Hi, good morning, everyone, and welcome to the Belite Bio session. Happy to have Nathan Mata here, CSO of Belite, and also Hendrik Scholl, Chief Medical Officer. Maybe we can just start out by giving everyone an introduction, an overview of the company, and just sort of start with that origin story and how you move into, and then move into the programs themselves.
Happy to do so. I'll kick off. We're Belite Bio. We're based in San Diego, California. We are a biotech company focused on advancing an oral once-a-day treatment intended for the therapeutic intervention in two different but somewhat related diseases: Stargardt disease, which is a juvenile inherited macular dystrophy, and age-related macular degeneration, which most people are familiar with, which, of course, is associated with aging. In both of these diseases, the accumulation of toxic byproducts of Vitamin A is implicated in disease progression. What our treatment does is reduce the amount of Vitamin A going into the eye as a means of slowing the accumulation of these compounds and therefore slowing disease progression and preserving vision. This drug is called tinlarebant. As I mentioned, it's an oral once-a-day tablet. It targets a protein called Retinol-B inding Protein 4.
This protein is the sole carrier protein for delivery of Vitamin A from the liver to the eye. As I mentioned before, the toxic byproducts that are implicated in disease progression in both of these diseases are derived from Vitamin A. By reducing the amount of Vitamin A going into the eye, we have a chance of slowing the accumulation of these compounds and, of course, slowing disease progression. We're focused on two indications, as I mentioned, Stargardt disease and geographic atrophy. If you look at the top of this overview slide, you see our trial designs in Stargardt disease. We've completed a two-year open-label study in adolescent Stargardt disease, which we see very promising safety and efficacy data. Based upon the promising data from that phase two study, we initiated a placebo-controlled phase three study. This is a two-year study, a global trial called DRAGON.
This study enrolled 104 adolescent Stargardt patients aged 12 to 20 years of age, and they're receiving the drug tinlarebant daily, once daily. This trial actually had an interim analysis in February where we received very positive information from our DSMB, which told us essentially that we're seeing efficacy in the data set. This is very promising. In addition, we have a very, very promising safety profile. The dropout rate in this study was less than 10%, and it's nearly completed. It's going to read out by the end of this year. That's the DRAGON study, the first phase III two-year study of tinlarebant. The other study we have going, which is also a phase III two-year study, is called DRAGON 2. This is a smaller study enrolling 60 subjects, the same age range. It's the same adolescent Stargardt patient population.
The difference with this DRAGON 2 trial is it's more focused on geographic regions in Japan, the U.S., and the U.K. It really is designed to take advantage of a recent designation we got from the Japanese Regulatory Authority. This is called a SAKIGAKE or Pioneer Drug Designation. It's equivalent to the clinical breakthrough therapy designation that you would receive in the U.S., which would help you expedite your development of your drug. Hopefully, we'll be able to get approval in Japan before any other country in the world. That's pending. That trial is actually still enrolling. We expect to close that enrollment sometime around September of this year. Of course, two years from that time point will be the top line readout. Our study in geographic atrophy is called PHEONIX. This is also a phase III two-year trial enrolling geographic atrophy subjects.
We're going to get 500 subjects in this study. We're almost to the enrollment number now. We believe we'll be able to close that enrollment in July at 500 subjects. That is a two-year treatment trial. In both of these studies, all subjects are receiving the same 5 mg dose of tinlarebant because in dose finding studies, what we've determined is that the 5 mg dose is effective to reduce the Retinol-Binding Protein 4 to about an 80% reduction below the baseline. In prior clinical studies, that level of reduction has been shown to lead to a slowing of lesion growth, which is the primary endpoint in both these diseases, to slow the growth of atrophic lesions in the retina of these patients with Stargardt disease and geographic atrophy.
One of the differentiators of our treatment versus the currently approved treatments for GA, the injectables, that is, the intravitreal injectables, is that our treatment, of course, is oral. That's the first thing. We are focused on treating patients with earlier stage disease because these molecules that are basically causing the pathology emerge early in the disease stage. We believe we can attack the disease early before there's really significant loss of retinal tissue or vision. Obviously, there's no approved treatments for Stargardt and no oral approved treatments for GA. We hope to be the first in both of these categories. We've received various designations, as you can imagine, being an orphan drug, various designations across the U.S., EU, and of course, as I mentioned, in Japan. We have a very strong patent family, 14 active patent families.
Most of these are matter of composition, not expected to expire until 2040. That's without any patent term extension. If I just go really quickly, I'm going to skip the market slide. You can see very, very briefly what the market overview looks like in both Stargardt disease and geographic atrophy. It's huge, to say the least. Here's the mechanism of action. I want to go over this very briefly just to have an idea about exactly what we're doing. Our drug does not intervene in the visual cycle. Actually, as I said before, what it does is it targets a protein called Retinol-Binding Protein 4, shown here in the lower right-hand corner. In the liver, Retinol-B inding Protein 4 binds to Vitamin A. This is A2. This is the chemical abbreviation for Vitamin A. Once that binding occurs, another protein called transthyretin binds to that complex.
What gets liberated into the circulation is a very large molecular size complex comprised of RBP4, Vitamin A, and transthyretin. Because it is so large, it resists filtration in the kidney. This is a mechanism whereby you can maintain a high steady state level of Vitamin A in the blood because, again, this complex is so large, it does not get filtered through the kidney. For the eye, it is very important to note that the eye has a unique preference for uptake of Vitamin A when it is presented on Retinol-Binding Protein 4. That is because of the presence of a Retinol-Binding Protein 4 receptor, which is not abundantly expressed in other tissues. Other extrahepatic target tissues do not have a reliance for Vitamin A uptake when it is presented on a Retinol-Binding Protein 4.
They can uptake Vitamin A from other carriers or in other forms. In the eye, it's a receptor-mediated process. The Vitamin A goes into the eye, goes through a series of enzymatic reactions where it's eventually converted to rhodopsin. Rhodopsin then is light activated, which releases an aldehyde form of Vitamin A called all-trans- retinal. This is a very reactive species of Vitamin A, and it's actually very toxic. If it accumulates in the eye, it can actually start destroying membranes. The way it gets out of the eye is through an active pumping process mediated by a protein called ABCA4. ABCA4 is essentially an enzymatic flip base, which grabs the retinal from inside the retina and flips it outward, availing it to another enzyme for further detoxification back to alcohol and reentry back into the visual cycle.
This is the normal processing of Vitamin A in a healthy, unaffected eye. In patients with Stargardt disease, there are genetic mutations that affect the function of this protein. Consequently, the aldehyde cannot be removed from the retina as efficiently, and it lingers within the retina where it condenses upon itself, forming these dimers of Vitamin A that are called bisretinoids. These are the toxic molecules I spoke about earlier. The most abundant bisretinoid toxin that's been identified in human tissue is known as A2E. This molecule has been shown to kill retinal tissue through diverse mechanisms. In Stargardt disease, it's very widely accepted that the reason for the initial pathology and eventual blindness is because of the accumulation of A2E and related bisretinoid molecules.
Of course, because these molecules are derived from Vitamin A, it stands to reason that if you can limit the amount of Vitamin A going into the eye, you can limit the production or the accumulation of these bisretinoid compounds. That's our approach. In geographic atrophy, it's important to note that these bisretinoid molecules accumulate similarly, not because of a broken pump or any specific genetic mutation, but rather because of pathology beneath and above this area of tissue called the retinal pigment epithelium, where all of these critical enzymes that metabolize Vitamin A reside. When that happens, there's an interruption of nutrient transfer across these cellular compartments, and that interferes with the processing of Vitamin A in this compartment. These bisretinoids can actually form locally right within the retinal pigment epithelium because of dysfunction of these different enzymes that metabolize Vitamin A.
Very quickly, I just do want to mention, from a clinical perspective, ophthalmologists can view these bisretinoids because they have an intrinsic autofluorescence due to their retinoid composition that emits a light, basically, when looking through a specialized camera. Here, what you see is a couple of case studies, a patient with Stargardt disease and a patient with GA, analyzed over time, looking annually at their lesion growth. What you can see, if we start with a patient with Stargardt disease at the baseline image here, you see these two blackened areas of tissue. This is dead retinal tissue that's never coming back. If you look peripheral to that tissue, you see this intense Zone of Autofluorescence surrounding those lesions on all sides. Those are the bisretinoid molecules.
Now, as you go forward in time annually through these images, what you can see is that dead retinal tissue actually spreads into the autofluorescent zone, and the autofluorescent zone continues to expand outward in a centrifugal manner to accommodate that dead retina. It shows you that wherever you have bisretinoids, you will soon have retinal pathology. The same thing we see in a patient with geographic atrophy. Here, the lesion is a little smaller in the lower left-hand image, but you can still see it. If you look peripheral to that lesion, you see these little punctate areas of autofluorescence. They're a little bit more clear here at the 12-month image. Those are bisretinoids.
As you go forward now in time, what you see is those little areas of autofluorescence slowly become atrophic lesions so that wherever you saw an autofluorescent little blip, you soon see retinal tissue. These are bisretinoids converting the retinal tissue into atrophic tissue that's never going to be revitalized. Because these are derived from bisretinoids that are sourced from Vitamin A, by limiting the amount of Vitamin A going into the eye, we believe we can slow the accumulation of these lesions and preserve vision in these patients. I'll stop there. That was quite a lot. I'm sure we've got a lot of Q&A lined up based upon that information. I'm happy to turn it back to Annabel for any questions.
Yeah. Maybe we can just start with some of the earlier phase II studies that you'd conducted.
I guess when we think about, and I'm going to start with GA because we're a lot more familiar with GA, but when you are talking about GA, we're looking at lesions, we're looking at inflammation. What is it that you saw? What were you measuring in phase two? Were you also measuring lesions, or were you measuring something else as far as the bisretinoids and the accumulation of the toxic material? What is it that got you excited about your phase two data that moved you, that got you moving into the phase three? Is it the same things that you were measuring as they've measured in past trials for GA, or was it something else since you're moving earlier in treatment?
The currently accepted endpoint for both Stargardt disease and geographic atrophy is to slow the growth of the atrophic lesions.
Basically, what you're seeing here in these images, these black blotches, is if you can statistically slow the growth of these lesions relative to placebo, that is an approvable endpoint. In phase two, that's exactly what we looked at, is we looked at the growth of atrophic lesions. It's very difficult to measure the autofluorescent area. That's not really an endpoint. In fact, the agency is only concerned about the death of photoreceptors. This black area of tissue represents the death of photoreceptors, which, of course, leads to blindness. That really is the endpoint that we've been looking at in all of our studies. Our pharmacodynamic biomarker is Retinol-Binding Protein 4. We know from a prior clinical study that a certain level of reduction, and that level of reduction is 70% or more, can lead to a slowing of lesion growth.
That was done with a different pharmaceutical product. It was a surrogate Retinol-Binding Protein 4 antagonist. It is not as effective and as potent and selective as tinlarebant, but it was used for POC, and that data was published by NiAN in 2013 in geographic atrophy. We use that data as sort of a precedent for what we need to do in terms of slowing lesion growth. We need to reduce the Retinol-Binding Protein 4 level by at least 70%. Over time, we believe that will lead to a slowing of the growth of these lesions because, again, they are spread according to the accumulation of bisretinoids in the back of the eye. Retinol-B inding Protein 4 is our biomarker.
We know once we get it down to a certain level, we're more likely to achieve a significant effect on slowing lesion growth in the retina.
Okay. Got it. In GA, you mentioned your ideal is to go earlier in treatment where they may not have as many lesions or they may not have the—it might be also a slower-growing stage of disease. How have you designed the phase three so that you can really explore the efficacy in these earlier stages of disease if you do not have as rapid a progressing stage once you hit the full GA with lesion growth and blinding or lesion death? Maybe you can talk about the differences between your trials in your specific stage of disease and the trials that we've seen in the past.
I think the biggest difference is the lesion size at baseline.
We're focusing on patients with smaller lesions at baseline. We've learned from other studies with a similar pharmacology as tinlarebant that lesions that get to a certain size, let's say in excess of 10-15 mm sq, that is the size of the lesion in the back of the eye, that the two-year treatment trial is not effective, let's say, long enough time to realize the benefits of a pharmaceutical approach like tinlarebant. If you go after lesions that are smaller, you have a greater chance in a two-year study of realizing or observing a treatment effect. I should mention that, thankfully, in GA, there's been a number of natural history studies that we know predictably what the lesion growth rate will be in various lesion size categories.
I can tell you, with respect to our recruitment and our enrollment for baseline lesion sizes, we're still in a very predictable growth range that we're not worried about, for instance, having a slower-than-expected lesion growth because, again, we can reference prior clinical literature that tells us within a certain size range of lesion what the growth rate will be. We feel comfortable about being able to achieve a treatment effect within a two-year range with our lesion sizes as selected.
Okay. Maybe if I can add, I mean, maybe you worry about smaller lesions growing not as fast, but there are ways to correct that, namely to correct for baseline lesion size. In geographic atrophy, you actually, if you do that correction, you bring the lesion growth to a linear growth rate.
The precision that you apply for measuring lesions for smaller lesions is comparable to larger lesions. Therefore, if you do this correction and you go for smaller lesion sizes, there's no reason to worry that your drug would not be able to slow progression or that the reading center would not be able to pick up that slowing by reading the images.
Okay. Got it. Maybe you can talk about enrollment into the trial. I think you in past needed 450 or 500 patients. How has that proceeded? How are you finding the patient willingness, given that some of them aren't as symptomatic and may not be as willing to treat? Maybe you can just talk about the dynamics there of enrolling such a trial.
Maybe talk about the enrollment, and I'll throw it to Dr.
Scholl to talk about, for instance, how these patients present and whether or not they're symptomatic. In fact, they're largely symptomatic. Talking about just the enrollment of the trial, it's actually gone very well. In fact, we thought that initially the approvals of Syfovre and Izervay, which are the injectable treatments for geographic atrophy, we thought that those approvals may slow our enrollment. In fact, it's quite the opposite. There are quite a large number of patients that are not interested in getting intravitreal injections. In fact, when presented with the opportunity to take an oral unapproved investigational drug or an approved injectable therapeutic, they largely opt to take the oral therapeutic because of the reduced treatment burden, right? These patients don't have to come to clinic. They don't have to get injections into the eye.
They can basically take the pill daily as a sort of like a vitamin supplement that they would take normally on a day-to-day basis. Enrollment has not been an issue. As I said, we're going after 500. We expect to close that enrollment probably in July. I think really there's a lot of interest from patients because, again, this is an oral treatment which has been shown to be relatively very safe thus far. I'd like to get Dr. Scholl's clinical opinion regarding how these patients present in terms of their vision loss or how they even come to an ophthalmologist to get diagnosed. Hendrik?
Yeah. Thank you, Nathan. A couple of considerations here. Number one, this is an elderly population. Life expectancy of patients that developed GA affecting vision is six to eight years.
We talk about an elderly population, and they typically are under regular care and would have had a diagnosis of intermediate AMD before they developed geographic atrophy. This is number one why patients would learn about such treatment trials or an existing treatment for geographic atrophy. Number two, even if the lesion stays outside the fovea in the beginning, right, many patients develop parafoveal lesions that would allow them to remain at 20/20 visual acuity, but they have a scotoma that is close or a blind spot close to the very center. They may very well and typically are symptomatic because it is still in the macula. They have visual field loss in the macula that may not affect recognizing small letters on a visual acuity chart. When they look at the newspaper, they may notice that large parts of the newspaper would not be visible.
Even if patients are at 20/20 visual acuity, they may very well be symptomatic. In actual fact, most of the patients enrolled into these clinical trials have foveal lesions and have some degree of vision loss.
Okay. Got it. Just out of curiosity, we are talking a lot about the intermediate stage disease. Is it only suitable for intermediate stage, or would it be also suitable for those in late-stage disease, even possibly as a complement to intravitreal injections?
By definition, right, we talk about late-stage. Geographic atrophy is one of the two late stages of AMD, right? Intermediate AMD would not come with any lesions. Number two, if you would like to target intermediate AMD, then you would need an approvable endpoint.
For intermediate AMD, other than visual acuity, and visual acuity typically is almost unaffected or within normal limits in intermediate AMD, there is none. I mean, we are conducting, in my academic activities, the so-called PINNACLE Study, which is one of the largest natural history studies in intermediate AMD. I can tell you it's difficult to agree on an endpoint that would be approvable, but tinlarebant would be an ideal drug to prevent vision loss in the future, right? Right now, what we concentrate on is patients that have, let's call it, real disease that eventually will become symptomatic or are symptomatic, and we have an approvable endpoint, namely the growth rate of geographic atrophy.
Great. Maybe in the time we have, I'd like to touch on Stargardt disease, which is obviously a very similar presentation.
Does this disease progress very much the same way as it does in GA, or does it have a slightly different presentation?
Maybe I can take the questions. We conducted the largest natural history study ever in the field called ProgStar Progression of Stargardt Disease Study. It was a worldwide international natural history study funded by the Foundation Fighting Blindness. What we found is that, number one, there are lesions that are almost identical to what we call atrophy in geographic atrophy. We coined the term definitely decreased autofluorescence. It is good that Dr. Mata is still projecting this image. You see on the top, as he explained, these large areas, we call them definitely decreased autofluorescence, which is kind of an intuitive term. This has been approved by the FDA and other regulatory agencies as an endpoint.
What we measured over time is that the progression rate shows pretty much the same variability. It also depends on baseline lesion size, which, again, can be mostly corrected by correcting for baseline lesion size. The progression rate, on average, is about a third to half what we observe in geographic atrophy. Having said that, since these patients have pretty much exactly 10 times the life expectancy when they develop symptoms, they're typically 10 to 20 years old instead of 70 to 80 years old. Even though the progression rate is only, let's say, a third or half, it is very significant for their visual performance for the rest of their life.
Okay. Got it. Okay. One question that we would have is that Stargardt is obviously a rare disease. Geographic atrophy is a very, very large population.
How can you balance the advantages of one being an orphan drug with its broader development plans? And how do you balance the two? And maybe you can talk about that dynamic.
Yeah. I think it's important to note, as I mentioned earlier, that in both of these indications, we're using the same dose. And of course, it's the same drug. So our Stargardt programs are ahead of the GA program probably by about a year and a half or almost two years. With success in our DRAGON trials, we expect to have approval for Stargardt disease first. Because it's an orphan disease, there'll be premium pricing there for that drug. It'll be in line with other orphan drugs. That pricing will go for a period of time until geographic atrophy gets approved, which could be two or three years, four years down the road.
At that time, we'll have to adjust the pricing because, again, the larger population of GA will basically sort of offset the smaller market in Stargardt, but of course, we'll have a smaller price. We don't expect to have any problems with that. These are sort of quality problems to have when you're worried about pricing. Right now, we're focused on execution in our studies and just making sure that we get through the goal line, the finish line with our DRAGON trials.
Yeah. Great. Okay. Maybe you can talk about just the next data points in the last minute or so and for each of the respective programs.
Right. In Stargardt disease, as I mentioned, the first phase III trial will end around September, and we'll probably have the study report available by end of the year or Q1.
That's the DRAGON trial. I didn't mention, but our DSMB took an interim analysis of that trial and recommended that we share the data with other regulatory agencies to seek drug approval. That recommendation would not have been made if, in fact, the data were not efficacious. We, as a study sponsor, are masked, so we don't really know the treatment effect. There's a limited number of people on our side that do know the treatment effect. Hendrik is one of those. That small team is actually leading the effort to go out to other regulatory agencies to share this data. We have a very promising outcome in DRAGON. That will be a trial that we intend to file on with confirmatory evidence from other studies.
Of course, our DRAGON 2 study is right behind that, roughly about a year and a half behind that, also in Stargardt disease. In geographic atrophy, as I mentioned, we will be closing the enrollment sometime around perhaps July of this year. In 2026, July of 2026 next year, that will be around the time of the interim analysis. One year after that, July of 2027, will be the top line two-year phase III readout in PHEONIX.
Intermediate-based use of the last couple of seconds, I can add that the interim analysis and the unmasked data were submitted to the FDA, and the FDA granted breakthrough designation last week.
Okay. Fantastic. On that note, I think we will close this out because we are a little bit over. Thank you so much for all the information. What an interesting program.
Thank you very much.
Thank you very much.