Belite Bio, Inc (BLTE) Earnings Call Transcript & Summary

Hello, and welcome to the Deutsche Bank Depositary Receipts Virtual Investor Conference, dbVIC. My name is Zaf Aziz, the Deutsche Bank team. I'm pleased to announce that our next presentation will be conducted by Belite Bio. Before I introduce our speaker, a few points to note. Please submit your questions in the questions box below the slides. Once the Q&A session has ended, don't log out, you'll automatically transferred to the Belite Bio booth where you can also continue to ask questions via chat and access shareholder materials. On a final note, all of today's presentations will be recorded and can be accessed by the Deutsche Bank website, adr.db.com. At this point, I'm very pleased to welcome Dr. Nathan Mata, Chief Scientific Officer of Belite Bio, which trades on NASDAQ under the symbol BLTE. Over to you, Dr. Mata.

Thank you very much. Greetings, everyone, and thank you for your attendance. At Belite Bio, we are advancing an oral once-a-day therapy intended as an early interventional treatment for macular degeneration. Shown here is an overview of our programs on the top. Until recently, we've had 3 clinical programs ongoing. We've recently closed a Phase II 2-year open-label study of our drug, Tinlarebant, in adolescent Stargardt subjects. That study closed with big promising data, and I'll show you some of that as we move forward. We also have completed enrollment in a Phase III pivotal study, our Phase III Stargardt study, also in adolescent Stargardt's disease, enrolling 104 subjects aged 12 to 20 years of age. We expect interim results from that study in mid-2024. In addition, we are currently recruiting a Phase III 2-year program in geographic atrophy, where we're aiming to recruit approximately 430 subjects. A little bit about the drug, Tinlarebant. This is an oral once-a-day tablet designed to bind serum retinol binding protein 4 as a means to specifically reduce retinol delivery to the eye. This approach is intended to halt or slow the formation of toxic retinol-derived byproducts, which are generated in the visual cycle and have been implicated in the progression of both Stargardt's disease and geographic atrophy. At Belite Bio, we believe that early intervention directed at emerging retinal pathology, which is not mediated by inflammation, would be the best approach to potentially slow or halt disease progression in Stargardt's disease and GA. In terms of the market, there are no FDA-approved treatments for Stargardt's disease, and there are no FDA-approved orally administered treatments for geographic atrophy. We have the advantage of having both Fast Track and Rare Pediatric Disease designation in the U.S. and Orphan Drug Disease status in the U.S. and Europe for Stargardt's disease. In terms of IP, we have a very strong patent portfolio with 14 active patent families with composition of matter patents not expected to expire until at least 2040. A little bit about how the market lies. Most people are aware of the Dry AMD market shown on the right-hand side. Dry AMD, as specifically geographic atrophy advances with age, cause mainly by exposure to both artificial and natural sunlight, which is very difficult to avoid. So there's going to be this natural progression. In fact, an exponential increase in the incidence of geographic atrophy as you age from 65 to 85 years of age. Stargardt's disease is an orphan disease. And even though it's an orphan disease, it is the most prevalent and most common inherited retinal dystrophy with an estimated prevalence of approximately 30,000 patients in the U.S. and about 150,000 in China. We mentioned China because we heavily recruited in China and they remain a contributor to our Stargardt disease program for Phase III. The drug itself was licensed out of Columbia University and was the effort of Columbia University investigators as well as the NIH to identify new treatments for degenerative diseases. They identified retinol binding protein 4 antagonists, like Tinlarebant, as promising first-in-class oral medications, which are intended to slow or halt progression of disease in Dry AMD and Stargardt's disease. A little bit about how the drug works. So it all begins with processing of vitamin A in the visual cycle. What I'm showing you here is a schematic of the normal processing of vitamin A in the healthy unaffected eye and it begins with the delivery of vitamin A to the back of the eye shown here as at-Ral, that stands for all-trans-retinol, that's the chemical name for vitamin A. In the liver, all-trans-retinol binds with retinol binding protein 4 and another protein called transthyretin. This complex is then liberated into the circulation where it travels through that -- throughout the bloodstream hitting all extrahepatic target tissues. What's very important to note, however, is that only the eye has a preference for uptake of vitamin A, all-trans-retinol bound to retinol binding protein 4. And that's because of the presence of a retinol binding protein 4 receptor, which doesn't exist in other tissues of body in appreciable amounts. So only the eye has this [indiscernible] of vitamin A retinol binding protein 4. When this complex docks onto the receptor, the retinol is admitted into the eye. It goes through a series of enzymatic reactions where it's eventually converted to a light sensing chromophore called 11-cis-retinol. This 11-cis-retinol begins with a protein called opsin to form rhodopsin, following light activation of rhodopsin, a molecule of all-trans-retinol is liberated. This aldehyde is a very toxic retinoid species and must leave the retina through some mechanism or it will start damaging membranes. The way it gets out is through an active transport process mediated by a protein called ABCA4. ABCA4 is an enzymatic flippase, which grabs the retinol from inside the retina, flips it outward, availing it to another enzyme for further detoxification and reentry back into the visual cycle. So this is the vitamin A process in a normal healthy unaffected eye. However, in patients with Stargardt disease, there is a genetic mutation that affects the function of the ABCA4 protein. Consequently, the protein becomes dysfunctional. It will not efficiently remove aldehyde from the retina. The aldehyde will linger and accumulate within the retina and condense upon itself, forming these dimers of vitamin A that we call bisretinoids. These are the retinol-derived toxins that I talked about earlier. The primary one that's been identified in human tissues of patients with Stargardt disease and geographic atrophy is known as A2E. And this molecule has been shown to kill retinol tissues through myriad mechanisms. So in Stargardt's disease, the only reason there is retinal pathology is because of the accumulation of A2E. In Stargardt -- sorry, in geographic atrophy, these bisretinoids accumulate as well, but for a different reason. It's because of pathology beneath the retinal pigment epithelium, that is this tissue where all the enzymology occurs and also debris above the RPE between the retina and RPE. These compounds, this debris that is accumulated in GA patients interferes with the transfer of nutrients from the bloodstream to the RPE, causing the RPE to become sick. It runs afoul and these bisretinoids accumulate nonspecifically. So these bisretinoids accumulate in both diseases, but for different reasons. And because these bisretinoids are derived from circulating retinol, it stands to reason that by reducing the amount of retinol going into the eye, we should have some effect on reducing the bisretinoids and slowing disease progression. That is what Tinlarebant does. Tinlarebant, our drug, works in the liver to compete with retinol for binding to RBP4. It will not allow the transthyretin protein to bind. Consequently, what gets liberated into the circulation is a complex of Tinlarebant bound to retinol binding protein 4. Because of the small size of this complex, it gets readily filtered through the kidney, in urine essentially, the net effect being a reduction of retinol going into the eye, and of course, a reduction in all of the bisretinoids downstream of that, including, of course, A2E. So this is the mechanism whereby we intend to get rid of the bisretinoids and then a slow disease progression because we believe these bisretinoids are causing pathology. And to give you a little bit of an idea about how they're causing the pathology [indiscernible] clinical presentations now. Here, you have images, retinal images of a patient with Stargardt's disease on the top and a patient with geographic atrophy on the bottom. Let's focus on the Stargardt disease patient in the upper left-hand image, the baseline image. You see these 2 central areas of atrophy, the black blotches you see, that's dead retinal tissue. But around the periphery, you see this autofluorescent banding, all around the perimeter of those lesions. And now if you go from baseline out to 57 months, what you can appreciate is that the lesions coalesce and they actually grow into the autofluorescent area, and the autofluorescent area expands outward centrifugally to accommodate the dead retina. So here, we have a very clear cause-and-effect example where the appearance of bisretinoids leads to retinal cell death in a continuing progressive pathology. On the bottom, we see a patient with geographic atrophy. We see a similar scenario. You see a central lesion on the lower left-hand image of the screen. Around that central lesion, there are punctate areas of autofluorescence, which are actually more obvious at 12 months. If you now contrast the 12-month image with a 55-month image, what I hope you can appreciate is that those areas that were previously just autofluorescent have now become retinal lesions. And now all of these new retinal lesions have a little annulus of autofluorescence about their perimeter as does the central lesion that we saw at baseline, which has now grown roughly 5 to 6x in size and has a very well demarcated zone of autofluorescence. So here, we believe diseases, we have the appearance of autofluorescent bisretinoids that precede the spawning of atrophic cell death, and of course, it just keeps spreading on and on from there. As I said before, in geographic atrophy, these molecules accumulate, but Dry AMD is a very heterogeneous disease. It's not just because of the bisretinoids, but there's lots of pathology happening. But I can give you some idea why we believe that our drug will be effective in slowing disease progression in geographic atrophy. And that comes from a study that I conducted approximately 13 years ago was a drug called fenretinide. So this was conducted when I was with a different company. I always wanted to answer the question, would reducing retinol delivery to the eye have any effect on lesion growth? So I enrolled 246 patients in a 2-year Phase II proof-of-concept study to answer that question. Fenretinide was not designed as a retinol binding protein 4 antagonist. It was actually an anticancer drug, but it has a side effect of reducing retinol binding protein 4 in blood. And that was something that was observed in all of the cancer trials in which fenretinide was examined. I repurposed that drug for this Phase II study, proof-of-concept study, to answer the question I asked earlier, would reducing retinol delivery to the eye have any effect on slowing lesion growth? What you see here in the histogram in the upper right-hand side is the growing of lesions from baseline over the 2-year study in 2 of the arms of this study. The black bars show you the placebo growth. And what you can see there is about a 50% expansion in the size, that means percentage, expansion of the lesion from baseline. In our high-dose group, the 300-milligram group, we saw something very interesting. There was a group of responders that had as much as a 70% or more reduction of retinol binding protein 4 from baseline. In those subjects, there was a profound slowing of lesion growth, which began at month 18 and persisted through month 18 and 24, giving us about a 25% reduction in lesion growth compared to placebo. Interestingly, subjects that received the same dose but did not get that profound reduction of RBP4 did not have any slowing of lesion growth and they look just like placebo. If we now look at the visual acuity status during the trial in those same cohorts that I showed you above, we can see that at the same time that the lesion stopped growing and the responders that is from 12 to 24 months, during that same time, we also have a stabilization of visual acuity loss at 6 letters. Meanwhile, the placebo group and the nonresponders in the high-dose group continue to lose letters out to about 13 letters. So at the end of 2 years, we have a profound reduction or stabilization of visual acuity and a profound reduction of lesion growth in these subjects. The only problem with this study was that only 1 in every 3 subjects achieved this profound reduction of RBP4, and that was owing to 2 properties, which are deficits of fenretinide. One, it has terrible bioavailability. Patients had to take this drug with a high-fat meal at dinner in order to increase blood exposure. We got really good in compliance during the first year, but compliance fell off during the second year and we could see that by simply measuring blood -- RBP4 in blood. The other problem is that the drug is not very potent. It's only as potent as the native ligand retinol in terms of an antagonist. So it doesn't stand a very good chance of reducing retinol very potently. With our drug, Tinlarebant, we've overcome all the deficits of fenretinide. First of all, it's not a retinoid, which gives us a better safety profile. Secondly, it has much greater bioavailability than fenretinide. And thirdly, it has a 100-fold greater potency. So we believe that with this drug, we'll have a better chance of not only capturing more patients that are responders, but we have a greater ability to go into different disease indications because it is an oral once-a-day tablet. Next, I'll go into a little bit about Stargardt clinical trials. First, starting with the open-label Phase II, which is shown on the left-hand side. This study enrolled 13 adolescent subjects that had an early form of a disease, which only shows autofluorescent lesions. These lesions are called QDAF lesions. They did not have the trophic lesions, which are those black blotches I showed you earlier in the clinical presentation. You can see there the various designs. It's a 2-year study, looking primarily at safety and tolerability. And you can see there at the bottom, the key inclusion criteria. The other study we have enrolled in Stargardt, as I mentioned, we completed enrollment of 104 subjects is this Phase III study, also a 2-year study in adolescent subjects that are 12 to 20 years of age. So not too much of a difference between the inclusion criteria. In fact, these studies are very, very similar in that they're 2 years in duration and they're looking at the same efficacy endpoints and the same assessments for safety and tolerability. I now want to share with you some of the data from the open-label Phase II where we have these 13 adolescent subjects completing study. These are -- this is a 24-month data looking at retinol binding protein 4 as well as Tinlarebant exposure in blood. The Tinlarebant exposure in blood is shown in the blue line and retinol binding protein 4 is shown in the red line. What you can see is there's a very good correlation between the increase of Tinlarebant in blood and the reduction of retinol binding protein 4. And then when we withdraw the Tinlarebant at month 24, there's a very nice correlation between the reduction of Tinlarebant and the rebounding of retinol binding protein 4. So we get roughly about 90% of the baseline value during approximately 1 month of drug cessation. So a very nice feature to have reversibility of the pharmacodynamic effect. Now I want to show you some lesion growth data, and this is a very profound observation that we've made and really hasn't been seen before in adolescent Stargardt's disease. I mentioned before it was an open-label study. So we had to use a comparator to understand what type of treatment effect we're getting. That comparator comes from a very extensive study. It's the largest natural history study of Stargardt's conducted to date called ProgStar. In this study, which involved mostly adult subjects, there are 450 approximately subjects in the study, there was a subgroup of subjects, approximately 51 subjects, that had the exact same baseline characteristics as our subjects in the open-label Phase II that is they were 18 years or younger at baseline, and they only had the autofluorescent lesion type, not the atrophic lesion type. So what we wanted to do is we wanted to look at the incident atrophic lesion growth in these subjects over time. And what we found at every time point when we do this comparison, we have a profound reduction in the instant lesion growth in our subjects treated with Tinlarebant versus ProgStar, such that by 24 months, we have a highly statistical significance between lesion growth in ProgStar and our subjects. And you can see there on the right-hand side, the numerical value, the 50% reduction. So 0.51 in ProgStar millimeter square per year versus 1 -- sorry, 0.51 in our group versus 1 in ProgStar. Most importantly, 5 of our subjects, 5 of the 12 in this study developed -- did not develop DDAF. So no atrophic lesions over 24 months. So they were completely stable from baseline, and that is profound, also never seen before. So we believe these data are very, very promising, and they bode well for our Phase III trial design, which is essentially the same as the Phase II in terms of its trial design, duration and assessments. A little bit on the visual acuity from that 24-month open-label study. You can see here a stabilization of vision. Our patients lost a mean of roughly 5 letters during the 24 months of treatment. And when you look at the overall BCVA outcome, a loss of less than 10 letters is not considered clinically significant. So we look at this as stabilizing vision. We don't believe we'll be able to improve vision by 3 lines, which is what the FDA wants for endpoint. But we believe by stabilizing vision and reducing lesion growth, we'll be able to provide patients with some clear benefit in terms of their functional outcome. Going forward now to the AEs. These are drug-related adverse events. We only see 2. There have been no systemic drug-related adverse events. So no clinically significant findings in relation to vital signs, physical exams, cardiac health or organ function. What we see are 2 AEs, ocular AEs, which are features of the drug. We want to see these because they're telling us we're having the intended biological effect on the retina. The first is a form of chromatopsia called xanthopsia. This is mediated by cone photoreceptors, which confer bright light and color vision. So when patients transition suddenly from a very darkened environment to a bright environment, this activates cone photoreceptors. Under our treatment regimen, the chromophore will only be slowly supplied to these photoreceptors. So there will be a delay in their ability to accommodate to full bright light. During that delay, patients will experience an artificial hue of color in the visual field as cone photoreceptors misfire until they fill up with chromophore. This lasts seconds to minutes. It's reported as mild. And as you can see, it's reported in the majority of subjects, but no one has left study because of this AE. The same can be said for delayed dark adaptation, which is sort of the opposite effect. Delayed dark adaptation is mediated by rod photoreceptors which confer dim light vision. So when patients transition suddenly from a very bright light to a darkened environment, they will have a delay in the ability to accommodate to dim light. And this could be somewhere between 10 to probably 15 minutes delay. Again, it's also reported as mild in severity, and it's occurring in a majority of subjects, and no one has left study because of this. A more severe manifestation of delayed dark adaptation in which the delay could go out to perhaps 20 minutes is called night vision impairment. We saw that in one subject, a more severe exacerbation of the chromatopsia [indiscernible] increasing error score on a color assessment called the FM100. We saw that in 1 of 13 subjects. So essentially, what that means is that the chromatopsia is lasting longer than the majority of subjects. And then finally, intermittent headaches come as a result from patients trying to strain [ without ] trying to see in both bright and dim light. There is ways to accommodate these AEs by simply moderating transitions from bright light to dim light and dim light to bright light, patients can significantly reduce the incidence and severities of these AEs. Going forward into the Phase III trial for geographic atrophy, I want to share with you first something very important. As patients age -- as subjects are healthy, human subjects age, we tend to get more fat. Our BMI increases and retinol binding protein 4 actually increases with increased BMI. So [indiscernible] going into our GA studies that we may have to use a dose higher than 5 milligrams daily to achieve the same pharmacodynamic effect that we saw in adolescent Stargardt subjects. That is a reduction of retinol binding protein 4 of about 80% or more. We've ran a PK/PD study with both 5-milligram and 10-milligram Tinlarebant in healthy adult subjects to match the higher BMI and age range of patients with geographic atrophy. And what we found is that the same 5-milligram dose that drives the retinol binding protein 4 to 80% reduction in adolescent subjects also does the same in healthy adult, elderly adult subjects. And you can see here, during the dosing period, we get about a mean reduction of retinol binding protein 4, which actually occurs at about the second or third dose, it stays reduced until we withdraw the drug and then approximately 14 days during drug cessation, you can see the nice reversibility of the pharmacoeconomic effect in these elderly subjects. So we can use the same exact dose for the GA study that we're using in the adolescent Stargardt study. A little bit about the trial design in geographic atrophy. I want to start by saying the Phase III trial design in geographic atrophy is nearly identical to the Phase III trial design in Stargardt's. It's 2 years in duration. There will be a 1-year interim analysis. The randomization is 2:1 favoring Tinlarebant. And of course, we're using all the same safety and efficacy assessments that we're using in Stargardt's disease. There's only 2 real differences in these studies. The first being the indication, geographic atrophy instead of Stargardt's, and the second being a higher number of subjects enrolled for GA to reflect the higher prevalence of GA in the population. We expect to begin enroll -- actually we begin [indiscernible], and we expect it will take anywhere from a year to 18 months to complete that enrollment of 430 subjects. Next, I want to just give you a sort of a snapshot of the key milestones that we have accomplished to date. So we've initiated our Phase III study in geographic atrophy. As I said, that study is recruiting. We have in -- this is back in April 2025 -- or sorry, this is earlier this year. We had an ARVO presentation of the 18-month data from our Phase II study in Stargardt's, which, of course, showed very positive results, as I showed you today. During the second half of 2023, we completed enrollment in our Phase III DRAGON study in Stargardt's. And just recently, in fact, this week, we gave a presentation at the AAO meeting, showing our 24-month data from the Phase II study in adolescent Stargardt's disease. You saw that data here today. And going forward into 2024, during the second half, we expect interim results from our Phase III DRAGON study to read out. With that, I will thank you for your time and attention, and please support Belite Bio. Thank you very much. I believe we'll take questions now.

So the question that we have here is, how large an addressable market for Stargardt's? As I said before, there's approximately 30,000 in the U.S. That is an underestimation. There's never been a proper epidemiological study to determine how many patients there really are. The closest one that's been done recently in Europe, we found a prevalence of 1 in 6,500. Now that's of the total Stargardt population. But remember, there's an adult population, and there is an adolescent population. So the adolescent population will represent roughly 40% of that 6,500. So you can sort of do the math there. So yes, it is an orphan disease, but with premium pricing on a successful drug. I think it will balance out in the end to be a very lucrative opportunity for most. Another question we have here is, will we disclose any baseline characteristics of our Phase III trial before the second half of 2024? The answer is yes. We'll be publishing that data either at a meeting or in a manuscript probably within the next [ 6 to 8 ] months, I would say. So yes, that baseline data will be disclosed at some point in time prior to the close of the study, of course. Another question we have is, who do you consider to be your peers? Any other companies pursuing solutions for Stargardt's? The answer is yes. There's a number of therapies in development for Stargardt's. There are oral therapies. There's an oral therapy that is a deuterated vitamin A therapy that's being advanced by a different company. This approach is intended to replace natural vitamin A with a synthetic vitamin A, which resists dimerization. So I told you earlier that vitamin A dimerizes and that's what forms these bisretinoids, these toxins that lead to retinal cell death. Well, their molecule is a form of vitamin A that doesn't dimerize as readily. So you would be replacing all your natural vitamin A with this vitamin A. We're essentially sort of in the same development plateau, if you will, with this company. Again, we're both oral therapeutics, but there are nice things about our drug that their drug doesn't have. One of them is reversibility. So it will be very difficult to come off of a synthetic vitamin A treatment when you essentially flooded your whole body with synthetic vitamin A, whereas with our drug, Tinlarebant, is readily removed from the [indiscernible] as I showed you. It doesn't have high residence time in blood. And of course, the pharmacodynamic effect is very reversible, as I showed you earlier, approximately 14 days to go from the lowest reduction of RBP4 all the way back to the baseline value. Another participant has asked, do we have any research partners? We don't have research partners, per se. We have KOLs and PIs who help us advance our drug and help us get the word out, but we're not currently working with any specific research partners. There is another question on the finance. I'm afraid I can't [indiscernible]. But I would ask that participant to please forward your question to our CFO, Hao-Yuan. You can find his e-mail address probably on this forum or certainly on our website. Although if I would have to speak to the drivers behind the nearly 4x increase in our stock price over the 5 months, I would have to say it's because of the steady stream of very positive data that's happened because we have done 6-month snapshots of our data. So we've had data from 6 months that has been very positive. So every time we've looked 6 months, 12 months, 18 months and now 24 months, we continue to see very positive data. And I think the market is simply responding to those positive outcomes from each of those analyses out to the end of 2 years. Okay. Nothing is forthcoming. So with that, I think we can close the session. I will turn it back over to the moderator.