to the fellow eyes -- eye. Sorry. As 2 eyes can be at the different stages.

I can probably begin on that one, and others can chime in. I think there are 3 options. With respect to seeking approval for a program like this. Those options are going to be some measurement of visual acuity such as the ETDRS, or best-corrected visual acuity. The second one that certainly jumps to mind is slowing the growth of an area of GA. Those 2 are the most obvious that come to mind. There's a third, actually, which is quite interesting. And I'm going to credit a particular health care investor who brought this to our attention as an idea. What if there were a response rate built around freezing an area of GA or reducing an area of GA, right, treated like an oncology program, where you've got a threshold around the responders. You can imagine that even a relatively low percent of responders by that criteria could be an approvable endpoint and provide a very significant clinical benefit, especially in light of the patient now that's gone 2 years with a GA that's smaller than baseline. So as we sit here on November 17, it's impossible for us to say with certainty which of the 3 paths or variations of them we might pursue, because I would say that today, the visual acuity data looks more compelling than the GA growth data. But we just treated 6 patients in 8 weeks. So we have this whole cohort. I call it the November graduating class. And those patients are going to add to the slides that you saw earlier from Dr. Riemann, and I think that's going to provide the information. Ultimately, what we want to do is pursue an endpoint which is most likely to be delivered by our treatment. So if our cells seem to do a great job in visual acuity, we know that's important to patients, we would lean in that direction. If we see a lot of variability in visual acuity, but we see clearness with respect to GA growth, we would go in that direction. But we also would explore other ideas, such as a responder's analysis with respect to patients that may be able to benefit from this restoration phenomenon, which we are seeking to repeat because we only saw it this past summer. So it's still a new finding for us.

I'd like to jump in here. I agree with everything Brian just said. And in terms of functional measures of visual acuity, we didn't show these slides this time around because we showed them at ARVO last time, is related to reading speed. So even modest improvements in visual acuity can sometimes be associated with stunning improvements in function by reduction of visual field deficits that improve reading speed. And we've seen, at least in a couple of patients, stunning improvements in reading speed.

Our next question comes from [ Chad Myers ]. Mr. Culley, after this data released, do you still consider OpRegen your lead candidate? Or will OPC1 or the dendritic cell therapy take the lead?

So I think we're most well-known for what we're doing in the eye today. I think that's the primary driver. We know we have a cohort of patients, a fairly meaningful number of patients that are going to be delivering data that gets really interesting after the first couple of months, right? I mean, the first couple of months, you don't really over-interpret what you're seeing. When you get out to month 3, 4, 5, 6, it really becomes quite rich. So I think we'll continue to have an emphasis on the dry AMD program, but it always pains me to put the other programs in a subordinate position, because I think the generalized approach of manufacturing specific cells and transplanting them to enhance the body's activity, whether it's in the eye, spinal cord or immune system, I think that ushers in a new branch of medicine. So we'd love to do everything simultaneously. But I do think that OpRegen continues to be the base case or the precedent setter for allogeneic cell therapy and cell transplant medicine.

Another question, follow-up question from [ Chad Myers ] is with the dose escalating OPC1 trial finding no real efficacy at 2 million cells and 2 to 3 levels at 20 million cells, could both OpRegen and OPC1 benefit from continued dose escalation?

Yes. I really want to keep the scope for this event on the dry AMD program, so we could take that up separately. But we did conduct dose escalation in the OpRegen program. We did not see a benefit at higher levels. Pharmacology is a funny concept in cell therapy because you're talking about whole cells that have the ability to divide. So we're quite comfortable with 100,000 cells in the eye. And as I say, these cells can divide. They will exhibit contact inhibitions. So they don't continue to divide. We haven't seen problems with foreign materials, cysts forming in the eye or anything like that. So I think some of the concerns around administering whole cells are perhaps a little overstated compared to what we're finding clinically to date, which is very encouraging. But as I said, I'd like to keep the questions focused on dry AMD for Dr. Riemann today.

Of course. Our next question is, how long will it take for the trial to come to conclusion? In other words, how long will company have to continue to invest before it may be able to market the treatment and begin realizing revenues if successful?