As people are transitioning in and out of the room for the next session, we'll get going here and get started. My name is Steve Seedhouse. I'm on the Cantor Biotech team. I welcome everyone to the next session. Really a privilege to be joined by our next participating company, and on stage with me is Belite Bio. I'm joined, of course, by Hao-Yuan Chuang, CFO, and Hendrik Scholl, CMO. It's a fascinating and exciting time for the company approaching what could be, of course, the first approval for Stargardt disease worldwide, on file with the FDA with priority review. As that review proceeds, maybe just to start, tell us what we can expect to hear from Belite with regards to updates and guidance and progress that you're making towards preparing for commercialization. Hao, what do you think? Sure. I can start. Yes, so far, I think everything has been very smooth. The FDA shows a lot of support throughout the last few years, and I think the whole thing as we expected. We don't want to comment too much about potentially what is coming, but definitely we see a lot of friendly, constructive processes going on with the FDA. We will update the market whenever we have any things that we can actually confirm. Sure. Hendrik, you've been involved intimately with the natural history work in Stargardt. Maybe you can talk a little bit about your experience with that and why something like that might be important here from the standpoint of regulatory approval and contextualizing the clinical data that you've been able to generate with Tinlarebant. Happy to, and I can only agree with Hao about the constructiveness of the FDA and how educated the regulatory agency actually is when it comes to endpoints in the field of ophthalmology, especially retina. The interaction with the FDA on finding and testing, validating, and implementing an endpoint for Stargardt disease goes back to the year 2011 when, initiated by the Foundation Fighting Blindness, a group of investigators met with the FDA in Bethesda in person. It was before all these online meetings, and we discussed about what would be needed to develop therapy for Stargardt in an arena where traditionally only visual acuity was an accepted endpoint. It was about that time when it was found that in GA, you can actually use atrophy image on autofluorescence imaging that correlates strongly with sensitivity loss in the retina to be used as a primary endpoint in GA. We had a precedence there in an important other disease and discussed with the FDA what would be needed, and they recommended a natural history study conducted as if it was a trial and to specifically look into imaging technologies such as autofluorescence and OCT to allow outcome measures to be validated. This is exactly what we did that led to the birth of the so-called Progression of Stargardt Disease study called ProgStar, and that was a worldwide natural history multi-center study looking into the progression of Stargardt disease in six monthly intervals prospectively and investigating a large database retrospectively. That allowed to establish autofluorescence imaging as an outcome measure and specifically the definition of lesions called DDAF, definite decreased autofluorescence, as a primary endpoint. ProgStar has been instrumental for the design of the DRAGON trial and instrumental for regulatory, especially FDA, how they understand Stargardt disease and why they are willing to accept an imaging endpoint as a real approval endpoint. Okay. Some of the secondary endpoints that you measured in DRAGON, can you maybe talk about some of those? In addition to DDAF- Yeah. and maybe also alternative ways to validate what you see on DDAF in terms of the lesion growth and ways that you've analyzed that. Can you just walk through some of those critical analyses and some of the supplemental data that ultimately will get FDA over the line here? Yeah. It's important that you mentioned supplemental data because obviously we seek approval based on one trial, and it is not a small ask with the FDA to approve Tinlarebant based on a single trial. But the trial data speak for itself, and we have a large package of so-called confirmatory data, and this is what is needed as a guidance of the FDA, what is being regarded as supporting evidence for a single trial, and we have that. First of all, in the trial itself, we have a key secondary endpoint that we call DAF, decreased autofluorescence, meaning all areas that show a decrease in signal when we measure autofluorescence imaging. That goes beyond just areas that are completely atrophic. When we look at DDAF, definitely decreased autofluorescence, and we look at histology, we find there's no photoreceptor left and there's no sensitivity left when we look at microperimetry. So these areas are completely atrophic. We have shown in the trial that Tinlarebant has a very significant efficacy signal in slowing down the growth of these lesions. That's clinically meaningful because a patient wouldn't see in these areas, and we can slow the growth of these lesions by 36%. When we speak about DAF, that's a more comprehensive measure of health or sickness of the RPE. DAF is the sum of DDAF, obviously, but also QDAF, questionably decreased autofluorescence, meaning these areas show sick RPE but are not as sick as the area of DDAF. What we find for DAF is that we find essentially the same efficacy signal, and that means because DAF could grow slower than DDAF because when DDAF is expand, then QDAF could become smaller on the expense of DDAF, but it is not what we find. We find that in the trial, DAF grows as fast as DDAF, meaning that not only allow us Tinlarebant to slow down the growth of these completely atrophic lesions, it appears to also slow down the transition from healthy RPE into sick RPE, meaning that likely that would allow to prevent incident lesions in the future. So this is trial data. I think this is confirmatory evidence from the trial, is the fellow eye data. We are not used to that any longer in ophthalmology because over the last 20 years, essentially every innovation was eye specific. If it was a device, if it was gene therapy, surgery, what have you, all of that was eye specific. We have an oral therapy. This has a systemic effect on both eyes. We looked into the fellow eye data that was available, and we find essentially the same effect size. We find statistical significance, although the trial could not optimize for the fellow eye. The fellow eye was all commers. There could be no lesion in the fellow eye, there could be a very large lesion in the fellow eye, and still we reached a significance level when we analyzed the fellow eye. So obviously, Tinlarebant works on both eyes together. When it comes to confirmatory evidence, we have access to this very large natural history database of the ProgStar study. We use that database to supplement our placebo arm in the DRAGON trial by a very large number of natural history controls. This has a very positive impact on the result that is already very positive, but it bumps the efficacy signal even further up and it bumps the P value even further down if we use that natural history controls out of ProgStar. Would the reason for that be that the control arm simply outperformed by virtue of the clinical trial design and The reason is simply a statistical- I see. issue, because by simply adding a large number of subjects that is also meticulously studied, so it was the same rigor in ProgStar and in DRAGON. It simply allows to reduce the standard deviation, standard error significantly, making it even more clean. Okay. What other anatomical measures were done in DRAGON that are relevant to Stargardt disease? Did you learn anything over the conduct of the study as some are better than others at sort of assessing the efficacy of Yeah. Tinlarebant or even assessing just the progression of the disease? Yeah. Autofluorescence is especially helpful in Stargardt disease because it reflects bisretinoid content in the RPE, which is also partly there in normal physiology, in normal turnover of the visual pigment in the eye. But in Stargardt, it shows a strong increase. We also used a technique called quantitative autofluorescence that allows to measure the content of bisretinoids indirectly in the retina, and we see a very positive signal in the study. But this has no clinical relevance. It just shows that our MOA really works in the eye and really allow us to stop further accumulation of these toxic bisretinoids. But the signal that is derived from quantitative autofluorescence has no immediate clinical impact. Obviously, there's OCT imaging also available, which is used very commonly in ophthalmology or specifically in retina. The only problem with OCT is when you look at, as an example, ellipsoid zone, which reflects health of photoreceptors as opposed to geographic atrophy. In Stargardt disease, the area of unhealthy photoreceptors is very large, and much larger than the DDAF area. And what we found in the trial is that already at baseline, many ellipsoid zone defect areas exceeded the imaging window, which unfortunately, at least in the DRAGON trial, make EZ DA or OCT imaging a suboptimal outcome measure. Okay. Actually, maybe just circling back to check the box on this, the Japan regulatory review process is also underway. Can you just talk about timelines and expectations there and what was different about that package? Obviously, you had DRAGON-2 underway to gather some data in Japanese patients. Maybe just remind us what was required for that filing. Sure. Well, first of all, I think we have the Sakigake designation, which the goal of that is to let Japan to be the first country to approve a drug in the world. It's a very rare and very hard to get designation. And with that, the PMDA are very, very supportive with the company to try to get the drug approved as soon as they can. So we expect with that fast track approval process, Japan could be approved very close to the PDUFA date from the FDA. So that's the first one. Sorry, what was the second part of the question? No, that was it, and just the timelines. Also, I guess since we're on the topic, you recently held your commercial day and you'd done some market research and sort of talked about the epidemiology in the U.S. Do you have similar understanding of what the prevalence and addressable market is in Japan yet? Yeah. We have. First of all, maybe two medical comments on Japan versus populations of European descent. When it comes to prevalence, the prevalence in East Asia, including Japan, is somewhat lower than in populations of European descent. We see a prevalence of about 6,500 in patients of Caucasian origin or European descent, while we see a prevalence of about one in 10,000- 11,000 in East Asia, meaning it's about two-thirds or so of the prevalence. When it comes to the phenotype, that's interesting. Phenotypically, race does not play any role in how the retina looks like when affected by Stargardt disease. Meaning, if I see a patient in Japan or an African American patient or a patient of Caucasian origin, the retina affected by Stargardt looks exactly the same. Karl Stargardt described in 1909, but this applies to all races and geographies around the world. This is important when seeking approval in Japan. The PMDA understands that if they want to be the first country in the world to approve Tinlarebant, they need to be willing to accept the DRAGON1 data as the main source for approval. But they want to see data in Japanese patients, especially PK/PD, and that was already completed a while ago. That was the phase I-B portion of the DRAGON 2 trial that we completed, and it confirms that the PK/PD in Japanese patients is very similar or identical to patients that were studied in the DRAGON1 trial from the U.S., the U.K., Europe, and Australia. This is important, and obviously we have 15 patients from Japan in the phase III portion of the DRAGON 2 trial. We seek conditional approval, so this will be based on the DRAGON1 data, but we will deliver to the PMDA data on our Japanese patients as soon as they become available. Okay, great. Your success in DRAGON, I think, has drawn a lot of attention, obviously, to Stargardt and a lot of excitement. I think kindled some interest really in your mechanism or yours and adjacent mechanisms. It culminated, I think, or probably stimulated a recent acquisition of a competitor, Alkeus, which just started a phase III. They are years behind, obviously, but there is some interest in this space. Just on competitive dynamics, how do you think Tinlarebant, first of all, stacks up against that? I think it is probably the only other oral in development. There are some sort of genetic medicine approaches. Is there any data or insights into that program that we have that you would compare and contrast Tinlarebant with that Alkeus molecule? We would not like to really comment on competitors. I think it is in the interest of the Stargardt community that there are several developments of treatment for this currently untreatable disease. What I can comment on is publicly available information, because there was a publication pretty much exactly one week ago in JAMA Ophthalmology, and this is now in the public domain. Maybe I can single out two observations in the JAMA Ophthalmology publication. One is on the safety side. I think it is important to understand that in order to replace natural vitamin A by deuterated vitamin A in the human body, you have to give very high doses to accomplish that. That belongs to the MOA. Maybe not surprisingly, there was a case, one in 15 at least, that showed increased intracranial pressure. When you look at the retina, that manifests as bilateral papilledema, meaning optic nerve swelling. That is an emergency in ophthalmology where you would need to send the patient to neurology, typically within an hour, because it is a life-threatening complication. That happened under this pretty high dose of vitamin A in a girl in the TEASE-1 trial. My reading of that is that this is quite significant. When it comes to terminology, I would rate that as a SUSAR, a suspected unexpected severe adverse reaction. The other is on the efficacy side. What we find in the publication is that the placebo group was supplemented with natural history controls that were self-read without a reading center, and the readers were unmasked to those natural history controls because you find that in the supplement that the readers actually knew because the time points would not match with the clinical trial time points, that these were actually controls, and they were unmasked to this effect. Therefore, I think when looking or trying to compare the DRAGON trial data to this TEASE-1 trial data, the more important conclusion is that we rather look at the non-supplemented placebo control, and then this is even reported in the abstract, the efficacy signal is 14%, so one four, and I think this is in contrast with our efficacy signal that we see in the DRAGON trial, which was pretty much exactly 36%. Great. Appreciate those insights, Hendrik. Going back to Tinlarebant, just want to walk through some of the key questions, I think, on the commercial outlook. First, just with respect to the narrow, I guess you could call it, eligibility criteria with respect to age, maybe characteristics of the lesions that you had in DRAGON. In light of that, do you still expect broad use and uptake of Tinlarebant on approval? Yes, and there are reasons for that. When it comes to disease stage and having a lesion of DDAF, that's the logic of conducting a clinical trial. The FDA requires an approval endpoint. This approval endpoint was used in the trial. Now when it comes to generalizability of the data to the total population out there, I think there's very good generalizability to all Stargardt patients out there, including patients that have a very small lesion, maybe no lesion at all, or patients that have lesions that go beyond the maximum lesion that was allowed to be enrolled into the DRAGON trial. The other is the age range. We meanwhile have learned from the literature that the youngest age of onset observed is as young as ONE year old, and the oldest is 84. There is a case reported in a paper out of the Netherlands where the age of onset was actually 84, and it was a molecularly genetically confirmed Stargardt case. We have this large variability in age of onset. Given that the cause of the disease is biallelic mutations in ABCA4 and dysfunction of the ABCA4 protein, there's no reason to believe that there's any other underlying pathophysiology in an elderly or a very young patient. Therefore, and this is in line with our conversations with the FDA, that there's very good generalizability of the DRAGON data to patients of all ages. Just as a point of fact, the age range in DRAGON was 12- 20. 12- 20, yeah. Presumably you would have enrolled some patients that were 19 or 20- Of course. on enrollment. Of course, meaning we have- In a two year study. That is absolutely correct. Meaning the trial itself, I think it was very wise to choose this age range, and I say that because that decision was made before I joined the company as CMO, that this trial population covers a pediatric and adolescent portion, but it also covers adult, young adults. Yep. On the sort of idiosyncratic adverse event profile here, which is on mechanism, and it includes xanthopsia and delayed dark adaptation. One question we have actually been getting a lot, and I wanted to just ask is, the actual event rates there at the interim analysis you guys have shared previously on final analysis through two years in that study, were they similar or the same as they were post year one or? It's obviously cumulative, so meaning they are similar, but the rate over time decreased significantly. Meaning that the observation that people on Tinlarebant need somewhat more time when transitioning from light to dark is typically observed in the beginning. There's an adaptation, potentially? That's an interesting word, because there appears to be a I don't know, psychological adaptation process to a psychophysical adaptation- deficit. That the psychophysical adaptation deficit is not very strong, but it can be noticed, and it was noticed by a third of subjects in the trial. It's important to understand the final threshold, when you wait long enough, is not affected. Right? Although it's a med term, and it was used in the trial, night blindness, for example, I don't think that night blindness is a good description of this side effect. It is indeed delayed dark adaptation, and I think this is easily manageable. This was the opinion expressed by the two KOLs we invited to the commercial day last week, Professor Michel Michaelides from the Moorfields Eye Hospital, and Professor Paul from the University of Utah in Salt Lake City, that both confirmed that those side effects that they managed patients in the DRAGON trial are easily manageable. Can you walk through the patient journey here for a Stargardt patient, including all the way up to diagnosis and genetic confirmation, and what that requires today, and what that cost burden is on the patient, on how difficult it is to even get them into that funnel? Belite as an organization with your commercial team that will be on the field in part to market the diagnostic, what can you do to sort of make that easier for the patients? Maybe I start on the patient journey. It is a severe disease that typically kicks in relatively early in life, typically in adolescence. These patients develop problems in central vision, visual acuity, recognizing faces, and so forth. When they seek healthcare, and they typically do, it is found that correction with glasses does not help. It must be something that is beyond refraction, and patients need to be referred to at least an ophthalmologist, if not a retinal specialist. It is typically managed by a retinal specialist. The disease is not so difficult to diagnose, because there are not many diseases that affect the macula in a 15 or 20 or 30-year-old. It comes with specific signs that Karl Stargardt already described with simple ophthalmoscopy in the year 1909. There was no fancy autofluorescence imaging, OCT imaging at the time. These new imaging devices help significantly to make the diagnosis. An extra step since the discovery of the ABCA4 gene as the cause of the disease in 1997 by Rando Allikmets at Columbia University, is that it belongs to the state of the art to actually genetically confirm the disease, meaning that patients should undergo genetic testing. That is an extra step. When we currently look at the diagnosed patient population out there, in our opinion, it is in the order of magnitude of 20,000. There are higher numbers that are being communicated by competitors, but we feel currently it is 20,000 that are diagnosed. A bit more than half carry a genetic diagnosis, 11,000. This is very concrete and firm data out of genetic databases. Meaning that we must make an effort to have the other 50% genetically confirmed. There are programs out there, but Belite Bio is making a major investment in terms of effort to bring more patients that are currently not genetically confirmed to a genetic confirmation. Maybe you can elaborate on that, Hao. Sure. Yeah. I think first of all, like Hendrik said, the disease probably is very easy for the patient to feel there's something going wrong, and they'll seek physicians to check. We believe the IRD community, the retinal specialist community, have a very good understanding about Stargardt disease. What we can do to really help will be the MSL team to really communicate with these doctors about the clinical data, so they are aware of potentially there could be a treatment coming. Second, for the broader kind of community with the general ophthalmologists, low vision optometrists, we could do a lot more about disease awareness education, marketing, to make sure that they are well aware of that this could be a Stargardt disease patient standing in front of me. I should either write a referral to the retinal specialist or maybe prescribe genetic testing, which is one thing that we are trying to do to bring more so-called genetic testing for IRD disease education out there to be. People are familiar with what are the potential lab and tools that you can get the testing. It's actually not that expensive. Some of them are even free because it's sponsored. What is the procedure, what could be the result actually means, et cetera, to make people, especially physician and the patients, to feel comfortable to getting the testing done. That will be a second key effort for our team. Besides so-called the marketing effort, the pay search or the geo promotion kind of things that you can do to make sure that people are well aware of, I could be potentially a Stargardt disease patient, or the physician is. I think the third part will be making sure you have a very friendly payer coverage. We have done several round of payer research, and I think the payers are very, very supportive. We're working with them and making sure that you have a friendly payer coverage. The last one will be the patient service. As we discussed on the commercial day, we expect to work with a strategic pharma to handle the prescription for the patients and deliver the drug to the patient's home. Follow up with the patients to make sure that any question they have can be well addressed, so have a good adherence rate. It's a great synopsis, I think, to end on, gentlemen, and congrats obviously on the progress to get to this point. We're looking forward to hopefully will be the first approval for Stargardt disease. Thanks so much for joining us at the conference this year, and thanks to everyone in the audience. Thank you for having us.