Belite Bio, Inc

Good afternoon and welcome to the BelitBio Q2 2023 Financial Results Conference Call. At this time, all attendees are in a listen-only mode. The question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions at lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Belief Bio website following the conclusion of the event. Before we begin, I would like to bring your attention to the forward-looking statement slide. During this call, we may be making forward-looking statements. Please refer to the language on this slide for further reference. On today's call, we have Tom Lin, Chairman and CEO, Nathan Mata, CSO, and Haoyang Cheng, CFO. With that, I'd like to turn the call over to your host, Tom Lin, Chairman and Chief Executive Officer at BelitBio. Please go ahead, sir.

Thank you, Sarah. Thank you, everyone, for taking the time to join this meeting. I'm Tom Lin, CEO of BelitBio. I'll start off by giving the overview and the milestones we have achieved so far. So for those that are new to the Belit story, the drug that we are developing, Teneriband, is a novel one-stage oral tablet designed to bind to serum retinal binding protein as a means to specifically reduce retinal delivery to the eye. This approach is intended to slow or halt the formation of toxic retinal derived by products which are generated in the visual cycle and are implicated in progression of Starler's disease and geographic atrophy secondary to AMD. Bilibio believes that earlier intervention directed at emerging retinal pathology, which is non-mediated bioinflammation, would be the best approach to potentially slow disease progression in Stargardt's disease and GA-dry AMD. So there is still significant unmet need for both indications. Currently, there is still no approved treatment for Stargardt's disease, and there are currently no approved oral treatment for TA, which oral treatments are expected to capture a much wider market for advanced dry AMD. We have so far received abstract designation, rare pediatric disease designation, and often drug designation, which allows us to frequently discuss with FDA of our progress and see how we can expedite the approval of this drug if we show positive results from our phase three study. I would also like to mention that we still have a long patent life with the first composition of meta patent expiring in 2035. And this is without patent extension and with new patents being filed, which will extend the patent portfolio into 2050s. Now, in terms of important milestones achieved this quarter, our phase two 80-month treatment data continues to show slowing of lesion growth. We are also expecting our Phase 2 24-month final data readout in Q4 this year. We've also recently completed enrollment of our Global Phase 3 Stargardt trial, and we are now expecting interim readouts around mid-2024. We've also started enrollment for our Global Phase 3 trial in GA Dry AMD. And with this, I'll pass it on to Nathan to go through the think of our results. Nathan?

Yeah, thanks, Tom. So I'd like to first start by providing an overview of the trials we have going on in Stargardt's disease. We have two studies, as Tom mentioned. We have an ongoing open-label phase two study. This is a two-year study, which is just about ready to end in October. I'll give you some more information about that as we move forward. But we've got 18-month data to share with you, and I'll provide that in a moment. There's also the phase three data, which, as Tom mentioned, has recently stopped enrollments. We've met our target. In fact, we've exceeded our target by about 10 subjects. We've got 100 subjects in there. Both of these studies are two-year studies. They're both looking at the primary endpoint, which is the growth of atrophic lesions, that is DDAF, and I'll explain what that is in a moment. So there's a lot of similarities between these designs. The differences are as follows. In the open-label Phase II, there's only 13 subjects, and these subjects came in with only autofluorescent lesions. And I'll show you some of the biology on how the autofluorescent lesions turn into this atrophic lesion that we call DDAF. So that's one of the differences. The other difference, of course, it's an open-label study. We're looking at the same efficacy measures, the same assessments by imaging modalities such as fundus fluorescent autophotography to look at the lesion growth. And you can see here at the bottom what the key inclusion criteria were. The Stargardt Phase III study is also a two-year study in design. Of course, it's global. There'll be a two-to-one randomization favoring tenlariban. And you can see there the various inclusion criteria at the bottom of the slide. Next slide, please. So I want to show you first, as Tom mentioned, this agent, tenlariban, is a retinal binding protein four antagonist. And so the first biomarker, if you will, that we will see is reduction in the retinal binding protein four levels in serum. And that's what's shown here from the phase two data out to 18 months. So you see the very first point, which is shown there at 100%, that's before the patients got dosed. And you can see over the period of 18 months, we've achieved about 80 percent reduction from baseline of retinal binding protein 4. you see here this target threshold of greater than or equal to 70 reduction this number has been determined in a clinical study in geographic atrophy with a different retinal binding protein for antagonists i'll share that data with you as well but this has become our market because we believe that you need to achieve at least this level of rbp4 reduction to affect a change in lesion growth and by the way The daily oral dose these kids are getting, these 13 adolescent Stargardt kids, is 5 milligrams per day, and no one's left out to 18 months. I'll go over the safety data as well. Next slide. A little bit about the biology. So early in the disease course, there are only autofluorescent lesions, and that's shown on the left-hand side here, the left image. These lesions are called questionably decreased autofluorescence by ophthalmologists. Basically, what they do, they represent cells laden with autofluorescent entities. These autofluorescent entities are bisretinoids. These are the agents that we're trying to reduce. Because these bisretinoids are formed from vitamin A, we've reasoned that by reducing the amount of retinol going into the eye, we can have effect on reducing the accumulation of these dysretinoids and slow the growth of these autofluorescent lesions. So these autofluorescent lesions are amenable to rescue. But if left alone, which of course they have to be because there's no treatment, they will transition into atrophic retinal lesions, which is shown on the right-hand side. You see that black demarcated image? That basically is irreversible photoreceptor cell loss. Those cells are never coming back. That atrophic area is what ophthalmologists refer to as definitely decreased autofluorescence and stopping the growth of that lesion type is the primary endpoint. But of course, ophthalmologists look at the combined lesion growth rate because both of these lesions are pathologic. And so in one study conducted in 2020 by Giorgio and co-workers, They found in 53 adolescent Stargardt kids, the growth rate of the combined lesion was roughly about 0.7 millimeters square per year. When we look at that same anatomical feature in our 18-month data and annualize it out to a year, we see a growth of only about 0.28 millimeters square per year. So that represents about a 60% reduction in the combined lesion growth rate based upon comparison to this very well-conducted natural history study, which, by the way, at that time was the largest natural history study conducted in adolescent patients. But we were very concerned about comparing the atrophic lesion growth because that is, after all, the endpoint. And for that comparison, we had to go to the largest natural history study of Stargardt's conducted today called ProgStar. This study enrolled hundreds of patients with Stargardt's disease Many of them were adult patients, but among these patients, there was a small group of 20 subjects that had the exact same baseline characteristics as our subjects in the open-label phase 2. That is, they were 18 years or younger, and they had no atrophic lesions at baseline, only autofluorescence. So we were able to compare the combined lesion growth rate in that ProgStar group to ours, as well as the atrophic lesion growth. The combined lesion growth is shown on the left-hand side. This is called DAF or decreased autofluorescence. So it represents the QDF area plus the DDF area. And you can see here out to 18 months, we're getting about a 50% reduction in the combined lesion growth rate. And you remember this slide previously showed you a 60% reduction. So it's a pretty good comparison between these two separate and independent natural history studies. When we look at the atrophic lesion growth as the DDAF, we see at 18 months about a 60% reduction in that atrophic lesion growth rate. And noticeably, not many subjects are converting. In fact, there seems to be a slowing of the conversion in our treatment group transitioning from the autofluorescent lesion to the atrophic retinal lesion type. And that is all very consistent with our hypothesis that we would first affect a change on the autofluorescence and then subsequently a change in the atrophic lesion growth. And we believe that's what these data are showing us. And I should have mentioned, but the investigators from both the previous study by Giorgio and this study, PROGSTAR, which was Hendrik Scholl, commented that we are seeing a definite bona fide treatment effect in these natural history study comparisons so that's very promising for us to see next slide this is showing you the visual acuity data we're showing you both eyes the study eye and fellow eye of course both eyes are going to get the same treatment because this is an oral systemically applied drug we're showing you this because in clinical studies you do have to designate a fellow eye sorry study eye and then the other eye just becomes a fellow eye we just want to show you that across 18 months we're having a stabilization of visual acuity in these subjects. And this is a very promising trend because typically these subjects lose anywhere from four to six letters per year. So the fact that we've stabilized over 18 months is a very promising trend that combined with the slow lesion growth tells us we're affecting exactly what we want to do, stop the lesion growth, and eventually have an effect on preserving or improving vision. And you can see there the letters lost is roughly within noise of the variability of the visual acuity assessment. Next slide, please. So now we want to get into the safety data. I should start by saying there have been no systemic toxicities or EEs noted to date. So no clinically significant findings in relation to vital signs, physical exams, cardiac health, or organ functions. What we are seeing are two expected features of this therapy. And they're expected because we are reducing the amount of vitamin A going into the eye. So we expect effects on rod and cone photoreceptors, which are the two photoreceptor cell types in your retina. The first AE we're finding is a form of chromatopsia called xanthopsia. This is mediated by cone photoreceptors. And it typically happens when patients transition suddenly from a very dark light to a very bright light, or for instance, from waking after sleeping and being exposed to very high room light or sunlight. And so basically, cone photoreceptors are activated. They will demand chromophore under our treatment regimen that chromophore doesn't get there quite as quickly. So there'll be a delay in the timing for these cone photoreceptors to fill up with chromophore. And during that time, they will misfire and produce these artificial electrical mediated hues of color in the visual field. In this case, xanthopsia is yellow. But you can see here the majority of subjects are experiencing xanthopsia, but no one's leaving study because of it. And in fact, we are seeing some recovery over time. And we're not taking subjects off drug. They are recovering while still getting dosed. The second ocular AE is known as delayed dark adaptation. This is mediated by rod photoreceptors. And again, when rod photoreceptors, when you transition suddenly from a very bright light to a very dim light, rod photoreceptors activate. They require chromophore. There will be a delay in the timing of that chromophore to fill up the rod photoreceptors. And during that time, these rod photoreceptors will not have maximum dim light sensitivity. So there was a delay in the accommodation to dim light. This is not night blindness. I want to make that very clear. This is simply a delay, sometimes 8 to 12 minutes. In cases where it's very severe, out to 20 minutes in this one subject. It's called night vision impairment. But overall, we're very satisfied with these findings. We basically lost one subject to follow up at 12 months. So out of 13 subjects, we are now at 12 subjects. at 18 months, but this is still very, very promising safety profile. Next slide, please. So now I want to talk about that proof of concept study I told you about the 70% marker. How did we get there? Well, this was a study I conducted approximately 12, 13 years ago when I was with another company. I always had this idea that reducing retinal delivery to the eye might have an effect on slowing lesion growth. I didn't have a drug to do that with, but I did find an anti-cancer drug called fenretinide, which had a side effect of reducing retinol-binding protein 4 in the blood. As I said before, it was developed as an anti-cancer drug. But in all the cancer studies, what investigators noted was a dose-dependent reduction of RB4. So I repurposed fenretinide into a two-year drug. Phase two proof of concept study enrolling 246 GA patients to see if this drug would have any effect on slowing lesion growth. There were two treatment arms and placebo, 100 milligram, 300 milligram, and of course placebo. I want to show you the lesion growth data just from the high dose arm and placebo because the middle dose of 100 milligram had absolutely no effect on lesion growth. What you're seeing here on this histogram shown on the left-hand side in the black bars is the lesion growth in the placebo group expressed as a percent increase from baseline. So we're getting about a 50% increase over 24 months in the placebo subjects. In the 300 milligram group, there was something very interesting. There was a group of subjects that had a very profound reduction of retinal binding protein of at least 70% or more. In those subjects, there was about a 25% slowing of lesion growth over two years. In the subjects that did not have this reduction of retinol binding protein for 70% or more, there was absolutely no effect on the lesion growth rate. So we're pretty convinced, especially in GA, that this is the level of reduction that would be required to affect a change in lesion. And of course, this is the same sort of approach that we're applying to Stargardt's disease. An interesting thing about this lesion growth reduction, you'll notice it started right at about the 12-month time point, and it stabilized between 18 and 24 months. But when we look at the visual acuity loss in these subjects, we also notice in these subjects that had a preservation of lesion growth, that is a reduction of lesion growth, there was also a stabilization of visual acuity loss right at about the same time, 12 months, there was a six-letter loss and there was no further loss out to 24 months meanwhile the placebo group and the patients the subjects that did not get that profound reduction are before continue to lose vision out to about 11 or 13 letters over the two years so we have a very significant visual acuity gain and a very significant lesion reduction that has never been observed before in a ga study the problem with this phase two study was that only one in three subjects actually achieved this profound reduction of rbp4 in the 300 milligram group And the reasons for that are twofold. One, fenretinide has terrible bioavailability. So we asked subjects to take this drug with a high-fat meal at dinner to increase exposure into the blood. Many patients complied out to about one year, but after one year, we had a lot of patients falling off of that compliance. And we knew that because the RVP levels in these patients would inflect upward, indicating, in fact, that they're no longer having suppression of RVP4. The second problem was the low potency of fenretinide. Phenretinide is a terrible drug for SNOPP4 antagonists because it has the same affinity for the target as does the native ligand vitamin A. With Tendleriband, we have designed a drug that specifically overcomes those deficits of phenretinide so it has greater bioavailability and 100-fold greater potency than does fenretinide. So we're convinced with this better purpose-designed RBP4 antagonist, we can achieve at least this benefit and probably even greater because, again, we'll have better compliance and we'll have greater potency of the drug on target. Next slide, please. So now a little bit of our Phase III study in geographic atrophy. This is important to note. So we were concerned that with a higher age and higher BMI of patients that have GA versus Stargardt's disease, we would have to do a dose higher than five milligram. So we did a PKBD study with both five milligram and 10 milligram. And what we found was a five milligram dose produces the same pharmacogenic profile as it did in younger subjects. So in these healthy adults, we're seeing about an 80% reduction of RPP4 across the dosing period With this five milligram dose, and it's also important to note, and we see this in the adolescent subjects as well, once you withdraw the treatment, the RBP4 levels start bounding back upward, showing a nice reversibility of the pharmacodynamic effect, which of course is a nice safety feature in the event of any untoward AE or you want to return the patient back to baseline status. Sorry about that. Now, a little bit about the clinical design overview for a phase three study we call Phoenix. This study design is going to be nearly identical to the phase three trial design for Stargardt's. That is, it's two years in duration. It has the same randomization frequency, two to one favoring tenlariband. It has the same endpoint measure. So we're still looking at the same DDAF measure as a primary measure for efficacy. And of course, we're looking at other measures such as BCVA and looking at the autofluorescence. There are two major differences. One, of course, is the indication, geographic atrophy and not Stargardt's. And the second one is that we'll be enrolling up to 430 subjects instead of the 90 that we targeted for the Stargardt's disease study. This, of course, reflects the higher prevalence of GA in the population. But otherwise, these studies are essentially identical. And I think Tom mentioned that we've actually kicked off this study. We've enrolled our first patient, I believe it was last week, and we continue to get more interest and more patients rolling into this phase three study as we move forward. With that, I believe I can turn it back to Hao Yan so he can discuss the 2023 Q2 financial results. Thank you.