Belite Bio, Inc ($BLTE)

As a quick background of Hendrik, Hallon and as well as Blight, Hendrik has served as the Chief Medical Officer of Belite Bio since September 2024. He is a clinically active retinal expert with more than 2 decades of expertise in treating retinal diseases, including Stargardt disease and age-related macular genetgeneration. Dr. Scholl is the coordinating principal investigator of the largest natural history study in starter disease. And for Houay served as the CFO of Bio since April 2020. Prior to joining Belite Bio, Mr. Tong served as Chief Financial Officer of Wynn BioScience. Belite Bio a clinical stage biopharmaceutical company focused on developing novel therapeutics for retinal diseases, including Stargardt disease and geographic atrophy. The company's lead out is Tinlabrant,LBS008, a novel oral RVP 4 antagonist that has initiated rolling NDA submission. Thank you both for joining.

Thank you.

All right. Well, to start, can you walk us through the mechanism of action and why targeting RBP 4 is the right approach for both Starter and GA?

Happy to. So -- both diseases are extremely similar in phenotypic expression. It's just that stages very early. It's a pediatric or disease the adolescent patient while altimeter degeneration Therefore, the name is age-related and it's a disease of the elderly. Both these affect the macular. In both diseases, what you observe clinically is that deposition of cytotoxic bisretinoids influence the disease progression. We can see that clinically when we use funds orders imaging, which is a standard of care imaging in a typical regime clinic. We see these compounds lighting up underneath the retina. And these are the drivers of disease. We have seen that in geographic atrophy already at the time with Frank Hall in 2007 in the largest natural history study at the time in macular degeneration that if you have increased autoprice around lesions -- this is a major driver of disease progression. When we get to a in stage, we have a very precise understanding of the disease. The disease is monogenic, it's inherited. It is due to mutations in a gene called ABCA4. It's an ABC transporter, a subfamily -- and ABCA4 plays an important role in the so-called visual cycle. What's the visual cycle, very briefly. I keep it brief, but it's complex. But the visual cycle is very well understood. But the visual cycle is the regeneration of the photo pigment. If we look at Light, if we send slide, our photofigment can sense that -- but then in that moment, it falls apart, so to speak, and it liberates all translational the preceptor Ultranet is tariff from vitamin A is very toxic. -- and has the propensity to react with itself to form dimers or bisretinoids the most important being A to E. ABCA4 function as a flip as to flip that out of the cell to -- into the visual cycle to get it regenerated. If ABCA4 is dysfunctional in stage disease, Altran retina accumulates is very toxic itself and then reacted itself informs these A2E depositions in the RPE in the support layer of Turitea, driving the toxicity in the disease. So now the question is, what can we do about that? So number one, we may repair the gene. This is not our approach, right, which is very complicated to accomplish that. You could also try to disrupt the visual cycle. And this has been tried is you would kind of induce a retinal disease. If you did that, we do not do that. Tinlaribant is not a visual cycle modulator. Tinlariband aims to reduce vitamin A in the photoreceptors. It reduces substrate of the visual cycle, therefore, having less compound to be developed into toxic depositions in the RP and therefore, having a therapeutic effect. So how do you now reduce vitamin A content in the circulation and only have an effect in the eye is that possible? The answer is yes. And the reason is the RBP receptor that expressed in the eye. Only the eye is dependent on sucking in vitamin A to the so-called RBP receptor, retinal binding protein receptor. And therefore, we can target with an RVP antagonist vitamin A bound to RBP 4, therefore, reducing RBP retinal in the circulation and thereby only reducing vitamin A in the full receptors, but not in the systemic circulation because the other organs extrahepatic organs have other routes of access to vitamin A, independent of Arbibefore. Therefore, Tinlaribant allows to very precisely almost with the precision of gene therapy because of the RP4 receptor to reduce the content of vitamin A in the photoreceptors and therefore, reduce toxicity in the eye without having any safety concern for any other organ.

Great. Makes a lot of sense. Maybe just flipping to the regulatory pathway for a quick second. You recently initiated a rolling NDA submission for StarCard. What are the key data points from the DRAGON trial that gives you confidence in the filing, particularly speaking, the primary endpoint of lesion growth?

Yes. Having a primary endpoint for an indication like Stage and it was very kind of you to mention the fact that I led the largest NATI study in the space called Proctor progression of stage disease. ProgStar was instrumental to establish the natural history, obviously, in stage disease and develop and implement a primary endpoint in consultation with the FDA at the time. In 2011, we met with the FDA in person at the time in Bethesda, and the FDA recommended for the drug development in Stage to implement a natural history study and to look at outcome measures very similar to, at the time, was done for geopiatrophy, namely to establish atrophy measured from funded order presence images as the primary endpoint for clinical trials in geographic atrophy. So that's exactly what we did at the time. We implemented the Procter study, when I was professor at the Wilmar Institute at Jans Hopkins, as a worldwide natural history study, and we measured all the present lesions, lesions on autoprice images, multicenter in a central reading center over the period of 2 years in 6 monthly visits, and we could establish DDAS definitely decreased order persons, very similar to what we see in GA, SGA lesions on order presence images, as lesions that can be precisely measured over time and they enlarge at a predictable rate. And it's also important, we could show that with data from ProStar are correlated with visual function long term. The limitation of visual function, if I may mention that because you could ask why don't you simply go for visual acuity is that visual acuity loss also established in ProgStar is very slow. It's only half a let per year on average in stage disease -- and with an 8-letter intercession variability, it's almost impossible to find a visual acuity, delta deficit over time in a reasonable amount of time in a reasonable cohort of patients. Therefore, we believe that with the FDA, we found an approvable endpoint that will be -- lead to success in our market authorization application with the FDA in the DRAGON trial, we use DDF as the primary endpoint and found that with 5 milligrams per day of Telaria the found progression rate of only 0.38 square millimeters per year by the placebo group showed a progression rate of 0.59 square millimeters per year. This was highly statistically significant using an unstructured covariance matrix that was prespecified. We found a p-value of 0.003. And a much better covariant structure for the data set we had also discussed with our DSMB at the time, namely an auto regressive model covariant structure. This allowed to arrive at a p-value that was smaller than 0.0001, So this was highly statistically significant. Importantly, in the DRAGON trial, our key secondary endpoint, decreased orders, which indicates tissue that is not as degenerated as unhealthy, if you will, as the tissue within DDF lesions also show the treatment effect that also reached statistical significance. Therefore, we are very confident that with that efficacy signal. We have a strong data set for our application. And I would also like to mention the safety data with tinlaribant, we had only 6 SAEs in our clinical trial of 104 star got subjects over 2 years, 4 of them, by the way, in the placebo group, only 2 of the SAEs in the treatment group. None of them was related to the treatment. The ocular AEs were related to the mechanism of action, mostly were mild, mostly resolved while on treatment, meaning that in -- with that combination of strong efficacy, excellent safety and tolerability and supporting evidence from natural history data from the PROXTARstudy, we should be in a very strong position with our market authorization based on only 1 trial.

Got it. Very helpful. Do you think as you think about physicians and the key end points that they think about, are there any differences between how they might view that? You mentioned visual acuity versus the regulators?

Yes. So in a typical retina clinic nowadays, clinical care is heavily image-based these clinical images such as fundus photography, OCT, or depresses imaging are being used for bad AMD for dry AMD, but also for IRDs. So currently, if a patient with an inherited macular degeneration comes into a doctor's office, the typical situation is that the patient would get retinal photography, artofrescence and OCT imaging and that would remain exactly the same when tinlaribant hits the market. Doctors are used to judge on the regional health based on these images. They use these images to make the diagnosis and they would also use these images to monitor disease progression, meaning that when tinlariban gets to the market, the standard of care would remain very similar with the only big difference, obviously, that patients would be on treatment would receive tinlaribant to slow down the progression, but the progression would be judged on order for sense images. And there would be no change in standard of care needed for that.

Got it. And then I know you touched already a little bit on the confidence that on Dragon trial should be sufficient for regulatory approval. As you think about the DRAGON 2 trial, what are some key objectives you're looking to accomplish with that?

Yes. So you should keep in mind is originally designed for Japan. In Japan, in designation of breakthrough pioneer drug designation to allow Tinlariban to be marketed as the first drug in the world in Japan for Japanese patients. And in order to fulfill the requirements to -- for a successful PMDA submission in Japan. We initiated the DRAGON 2 trial to collect data in Japanese patients, but since Japanese patients could not already participate in the Dragon 1 trial, we needed a second trial. And we took an opportunistic approach with the DRAGON 2 trial, running a trial with essentially the same design to allow patients that have waited in the U.S. and the U.K. to participate in the Dragon program to participate in the DRAGON 2 trial. So the DRAGON 2 trial is not intended as a second trial to support our submission to the FDA, but it could in a given scenario, support our application, if needed as a post-marketing commitment.

Got it. Very helpful. And as you think about, I guess, submission to FDA, the label that you potentially are looking to get, do you think it would be a broad label? -- younger pediatric patients if need, what would be the subsequent pathway to that?

Yes. So this was discussed with the FDA, and it is, I think, an easy case to argue for us that Stargard disease is the same disease regardless of the age of onset. It's due to dysfunction of ABCA4, -- but we also have natural history support for claiming that starter disease of 12 years and older, which would be our intended designation for Tinlariband is supported by natural history, which shows that the progression rate in Proctor, for example, of the age groups plus until 50 years was essentially the same, meaning that there should be no difference if we intervene early or late for patients having successful and safe treatment being on tellaribant. Maybe a comment on how early and late we can and should treat. If you think about stockout, -- there was the reason why we enrolled patients with lesions define autoprice images in the DRAGON trial, namely because we needed something that can be tracked over time. The question is the generalizability of the data to patients that are even earlier in disease stage or later, in my opinion, there's very good generalizability, meaning that patients that are early in the disease stage have not yet developed lesions or not lesions as large as needed for being enrolled into the Dragon program would definitely benefit from the drug because we can or could keep them for longer on very good vision. Also, patients that reached relatively low levels of vision like 2020 in the better C&I, which would correspond to legal blindness in the United States. These patients still have a lot to lose, meaning that they will continue to lose down to 2,400, 2,800 to even NLP, no-light perception. ABCA4 belongs to the very few genes in the disease space of IRDs that can lead to no vision at all, no light perception. And we would like to avoid that or at least delay that, meaning that the addressable patient population out there is large in my personal opinion, includes almost all patients affected by stock hold.

Got it. And then maybe just moving to post potential approval, what do you think about the competitive landscape in both Stargard and GA across modalities and where this might fit in?

Yes. Welcome competition and we welcome the search for a therapy, a new therapies for stage disease. I've seen these patients for more than 2 decades, and there has been nothing for these patients. And they go blind. And the only thing that you can help them with is low vision aids and and obviously advise not to supplement vitamin A as an example. So we certainly welcome the competition in the space. When the gene was discovered in 1997, this was actually the start of my residency. People thought now that we have the gene it may only take a few years, and then we will have gene therapy to target stage disease. And it turned out to be so difficult. -- years of the approval of Luxtona for RPE65 disease, there has not been a second gene therapy in the whole space. And we have learned how difficult it is to develop gene therapy and still most of the competitors are trying to develop gene therapy for Stargard. There are a couple of very important problems -- the -- it's very difficult to target photoreceptors as opposed to RPE. Transduction efficiency is variable. You infuse inflammation. You can only deliver the gene surgery underneath the retina. You have to detach the retina in Stargard specifically the macular surgically, you should never detach the retina otherwise, obviously, -- and in Stargard you have the specific problem that ABCA4 exceeds the packing capacity of AAV and therefore, it makes it even more complicated, for example, to use to vectors or to try to use intent technology to blue 2 proteins together in order to have a compound that could compensate for the loss of function of ABCA4. Long story short, there is very little competition currently specifically in the gene therapy, but also in the stem cell arena of therapy approaches for stage disease.

Got it. Maybe switching gears just to kind of starting to talk through commercial opportunity, maybe patient population size. How do you think about the size of opportunity for Stargardt. Are there areas you bifurcate them or kind of divide them out? Just maybe more broadly there, and we can dive into a couple of specific nuances?

Yes. So Until recently, it was very difficult to actually know about the effective patient population in major countries like the United States. -- population-based studies like the vote in the U.S., rather them in Europe or Blue Mountains in Australia, provide us with good estimates for common diseases like altacare degeneration, diabetic retinopathy, but really nothing for rare diseases like stage disease. But until recently, maybe about a decade ago, genetic databases have become available. And we know about the prevalence of carrier rates of mutations in target genes like ABCA4, plus we know the penetrance rates of these mutations in stage disease. And taking that together in research over the last decade allows us to estimate the patient number, taking all races in the race mix in the United States, Caucasians, African origin, East Asian origin into account, to arrive at a patient population of between 49,000 and 57,000 patients in the United States. That means all patients of all ages, it also means all patients not necessarily diagnosed and certainly not necessarily genetically confirmed. But at least we have a good estimate of the total population of stage patients in the United States. So now we get to the fraction of patients that carry a diagnosis. That number is presumably pretty high because it's a severe disease that would not remain without any diagnosis, but it doesn't necessarily be the precise diagnosis. When it comes to genetic confirmation, that is another hurdle. And we anticipate a relatively high price tag for the drug. And clearly, the reimbursement system will demand genetic confirmation and I personally believe that the standard of care must include genetic information for stage disease. Therefore, this is 1 of the efforts we are currently having for our launch to get as many patients as possible genetically tested in order to maximize the number of patients that can benefit from the treatment.

Yes. Maybe Polin , are there any specific initiatives you can talk about this time? Or is that something for later around what you might be doing to?

Yes, maybe I pass it over to Hal.

Well, first of all, they are existing labs that provide the testing and 1 of them is actually fully sponsored by the foundation of fighting blindness. And I think the other 1 does probably screen for more -- slightly more IRD However, the insurance will cover the majority of the costs as well. So I think to Andrew's point, we see that the gene testing becomes more and more available nowadays. And also, hopefully, with a treatment available, that's going to be additional incentive for the patient to be incentivized to take the testing. For us, it's moving more about on education about the disease and about helping the physician and the patient to understand what are the testing available to get the can -- sometimes people are not taking the where to go to the testing and what's the consequence of that. I think in the past, there has been some misunderstanding or worries that people think that, oh, if I get the testing down, but there's no treatment -- does that affect any of my insurance premium, that kind of worries, right? So with the treatment coming or with the treatment available, that will really change a lot of that kind of worries. So what we're doing, of course, before the drug is approved, all we can do is just continue to bring the awareness of the disease and people to be aware of the testing.

Got it. And I guess in addition to kind of education and maybe zooming a out in terms of your guys' preparation for commercial readiness, are there other initiatives you're taking to make sure that you are ready?

Well, I think at this point of time, we have done several research pricing research, patient journey research. We look into different database in the U.S. So to get a good sense about how many patients are already diagnosed a disease and genetity confirmed. That's why we plan to have maybe a commercial day event in September to share like what we know. But we do see that Saga is a huge unmet need. Like Henry said, patients definitely -- most of them will seek help. And we see U.S. retina specialist community is very well aware of the disease. And there's a majority of those retina specialists do prescribe genetic testing. So we do not worry too much about the awareness from that community, maybe more education, awareness is required for the general of milages or low-vision automats just to make sure that they could be aware of when they the certain symptoms of the patients.

Very helpful. And I guess and position, ability to fund a lot of the commercialization you have ahead of you. Can you guys just talk through that a little bit?

Sure, sure. SP1 So well, we do see that launching for Saga in the U.S. is something that we can do given this rare disease. And we do believe that we have a team that experience about IRD -- at the same time, we do sit on $800 million cash. So our budget for commercialized for this in the U.S., probably somewhere about $300 million. with our existing pipeline, probably cost of $150 million for the next 3 years. So in total, we're thinking about somewhere like $450 million to $500 million is going to be the burn rate for this year and the next 2 years. So with $800 million cash, we think we are pretty comfortable that we should be able to launch this in the U.S.

Great. And then you guys may also be eligible for PRVs. Does that factor in your thinking as well?

Well, yes, so with the rare pediatric is destination, if the drug is approved, we should be qualified for PRV. The calculation that I just shared does not include that potential additional $100 million to $200 million proceeds from PRB.

maybe just final question. Obviously, you mentioned pipeline and kind of other indications. Anything you want to comment on in terms of ability to continue to expand?

Yes, that's a good question. So we have been really focused on star for the last few years, and we know how big the potential is, how strong the med is. So the team has been very devoted on the development of both Stoop and GA. But once we got some revenue coming in from Saga, we definitely are open to look into other expansion. One of the areas that you could potentially think about we'll be expanding to more IRD disease. I think currently, the market does not have a company-specific focus on IRD and with some successful saga that could be a good foundation for us to continue to look for treatment for other IRD DCs.

Great. Thank you very much.

Thank you.