Good morning, everyone, and thank you for joining the H.C. Wainwright Fourth Annual Ophthalmology Virtual Conference. My name's Arabella, and I'm an analyst on the corporate access team at H.C. Wainwright. H.C. Wainwright is a full-service investment bank dedicated to providing corporate finance, strategic advisory, and related services to public and private companies across multiple sectors and regions. We have a total of 24 publishing senior analysts and over 650 companies covered across all sectors. If you would like more information, please go check out our website, hcwco.com. From a logistics standpoint, please make sure to reference your virtual conference online portal that provides your individual links to your meetings and all presentations. With that said, have a productive and enjoyable day, and I'd like to introduce our presenter, Nathan Mata, who is the Chief Scientific Officer of Belite Bio.
Thank you, Arabella. To start, I wanna give you an overview of Belite Bio. At Belite Bio, we're currently advancing through phase III development, our lead asset, Tinlarebant, in two separate but somewhat related indications. The first is a genetically inherited macular dystrophy that primarily affects children. It's known as Stargardt disease. The second one is on the opposite end of that age spectrum. This disease, this is known as advanced dry age-related macular degeneration, which, as the name implies, affects the elderly. In both of these diseases, the accumulation of toxic byproducts of vitamin A is implicated in disease progression.
Because these byproducts are formed from circulating vitamin A, our approach is to reduce vitamin A delivery to the eye as a means of slowing the production and accumulation of these compounds, and eventually slowing the course of disease. Now, because these compounds appear early in the disease course, our treatment is really intended as an early intervention for both of these indications. I'll talk more about the MOA as we move forward, but first, I wanna give you an overview of the clinical trials that we've initiated. The first is a Phase II trial, a 2-year trial that we have actually recently completed. This was performed in 13 adolescent Stargardt kids, aged 12 to 18 years of age, and we have very, very promising safety and efficacy data from that study. I'll share with that- I'll share that data with you in just a moment.
The second study we have is a phase III, 2-year study that we call DRAGON. This study completed enrollment of 104 subjects, aged 12 to 20 years of age. We're roughly about 1 year into that 2-year study, and we're expecting an interim analysis from our DSMB in the fourth quarter of this year. We've also initiated another 2-year study, a phase II/III study called DRAGON2. This study is focused on patients in Japan, U.K., and U.S., and is really designed to take advantage of a recent designation we received from the Japan regulatory authorities, known as Sakigake or pioneer drug. It is essentially equivalent to a clinical breakthrough therapy designation that the FDA grants for drugs that are particularly promising for unmet needs in disease. So these are important studies.
The nice thing about the DRAGON2 study is there's the potential here now because the Japan regulatory authorities have shown a willingness to express or to give out approval based upon just a single phase III study, so we have an opportunity for an early approval in Japan. The other nicety of the DRAGON2 study, it could be used as a confirmatory study for DRAGON1, if in fact it comes that that is actually needed. And finally, in geographic atrophy, we have another two-year study, a phase III study that we call PHOENIX. That study is currently recruiting. We're shooting for about 429 subjects. We're roughly about halfway into that enrollment goal. We expect to close enrollment by Q1 of next year.
The following year, Q1 of 2026, would be the interim analysis from that, and of course, one year later would be the top line 2-year data from that phase 3 study in GA. A little bit more about Tinlarebant. So exactly how does it reduce vitamin delivery to the eye? Well, it targets a protein called serum retinol binding protein 4, which is the sole carrier protein for delivery of vitamin A from the liver to the eye, and of course, it's oral once-a-day tablet. As I said before, it's meant to slow the accumulation of these toxic products that are implicated in the progression of Stargardt disease and GA. And I'm gonna show you some of the mechanism in more detail in a moment.
We believe that, you know, early intervening with these two diseases actually goes after a point of disease which is not mediated by retinal inflammation. That's important because once the inflammation kicks in, the disease is much more hard, much more difficult to manage. So again, our one of our differentiators is early intervention, in addition to being an oral once-a-day tablet. In terms of the market opportunity, there are no approved treatments for Stargardt's, and there are no orally approved treatments for GA, and we think that's significant because currently, right now, these patients that are getting treatment for GA have a tremendous treatment burden. They have to go to the clinic every other month or every third month to get intravitreal injections of these anti-inflammatory agents in their eye, right?
So with an oral once a day, we could significantly reduce the treatment burden for these patients. We're really optimistic about being able to do that. We have Fast Track designation, Rare Pediatric Disease designation, and orphan drug status in the U.S., EU, and Japan. And as I mentioned before, we have a pioneer drug designation in Japan for Stargardt disease. Our patent portfolio is quite strong, 14 active patent families. The majority of those are composition of matter patents, which won't expire until at least 2040, and that's without any patent term extension. So let's get a little bit more into the mechanism of action of Tinlarebant and exactly how the disease progresses and what our drug is doing to correct it or address it. This is a schematic of the visual cycle, basically the back of the eye.
There's three compartments: the bloodstream, and then the intervening tissue in the middle of the back of your eye is called the retinal pigment epithelium, and just above that are your photoreceptors. On the bottom right-hand corner, what you see is this complex of RBP4, ATROL, and TTR. ATROL is the abbreviation, chemical abbreviation for vitamin A that stands for all-trans-retinol. This is the complex that gets liberated from the liver into the circulation and delivers vitamin A to extrahepatic target tissues. There's a couple of important things to know about this complex. First, it essentially cocoons vitamin A in sort of a protein shell, so it protects vitamin A from degradation as it traverses through the bloodstream.
Secondly, it's a very large molecular size complex, so it resists filtration in the kidney, allowing to maintain a high, steady state level of vitamin A in the blood. But most importantly to note is that only the eye actually recognizes this complex and requires it for uptake of vitamin A because the presence of an RBP4 receptor. So the vitamin A absolutely requires a vitamin A delivered on the RBP4 receptor in order to uptake it. So once this complex docks onto that receptor, vitamin A is admitted into the back of the eye. It goes through a series of enzymatic reactions, where it's eventually converted to rhodopsin. Light activation of rhodopsin liberates the aldehyde form of vitamin A, called all-trans-retinal. This is pumped out of the eye with a very special protein called ABCA4.
This protein essentially grabs aldehyde from inside the retina and flips it outward, availing it to another enzyme for further detoxification and re-entry back into the visual cycle. So the function of this ABCA4 protein is very critical because if that aldehyde lingers within the retina, it can actually destroy cellular membranes, and that's what's happening in Stargardt's disease. So in Stargardt's disease, these patients have genetic mutations which affect the function of the ABCA4 protein. Consequently, the aldehyde does not get out of the retina as efficiently, and it condenses within the retina, basically binding to other aldehydes, forming these dimers of vitamin A that are called bisretinoids. These are the byproducts that I mentioned earlier. The primary bisretinoid that's been identified in human tissue is known as A2E, and this compound has been shown to kill retinal tissue through diverse mechanisms.
So in Stargardt disease, the whole reason there's retinal pathology is because of the accumulation of A2E and related bisretinoids. What does Tinlarebant do? Well, Tinlarebant works in the liver to bind to retinol binding protein, actually competes with vitamin A for binding to the active site. In fact, it has a 100-fold greater affinity for RBP4 than does the native ligand, and it doesn't allow the binding of transthyretin. Consequently, what gets liberated into the circulation is a very small complex of Tinlarebant with retinol binding protein 4, and it gets readily filtered to the kidney. The net effect being a reduction in the wild-type complex of RBP4, TTR, and retinol that's normally delivering vitamin A to the eye, and when that complex goes down, vitamin A delivery to the eye goes down, and of course, all the retinoids cascading downstream, including the bisretinoids, also decrease.
I should mention that in geographic atrophy, these bisretinoids accumulate as well, but not because of a broken pump, but rather because of pathology beneath and above the retinal pigment epithelium that interferes with vitamin A metabolism in the eye. And in fact, we've actually identified A2E in post-mortem eye globe samples from patients with GA, so we know it's there. But because these bisretinoids contain vitamin A, they actually fluoresce. So we can see them clinically when ophthalmologists look and evaluate patients with this disease. You're seeing here a series of panels, retinal images, over a period of about 4.5 years of disease duration in a patient with Stargardt disease on the top and a patient with geographic atrophy on the bottom. Let's start with the patient at baseline, the Stargardt patient in the upper left-hand image.
You see these two central areas of atrophy in the center of the image, but peripheral to those lesions, you see these zones of autofluorescence. That's where the bisretinoids are. And now, if you go from baseline out to the end of the observation period, what you can see is those lesions actually spread into the autofluorescent zone, and the autofluorescent zone expands in a centrifugal manner to accommodate that dead retina. So here, what we're seeing is a cause and effect where the appearance of the bisretinoids causes the atrophy, and wherever you have autofluorescence, you will soon have atrophy. So it stands to reason if you can get rid of the autofluorescence, i.e., the bisretinoids, you can slow retinal pathology. We see the same pattern in the patient with geographic atrophy in the bottom series of panels.
The lesion's a little smaller here, and the autofluorescent presentation is a little different. It's like little punctate areas of light around the lesion. They're more clear at the 12-month time point. But now, if you compare the 12-month time point to the 55-month time point, which you can see those areas that were previously just autofluorescent, have now become retinal lesions, and they all have little zones of autofluorescence around their perimeter. So it's important to note that we recognize that geographic atrophy has a diverse etiology. There's no one specific cause of, of GA. There's, it's a multifactorial disease. So the real question is, to what extent do these bisretinoids contribute to the disease process in geographic atrophy? And we can answer that with a clinical study that I performed about 13, 14 years ago with a different drug called fenretinide.
So fenretinide was not developed as a retinol binding protein 4 antagonist. In fact, it was developed as an anti-cancer drug. But because of its chemical similarity to vitamin A, it can actually act as an RBP4 antagonist. And in fact, in all of the oncology studies that evaluated fenretinide, patients experienced a dose-dependent reduction in retinol binding protein 4. So I repurposed fenretinide in a two-year proof of concept study, enrolling 246 GA patients to answer the question: Would reducing retinal delivery to the eye have any effect on slowing lesion growth and preserving vision, potentially? And the short answer is yes. What you're seeing here is the lesion growth data from that study.
The black bars show you the increase of lesion expressed as a % from baseline in the placebo group, and the green bars are from our high-dose group, the 300 milligram group. So there was something very interesting about this high-dose group. There were a group of subjects that were very responsive to treatment and had at least a 70% reduction of retinol binding protein 4. In those subjects, there was a profound slowing of lesion growth that began at month 12 and persisted through months 18 and month 24. In those subjects that did not have that profound slowing of lesion growth, there was absolutely no change in the lesion growth. They looked just like placebo.
So these data are important because they're telling us you need to achieve a certain level of RBP4 reduction, that being at least 70%, before you can start effecting a change within the eye. Another important thing about these data is we also saw a stabilization of vision, in fact, a complete halting of vision loss in those subjects that had that response to treatment. Meanwhile, the placebo group and the non-responding group continued to lose letters. So we have a very nice visual acuity benefit and a very profound lesion growth reduction in this study. The problem with this study was that only one in every three subjects experienced this profound reduction of RBP4. That was owing largely to the low, low bioavailability of fenretinide. It had to be taken with a high-fat meal at dinner. Many patients didn't comply, particularly during the second year.
Secondly, it had very terrible potency. It only is equally potent as vitamin A for binding the target. But with Tinlarebant, we've overcome those deficits. First of all, Tinlarebant is a purpose-built RBP4 antagonist. It's not a side effect of the drug. It has great bioavailability, so it can be taken without regard to food, and it has a hundredfold greater potency than does fenretinide. So this is a superior RBP4 antagonist that we feel very confident going back into GA with to achieve this level of efficacy, if not better, but in all subjects, not just a subgroup. So let's go now into the phase 2 study of Stargardt's, where I told you I'd share some data with you. Showing you on the left-hand side is the clinical trial design overview.
Perhaps the most important thing to point out in this study is that these subjects came in with only autofluorescent lesions at baseline. They have not, not yet converted to the atrophy. The autofluorescent lesions are referred to as questionably decreased autofluorescence, whereas the atrophic lesions are referred to as definitely decreased autofluorescence. So we wanna watch the conversion of these two lesion types in this study. We've determined that the 5-milligram dose was effective to get to below that 70% reduction. Again, that is our sort of threshold criteria for potential efficacy. And on the right-hand side, you can see the pharmacokinetic and pharmacodynamic profile of that dose in these kids. The blue line shows you the level of Tinlarebant in blood, the red line shows you the decrease in RBP4, and you can see we're getting about a mean 80% reduction with the 5-milligram dose.
Until we withdraw the drug, there's a rapid clearance of Tinlarebant from blood and a rapid increase rather of RBP4 as it goes back toward the baseline value, showing a nice reversibility of the pharmacodynamic effect. Another important thing to understand about Stargardt studies is you really have to understand the genetic profile. There's over 1,500 known mutations that are thought to be associated with Stargardt disease. Not all of them are pathologic. Many, in fact, are benign or mild. But in our patient cohort, 11 of 13 subjects were found to have severe biallelic mutations, and in those two subjects who had a moderate allele, you can see here subject 3 and subject 5, in vitro testing showed those alleles to be pathogenic. So our entire cohort has very severe mutations that would predict a rapid disease course.
Incidentally, the CADD score you see here is a designation in which values above 20 predict the most, 1% most deleterious mutations. So again, our subjects are very highly affected. But despite these significant genetic mutations, we have 5 subjects that never transitioned to atrophic lesions. In fact, their disease was essentially static. They didn't go anywhere, so that's very profound. And in the subjects that did grow atrophic lesions, as we showed in prior presentations, the growth rate of those lesions was significantly lower than natural history subjects that had the same baseline characteristics, approximately twofold lower. Another interesting thing about this cohort is we saw 2 pairs of siblings that had the exact same mutation. The reason this is important is because there's a competing company that is using as a premise the idea that identical mutations predict identical disease course.
So this gives us an opportunity to evaluate that to see if that's true. I can tell you from the outset, it's not true for visual acuity. What we did here is we looked at the visual acuity loss in subjects prior to enrollment. We identified 5 subjects that had bilateral vision loss of 10 letters. That means they were losing a mean of 10 letters in each eye over time, and those are shown in bold here. Regarding the genetics, look at subjects 9 and 10. They had the same genetic mutation, but yet... and they had the same disease duration, but one brother is losing vision, the other brother is not. Subjects 12 and 13 are a sister-brother pair. The sister has had a longer disease duration than the brother, yet it's the brother who's losing significant vision, not the sister.
So at least in terms of visual acuity, it doesn't look like identical genetic mutations predict identical disease course. Here's the profile of best-corrected visual acuity in all subjects shown on the left, and in those subjects with bilateral vision loss prior to coming to study on the right. In all subjects, we get a mean loss per year of about 2.5 letters, and in those subjects with a prior 10-letter loss per year, we're now only seeing 1.9 letters. So we've significantly improved visual acuity in these subjects. Going forward to another very interesting observation, so I told you earlier that looking at the traditional image of retinas, we didn't find any atrophic lesions at baseline in our subjects.
That evaluation was done with a software called RegionFinder, which is really subjective to a lot of reader bias, because typically, readers have to score these images visually. Not each reader will score the image the same way, so there's a lot of intra and intra-reader variability. And also, they're looking across the whole retina for different variances. They're not focusing specifically on real key areas like the macula. So in order to address those shortcomings, our reading center has developed a new grading method, which is an AI-based method. It's purely computer-driven. It doesn't use a reader at all. It uses a mathematical classification of lesions to score the intensity of gray from healthy retina to the optic nerve disk, which we consider dead retina. And using this...
And by the way, I should mention, focuses just on the macular region, which is the 6-millimeter zone here in the center of the eye, and the images you see here are taken from one of our subjects. So this, using this grading method, we actually found 12 eyes of 8 subjects that did have atrophic lesions in the macula at baseline that the RegionFinder software did not pick up. So we went back and reread all the images to look at what the growth pattern looks like for these macular lesions, and that's shown here. What you can see, there's pretty linear growth of lesions into the macula until in month 16, and then after month 16, for the following 8 months, it completely stops. So there's no further growth into the macula.
Shown on the right-hand side is the same data, but expressed as a percentage, where 100% involvement would mean the total, the all 6 millimeter zone is occupied with lesion. You can see our kids never get above 7%. So we have halted growth into the macula, and this is, we think, why there's stabilization of vision. Because if you can stop lesion growth in the macula, you will preserve vision. So the data are internally consistent. Here's the AE profile. I can tell you we've had no systemic drug-related AEs whatsoever, and no AEs that have led to withdrawal. What we're seeing are two forms of drug-related ocular AEs that are very mild and manageable. These are light-mediated events, so we can mitigate the incidence severity of these in patients by moderating transitions from light to dark.
But suffice it to say, this is a very well-tolerated drug over time. A little bit about our study, our study in geographic atrophy. I first wanna show you that the same 5-milligram dose that we saw produce an 80% reduction in our adolescent Stargardt kids produces the same dose in healthy adults with a higher BMI and higher age range, meant to match that of GA subjects. So we can use the same dose, we can use the same trial duration. In fact, the study designs for the phase 3 Stargardt study and the phase 3 GA study are essentially identical. Only the disease indication is different, and the number of subjects being enrolled is different. Higher, of course, than the GA study to match the higher prevalence of disease in the population.
Now, because of the similarity in the pathophysiology of these diseases and the similarity in the trial designs, and the fact that our Stargardt studies are proceeding ahead of the GA, and they're reading out well, we believe that whatever we see in the Stargardt phase 3 will be predictive of what we can expect to see in the phase 3 in GA. And again, we're very, very optimistic, based upon the very promising phase 2 data. So with that, I'll thank you for your time. Turn it back over to the moderator.
Thank you so much to Nathan for leading such an interesting presentation. We really appreciate the time and effort that went into putting it together, and we're so grateful you were able to attend our conference. And thank you again from the whole H.C. Wainwright team.
Thank you.