Belite Bio, Inc (BLTE) Earnings Call Transcript

Welcome to our KOL webinar with Belite Bio. Today, I'm happy to have with us Tom Lin, the Chairman and CEO; Nathan Mata, CSO; and Dr. Michel Michaelides from University College London Institute of Ophthalmology and Moorfields Eye Hospital. Thank you all for joining us. So I've laid out the overall agenda -- we'll just show this, the overall agenda for the webinar. As we go through these topics, people in the audience can feel free to submit questions via the chat. We'll try to address them if time allows. A quick disclosure, the speakers have confirmed that they will not disclose any material nonpublic information, the audience should frame their questions appropriately.

So maybe we can dive right in. Dr. Michaelides, maybe we can start with you. Can you give a quick introduction and overview of your practice and background, including how many Stargardt and GA patients you treat?

Sure. So I'm attending Moorfields Eye Hospital. I've been attending for about 12 years. I spend half of my time seeing patients with retinal disease, both inherited retinal disease and AMD. And the other half of my time seeing -- in clinical research, predominantly clinical trial design, in developing novel endpoints, structure function associations, genotype, phenotype correlations. In terms of how many patients I see with Stargardt disease, it would be the second commonest disease that I see in terms of inherited retinal disease the first would be RP. I see about 50 adults with inherited retinal disease a week and about 30 children with IRD a week. And of those sort of 80 patients, 15 to 20 will have Stargardt disease a week. And then in terms of how many patients with GA do I see in a typical week, I'll see sort of 5 to 10 patients a week.

Okay. And when you're -- since this discussion is going to focus both on Stargardt and geographic atrophy, can you walk us through how diagnosis looks like in those different patient populations and also the kind of variance you might see in terms of disease progression, that one might expect related to patients.

Sure, absolutely. So Stargardt disease is monogenetic disease, there is one gene that causes Stargardt disease called ABCA4. There are three main presentations of Stargardt disease in terms of age of onset. You've got, by far, the commonest presentation is childhood onset. The second commonest will be in adulthood. In sort of 20, 30s and the least common and mildest form of Stargardt disease would be the late onset foveal-sparing form of Stargardt disease. In terms of diagnosis, there's often a delay of all three of those presentations in the early stages, especially in the childhood form and to some extent, the adult form, the findings can be really quite subtle and could be readily missed if the appropriate investigations, especially retinal imaging, are not performed early. And in the late onset form, it's not unusual that may be misdiagnosed as age-related macular degeneration, especially the dry form, so GA. The way it's confirmed is with genetic testing, which is now readily available in most developed countries. And 70% to 80% of patients with Stargardt disease with clinical diagnosis, you'd anticipate to make a genetic diagnosis. In terms of Geographic Atrophy, again, very common condition that we see. It depends on where you are in the Western world. In the U.K., often patients are diagnosed and not regularly followed up and then may be monitored by their optometrists. I think in the United States, they're more readily followed up long term by retina specialists in terms of giving them some sense of the rate of changes occurring over time, warning them and looking out for any potential complications such as the development of wet macular degeneration, which clearly is treatable. And in terms of the diagnosis, again, it's very imaging-based fundus autofluorescence imaging is very helpful as is optical coherence tomography.

And then in terms of available treatments, how do you treat your Stargardt patients? And how do you treat your GA patients?

Sure. So there is no approved therapy for Stargardt disease. And so we provide some information on healthy living that we really extrapolate from some of the AMD studies suggesting that could be helpful for patients in Stargardt disease. Arguably, the most important two things we tell patients with Stargardt disease is not to take vitamin A supplementation. There's concern that taking vitamin A would accelerate the rate of progression. And we also tell them to avoid excessive exposure to natural sunlight. Again, suggestion that excessive UV light may be harmful. So again ask them to wear good UVA, UVB blocking sunglasses. We also provide them with supportive measures, so low vision aids, spectacles, magnifiers, lots of different assisted technologies and then provide registration, which provides additional support but there is no treatment or cure to slow, halt or improve vision.

And GA?

And for GA, in the U.K., we don't have any available therapies for GA. If they have GA [indiscernible], we will advise them to take AREDS2 that may slow rate of progression. So there's quite a high pickup with taking AREDS2 supplementation. And again, it will be a similar lifestyle in terms of avoiding excessive exposure to bright sunlight, wear good sunglasses. We'll also add in the smoking, which is a decent good evidence there that people should stop smoking. And then we tell them about the therapies that you have on the slide that are available in the United States. As you know, Syfovre was not given EMA approval. Primarily based on lack of functional improvement with some concern about safety, and Izervay is currently under assessment by the EMA is my understanding.

And if you had to assess any limitations or ongoing unmet needs in each of those patient populations, what are sort of the key things that patients are still looking for?

Certainly both will be looking for a slowing or a halting of their disease progression. It always progresses. And so they're certainly looking for that. The children, in particular, in addition to having difficulty with central vision, also start losing peripheral vision. And so it's sort of -- they have both of those aspects. GA, clearly, central vision, been childhood onset Stargardt, they have both central and peripheral loss of vision over time. So they're even more visually compromised. Of course, once one is able to slow or halt progression, the human species wants more, it always wants more. So it would want improvement of vision and after improvement it want full restoration. But it's a great place to start with slowing a halting progression and certainly, all patients ask me, is there anything they can do that might slow progression, and they allude to lots of other therapies that certainly aren't approved and aren't advisable. So there's a huge appetite for slowing a halting progression.

May I ask a hypothetical because like you said, the complement inhibitors aren't approved in the UK. They are approved in the U.S. If they were available in the new market, are there still unmet needs that you see with those treatments?

Sure. No, absolutely, there are unmet needs. I mean looking at the data, it looks as if it slows progression by about 15% to 25%, something like that. So there's clearly scope for greater levels of disease modification, slowing progression. There clearly are concerns about Syfovre, certainly in the U.S. and I just got back from the U.S. meeting, and I'm aware some of my [ retinal ] colleagues in the U.S. are sort of somewhat reluctant to use Syfovre because of the retinal vasculitis and the inability to predict who will develop retinal vasculitis. And when you do develop it, it can be sight threatening. And then there is association of both of these with the development of wet macular degeneration which does seem a bit counterintuitive to be treating dry macular degeneration GA and inducing wet macular degeneration, although we do have very good treatments for that. So I think there is some concern. And, of course, we're not really sure yet whether Izervay will have some of the similar side effects of Syfovre. Of course, I hope it won't have that retinal vasculitis concern, very different doses of those two drugs. So maybe that different dose will come into play.

And maybe turning back to how this how or [indiscernible] the mechanistic rationale for Tinlarebant and maybe this question is for Nathan if you like. Some people in the audience might be less familiar with how Tinlarebant works and its history. Can you walk us through the mechanistic rationale of that asset?

Sure, Jennifer. Yes, I think -- the first point to make clear is that in both Stargardt disease and Geographic Atrophy, the accumulation of toxic vitamin A byproducts it is implicated in disease progression. These byproducts are called bisretinoids and they're derived from vitamin A that is retinol that is circulating in the blood. And so -- and you see it here as a schematic -- this is a schematic of the visual cycle. The retinol abbreviated, AT, that's vitamin A. In the liver, vitamin A binds to retinol-binding protein 4 and then another large accessory protein called transthyretin binds to that complex. And what can [indiscernible] into the circulation is this ternary complex of retinol binding protein 4 retinol and transthyretin is a very large molecular size complex. So it resists filtration in the kidney. So this is biology's way of maintaining a high steady-state level of vitamin A in the blood. But what's very important to note is that only the eye has a need for delivery of retinol bound to retinol binding protein 4. And that's because of the presence of a retinol binding protein 4 receptor into the back of the eye, which is not present in other extrahepatic target tissues. So in the eye, there is a unique dependence for delivery of vitamin A bound or retinol binding protein 4. When the complex stocks under the receptor, the vitamin goes into a series of enzymatic reactions where it's eventually converted to rhodopsin and then light activation of the rhodopsin liberates retinoids, species of vitamin A, which is very toxic to membranes. And it has to get out of the retina or it will actually start damaging retinal tissue. And that's where the ABCA4 protein comes in. This is the protein that's encoded for by the ABCA4 gene, which, of course, is mutated in Stargardt's disease. So without that mutation and with a functional protein that retinol can readily leave the retina and reenter the visual cycle. But in the case with Stargardt disease, where there are mutations that affect the function of the ABCA4 protein, the retinol cannot officially leave the retina. It lingers within the retina and it complexes upon itself essentially forming these dimers of vitamin A. So two pieces of aldehyde bound together and basically, these compounds, which we call bisretinoids are highly toxic. The one that's been identified in greatest abundance in human tissue is called A2E. And this molecule has been going to be very stable, and it kills retinal tissue through diverse mechanism. So there's nothing good about this compound. It really is the whole reason for retinal pathology and Stargardt. In GA, these -- this -- bisretinoids is accumulated as well but for a different reason. They accumulate because of their debris beneath and below the retinal pigment epithelium. This interferes with nutrient check transfer and trophic sort of influences at the RPEs on the retina. And it also causes the dysfunction of the enzyme within the RPE that normally metabolize and process vitamin A. What happens when they run them up, is these bisretinoids form locally right within the retinal pigment epithelium. So in both diseases, they form, but in different ways. For Stargardt, it's a genetic insult, and in Geographic Atrophy, there's a whole series of events, including these -- the accumulation of drusenoid bodies within the RPE that caused the RPE to become sick and the bisretinoids will form locally there. There's an interesting study right here. This is actually not a study actually it is sort of a case history of two subjects with disease, Stargardt on the top, geographic atrophy on the bottom. And you're looking at a series of retinal images, looks at these all the time. These are fundus autofluorescence photography images, and they allow the ophthalmologists to visualize what's happening in the back of the eye. The black blotches you see in all the images are atrophic retina, that's dead retina that's never coming back. But the whole point of these images here is that if you look chronologically from baseline out to 57 months and roughly about 4.5 years in each series of images, what you'll see is that the appearance of autofluorescence precedes the onset and spread of atrophic lesion growth. So when the Stargardt patient, you see at baseline, these two large areas of atrophy is surrounded by autofluorescence. And as you move forward in time after 57 months, you see that the darkened area is spread into the autofluorescence zone and the autofluorescence zone continues to expand centrifugally to accommodate that dead retina. You see the same thing in GA. It's sort of a different pattern. The autofluorescence there is sort of in speckles, little punctate, pieces of light, if you will, you can see them a little bit more clearly at 12 months. And as you go forward from 12 months out to 55 months, what you see those areas that were previously just autofluorescence have now become retinal atrophy, and the new areas of retinol atrophy have little zones of autofluorescence around their perimeter, just like the large lesions. So in both diseases, we believe these bisretinoids are implicated and this clinical data sort of confirm that. There's also some very interesting histological data that show us the presence of these bisretinoids within the tissue of Geographic Atrophy patients. So what you're looking at here in slide -- sorry, Panel A, is a cross-section through the back of the eye, of course, is a postmortem tissue from a patient that had geographic atrophy and they're using a fluorescence microscopy to visualize where there's autofluorescence. And the reason they're doing this is because these bisretinoids fluoresce because they contain vitamin A. If you shine the appropriate light at them, they will shine back light. And that's what you're seeing in panel A is -- and we're focusing really on this pink band that you see throughout the retinal pigment epithelium. This pink band actually has a spectral what's called a fingerprint, if you will, just like humans have fingerprints on their fingers. Molecules have spectral fingerprints that are very unique to the each molecule. So what you see in B is the spectral fingerprint of that autofluorescence that's shown in panel A, that peak band. And on Panel C, what you see are authentic spectra from a Stargardt patients, postmortem Stargardt patient showing the A2E molecule and its precursor called A2PE. And now if you overlay the two Jennifer, you could hit a key stroke. You can see that the spectral fingerprint obtained from the GA tissue is identical to the spectral fingerprint obtained from the Stargardt patient. So once again, this is telling us that these molecules, these bisretinoid molecules do, in fact, accumulate in GA tissue and again, as they're doing in Stargardt's disease, they're ravaging tissues. So there's nothing good about them. They're derived from vitamin A and so that's our approach. Really is to limit the amount of vitamin A going into the eye as a means of reducing the accumulation of these nasty toxins. Next slide, Jennifer? And so that's what Tinlarebant does. So Tinlarebant is an oral available small molecule that goes into the liver and competes with retinol for binding to RBP4 and it doesn't allow the larger protein transthyretin to bind to it. Consequently, what can liberate into the circulation is a relatively small complex of RBP4 and our drug bound to it. And because it's so small, it gets readily filtered through the kidney. So the net effect of that function then is to reduce the level of retinol binding protein 4 in blood, which, of course, would reduce the native complex Keystone, Jennifer. The native complex of RBP4 retinol and TTR, that would go down. And of course, once that goes down, the amount of vitamin going into the eye goes down. And of course, all the retinoids cascading downstream, including those end product bisretinoids would also decrease. So this is the mechanism whereby we intend to slow lesion growth by going after these bisretinoid toxins, which we know are implicated in the progression of lesions, spreading of lesions in both Stargardt disease and Geographic Atrophy.

Thanks Nathan . Dr. Michaelides, what are your thoughts on to [indiscernible] approach from a mechanistic standpoint. Does your enthusiasm differ from Stargardt to GA? Or does it make sense in both diseases in your view?

It makes sense in both diseases. I think Nathan made the argument very compellingly. I like the fact that it is targeting what we think believe to be the underlying central pathogenesis of disease in both. I like the fact that it's also reducing the amount of retinol available to the eye specifically. So there's no reduction in retinol availability to any other tissues. There's no systemic deficiency. It's targeted to the target organ. And also, I like the fact that it's reducing the amount of retinol, but it's not affecting the rate at which the visual cycle operates. And that's sort of quite different to some of the other agents out there. So yes, mechanistically, I like it, and let's see if it works.

Yes. So that takes us to our next focus. The data to date for Tinlarebant. I know a lot of the data we've seen have been from the Phase II study in Stargardt. There are some interesting new analyses that Belite presented out of ARVO recently. Nathan, would you mind walking us through that data?

Sure. Absolutely. Yes. So this is the -- it's an overview first to give everyone a sense of exactly what we're doing. The Phase II study that you see, box there, that was the open-label study that enrolled 13 adolescent Stargardt subjects again, open-label study, 2 years in duration. This is the one we recently completed, where we've had a lot of very interesting data come out of, very, very promising efficacy and safety data. Just an overview of the study. Important thing to note, these 13 subjects coming in had a very early stage of the disease where they just have the autofluorescence lesions. So they haven't yet converted to the atrophic lesions. Based upon natural history and the size of the location of these autofluorescence lesions, we predicted that majority of them would convert to atrophic lesions over a 2-year period, which was a study period. So the autofluorescence lesions are called questionably decreased autofluorescence. That's where you see that abbreviation. And they will convert or transition into definitely decreased autofluorescence, which are the atrophic lesions. So we're in this study, we're monitoring that transition. And in those subjects that actually grow incident atrophic lesions, we want to measure that growth rate. So I'll show you that in a moment. And then you can see the pharmacokinetics and pharmacodynamics of Tinlarebant at 5 milligrams daily. This is from the Phase II study. So you can see here, there's a very nice correlation between the increase of Tinlarebant in blood that's shown in blue and the decrease of retinol binding protein 4 in blood that has shown as a percent of the baseline value. So by the time we get to what we call steady state, we're getting about a mean 80% reduction of retinol binding protein 4 in blood. And then at the end of month 24, we will withdraw the treatment. You can see there's a rapid removal of Tinlarebant when you see the blue line was straight down. And the retinol binding protein 4 bounces right back toward the baseline value. So this is very nice to see this, a very rapid reversibility of the pharmacogenetic effect. Should there be any untoward concern where you need to bring a patient back to their baseline status, you can do so quite readily within a month. These are the data from the patients in the study. We did lose one subject to follow-up at month 12. So we're talking about five subjects here in this efficacy analysis that you're looking at. We're looking at first, as I said before, the transition of the autofluorescence lesion to atrophic lesion. And strikingly, 5 of 12 subjects, that's 42% of the cohort never converted to atrophic lesion over time. And again, as I said, we would have predicted that most of those kids would have converted, but to see 42% not convert despite having very significant autofluorescence lesions is actually quite promising. The other interesting point is that in those subjects that have actually converted to atrophic retinal lesions, most of them occurred after month 12, so they were sporadically in month 12, month 18, but the growth rate of those lesions was considerably lower than the growth rate that has been seen in natural history from subjects that have similar baseline characteristics as subjects in our Phase II study. And that's shown in the blue line. This is from the largest natural history study of Stargardt's conducted today called ProgStar, largely enrolled adult subjects, but there was a cohort of younger subjects that matched our subjects in the Phase II, and we looked at just on the growth rate of those subjects and you can see in the blue line, there's roughly a doubling of the growth rate compared to what we see in the Tinlarebant treatment. And you can see the numerical data on the right-hand side. So this is a very, very promising. We're slowing the transition of the autofluorescence into atrophic lesion. And then once the atrophic lesion is formed, we're seeing a slowing of that growth rate. These are all consistent with the MOA that I just explained earlier.

And then you showed some new data at ARVO. Can we go into that?

Yes. So we did a genotype-phenotype relationship analysis. We hadn't done this previously, of course, the genetic data we've had, but we are waiting for it to get analyzed by Dr. [indiscernible]. He's the individual who identified the gene associated with Stargardt's disease that is the ABCA4 gene. So he read these genetic data for us, and he provided the outputs that you see here. The primary score is called the CADD score, the Combined Annotation Dependent Depletion score. And it's basically a numerical value that tells you how severe a lesion is -- sorry, a mutation is. Values that are 20 and above are predicted to be among the 1% most deleterious, is where you can see here is that 11 of 13 subjects have very high CADD scores. That means they have very severe biallelic mutations, there's only 2 subjects that don't have severe biallelic mutations. Subject 3 and 5, you can see they have an allele that is moderate on each -- for each subject. But if you look at the in vitro testing, you can see that both of those model allele were in fact found to be pathogenic in, in vitro testing. So suffice it to say that overall, this cohort is very largely and severely biallelic-mutated, that is they're going to have pathogenic lesions. But despite having all these pathogenic lesions, 5 of those subjects I told you earlier, never transition to -- from an autofluorescence lesion to an atrophic lesion, and their autofluorescence was quite stable. So in these subjects, we've really stopped, we believe, the progression of the disease. That's one new piece of information that we've had There's another one as well regarding siblings.

Before we go into that Dr. Michaelides, when you look at this type of data, how does it play into your interpretation of the disease progression you've seen and the kind of data you see for Tinlarebant?

Sure. So it's very impressive. I mean, of course, obviously, it's 13 patients, okay? So the patient number is small, all right? But if we just park that, that inherent limitation of small numbers of patients, this is a very severe group of patients, the childhood onset disease is the most severe form of Stargardt disease. It progresses most rapidly. It generally has generalized involvement as we described, central and peripheral visual loss. So you could argue they're the hardest to prevent progression. I've always advocated for them because they progress rapidly. One should be able to see something early and have a bigger impact on this patient group, on these children. So to see this to actually prevent the inexorable progression of QDAF to DDAF is significant. And then even the ones that did progress did have new DDAF. The rate of reduction of 50% is huge.

You also presented this data? Nathan?

Yes. So yes, so the whole point here is that in -- well, first, going back to those 5 subjects, so the slowing of transition could not be attributed to mild [indiscernible] mutations, they're very severe. The other find is very interesting is that, we have 2 pairs of siblings that have the exact same genetic mutation, and that subjects 9 and 10, which are two brothers, approximately 1 year apart. And subjects 12 and 13, which are brother and sister, I think they're about 6 years apart. Why this is important is because there's been some claim that identical mutations predict an identical disease of course. And this is not something we've seen in our data set, and we're using these 4 patients as sort of an example of that. And as we go through the data, you'll see what I'm talking about in just a moment. So here it is, actually. This is sort of a separate analysis, but it's sort of two in one, if you will. One, we looked at the visual acuity outcomes prior to coming in the study. So we're looking at visual acuity in the subjects prior to enrolling into the study, and we're looking to see which subjects have bilateral vision loss that is vision loss in both eyes prior to coming into study. Turns out there was a total of 6 subjects that had a mean of 10 letters loss per year in each eye. So that's significant in over a 2-year period, which is our clinical study duration, 2 years. We predict you'd have roughly 20 letters lost. Put a note on that because that's not what happened, but it's significant to note that these kids were losing significant vision prior to coming into the study, and they don't have atrophic lesions at this point. They only have autofluorescence. So this does tell us initially that autofluorescence encroaching into fovea does in fact -- impact vision, more on that later. But the other point now is if you look back at subjects 9 and 10, which again are identical mutations, they have the exact same mutations on each allele. They have a similar disease duration approximately 1 year, but they have very different visual acuity outcomes. You see subject 10 was losing letters over time before coming into the study. But the brother subject 9 didn't lose any, in fact, fared quite well. And again, subjects 12 and 13, they have a different disease duration. But if you look, subject 13, again, identical mutations is subject 9 and 10, subject 13 only had 2 years of disease duration but lost a mean of 12 letters in each eye. Meanwhile, the sister with 8 years of disease duration did not lose any visual acuity, at least not significantly. So these data are telling us just from a genetic perspective that visual acuity outcomes, at least are not predicted by identical genotypes.

And another question maybe for Dr. Michaelides. Does that analysis fall into what you see in your patients? Like does 1 sibling -- is 1 sibling predictive of another in your experience?

No, almost never. So it's very common to have significant within family variation and between family variation even when they harbor exactly the same disease-causing mutation. It's actually a characteristic of inherited retinal disease. So it would be very unusual and undesirable, not recommended to be trying to predict disease progression based on what happened to a sibling. So I'm not surprised by this data. We have our own data at Moorfields that we've been keeping with this. We published it. I know that the Dutch groups have published similar findings in sibling showing how those siblings are [ discordant ] in terms of their rate of progression, even when their phenotype of baseline might look reasonably similar, but the progression is very different.

Nathan, do you want to kick on?

Yes, these are the visual acuity outcomes are broken out in two different groups. On the left, you have the visual acuity outcomes in all subjects and you can see here, over 2 years, there's a mean letter loss of about 5 letters that's 2.5 letters loss per year. This is well within a standard error or deviation of the BCV Assessment. So we call this stabilized vision, and we're very happy to see it because it is telling us that things are slowing down, right? The lesions are slowing down, visional acuity is stable. So this is a very positive outcome. On the right-hand side, you see a similar analysis, but this is just for those 6 subjects that were losing 10 letters per year before coming into the study. While on study, they only lost about 1.9 letters per year. So we've significantly slowed visual acuity loss in this small cohort of subjects. Again, it's a small group overall, but the trends are going in the right direction. And again, everything is in keeping with the mechanism of action of the drug. The slowing of the lesions encroaching into the fovea, you would predict would have some effect on slowing or stabilizing visual acuity, and that's exactly what we're seeing here.

And I want to turn it back to Dr. Michaelides again. Can you confirm in your experience, does the pre-enrollment mean bilateral loss of 10 letters. Would you expect that to be predictive of future loss rate?

It's certainly within what I would predict would be the visual loss. These are children that lose visual acuity really quite rapidly throughout their teenage years. The magnitude of the change, I think, is significant. Even if it hasn't kept it dead stable, it significantly slowed the rate of visual acuity loss and the fact that you have structural function going together is also reassuring. Again, of course, it's 13 patients, but the data is what it is. It is promising, it's compelling. It looks plausible.

Nathan, what should people know about QDAF and DDAF?

Yes. I think what's important on the slide really is to sort of the take-home messages that visual on the upper right-hand side, the DDAF lesions largely form within the area of QDAF. And so the overall size of the lesion doesn't change. So you can see here the baseline image. This is for the subject 10, by the way, this is the actual data. This is the autofluorescence lesion at baseline. And then at month 24, you can see within the autofluorescence lesion grew some atrophy, which we call definitely decreased autofluorescence. And the graphic on the bottom is it's basically a histogram to show you there's a clear proportionality between the decrease of the autofluorescence size and the increase of the atrophic lesion size in each subject, you see this very interesting correlation. Only in the subject 5 was there a lesion that was identified outside or away from the initial lesion that was identified at baseline. And we believe this is really attributable to an image error or sort of a lesion was there, but it didn't get picked up by the region finding software or the readers that were grading this image because it essentially appeared out of nowhere and it was probably there all the time. So this is very important because it sort of leads us to this next idea about new imaging modalities for assessing atrophic lesions in patients. And so -- as I mentioned to you before, before coming into this study, all of the subjects had only autofluorescence lesions. The region finding software that comes with the Heidelberg instrument that is used to visualize the lesions in the retina basically is used with a reader. So basically, the software identifies areas of changing autofluorescence and then the reader goes in and essentially draws a boundary or identifies really where the atrophic lesions is. So there's really some subjective input or you could call it bias for doing this type of reading. Our reading center, [ IRCC ] and Palo Alto has developed a new rating algorithm and it really does remove the subjective reader bias because it's based on a pure mathematical classification of lesions. It's looking basically at pixel density, single pixel densities, and it's grading them based upon a greater scale overall from really healthy retina to the darken area, which is the optic disc. So it's looking at a continuum of gray levels. It's removing subject to reader bias, and it's highly sensitive and highly reproducible. Moreover, it's focused purely on the 6-millimeter area, which is essentially your macula. Of course, we can look at the 1 millimeter and 3-millimeter million 6-millimeter ring, but this is focusing right now on just the 6-millimeter ring. And when they use this new imaging or grading modality to look back at those images from baseline and forward, we saw that, in fact, there was 12 eyes of 8 subjects that actually had atrophic lesions within the macula at baseline. And again, this was only accessible through this new grading method. So Jennifer, you go to the next slide, I'll show you the growth of those lesions. So on the left-hand side, are though the data from those subjects, the 12 eyes of 8 subjects that had the atrophic lesions identified within the 6-millimeter ring at baseline. You can see that atrophy tends to grow into the macular area up to about month 16. And then from month 16 to month 24, it's essentially halted. By the way, the dotted line, you see the dotted redline is a third order polynomial, it's a function drawn through the data points. So you can see the trend line. So you can see very clearly there is a stasis of growth into the macular area from month 16 to month 24 in these subjects. And on the right, we look at the percent of the lesions within the 6-millimeter zone. So all of the 6 millimeters almost occupied with lesion, it would be 100%. But you can see in our subjects. It starts at 4, goes to 7 and really doesn't change much more over time. It's 7% involvement into the macula of the 6-millimeter zone. So this is really, again, that's consistent with what we should previously, that is slowed lesion growth, stabilization of visual acuity because you got to know that if you're slowing lesion growth in the macula, you will definitely be slowing visual acuity loss or at least preserving whatever healthy vision is there.

So is my interpretation of it correct that using this new imaging method allows you to better detect the treatment effect in the completed Phase II trial? Is that what the sort of goal.

Well, I wouldn't say it's about treatment effect. It's a better way to identify the atrophic lesions. That's the most important element. That's the key to this. And it's very fast. So in cases where two readers disagree about a certain single image, typically, that has to go to an arbitrator. The arbitrator is sort of the tiebreaker. That process can take up to 2, 3 hours at some reading centers. This imaging modality, this grading out modality does it in the seconds. So it quickly can discern this at a very high level. And as I said, at the single pixel level. So we're moving forward hopefully to get this validated, we'll be speaking to the FDA about that because we're really confident this is really a superior grading method to use forward in our Phase III study.

And in the Phase III trial, one design difference is that patients at baseline do have atrophic lesion is correct?

Absolutely. That's important, Jennifer, because the primary endpoint for approval in Stargardt's and GA is slowing the growth of the atrophic lesion. So you have to start with some atrophic lesions at baseline as a reference point to measure subsequent growth.

Dr. Michaelides, do you have any thoughts on this new imaging portion? Does it feed into, how you think about the Phase III program?