Belite Bio, Inc

Good morning and welcome to the Be Light Bio Quarter 1, 2023 Financial Results Conference Call. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. As a reminder, this call is being recorded and a replay will be made available on the Be Light Bio website following the conclusion of the event. Before we begin, I'd like to reference you to the forward-looking statements and legal disclaimer slide on the screen. Joining us today on today's call is Be Light Bios Chairman and Chief Executive Officer, Dr. Tom Lin, Chief Scientific Officer, Dr. Nathan Mata, and Chief Financial Officer, Haoyuan Zhuang. With that, I will now turn the call over to Tom.

Thank you, Tara. Thank you, everyone, for joining our financial results for first quarter 2023. Joining me today is our CSO, Nathan Mata, who will be updating our recent clinical trial progress, and our CFO, Hao Yuan, will be updating our Q1 financial results. For those that are new to the Be Light story, the company is developing a novel oral once-a-day treatment that potentially slows disease progression in Starless disease and geographic atrophy in dry AMD. There is still a significant unmet need for both indications, as currently there is no approved treatments for Stargardt's disease, and there are currently no approved oral treatments or no approved noninvasive treatments for geographic atrophy, which is predominantly in an elderly patient population. We are currently in global phase three for both indications, and so far we have been granted fast track designation, rare pediatric disease designation, and orphan track designations. As mentioned, we are currently in phase three development, and we have composition of meta patents until at least 2035. And with patent term extension and new patents to be filed, which will take us well into the 2040s. So we still have a very long patent life on this drug. So for the Stargardt indication, the phase three is already two thirds enrolled with estimated interim readouts by mid 2024. We've also just recently presented very promising 18-month treatment results from our Phase 2, which our CSO will be presenting the results later on. We also expect to have the 24-month final data readouts for the Phase 2 study in Q4 this year. For the geographic atrophy in dry MD indication, the Phase 3 is expected to start enrolling subjects in mid-2023. And I would like to pass it on to our CSO to give an update on our clinical trials. Nathan.

Yeah, thanks, Tom. Hello, everyone. I'm Nathan Mata. So as Tom mentioned, this is an oral once a day treatment. The drug is called tenlariband. This drug is a retinol binding protein for antagonists. So our approach is to use this drug to limit the delivery of retinol to the eye as a means of reducing the toxic retinoids, vitamin B products that have been implicated in disease progression of both starter disease and advanced dry MD. So in both these studies, we are trying to slow the growth rate of retinal lesions. That is the FDA primary accepted endpoint for both Stargardt disease and geographic atrophy. What you're looking at in front of you are the trial design overviews for our ongoing open label phase two, where I'll share some 18-month data with you. In fact, we've had interim analyses periodically six months throughout the study, and we presented those data at international ophthalmology conferences, AAO and ARVO, and we just recently presented the 18-month data at ARVO. You can see here the overview of the study in the phase two outline, 13 subjects. These subjects came in with no atrophic retinal lesions, but they had very prominent autofluorescent lesions, which are the lesions that precede the atrophic lesion growth in Stargardt's disease. These subjects came predominantly from Australia and Taiwan. It is an open-label study, as I mentioned, at two-year in duration. We're looking primarily at safety and tolerability. We've already established the optimal dose at five milligrams daily. In fact, that dose is effective to achieve the same pharmacodynamic response in both adolescent Stargardt patients and elderly healthy patients. I'll show you some of that data as we move forward. we're looking at the growth rate by an instrumentation called fundus autofluorescent photography this allows us to visualize both the atrophic lesion which of course we're trying to slow as well as the precedent atrophic lesions which are as i said precede the the the growth of atrophic lesions and in fact are where the bis retinoids are sort of residing you can see the key inclusion criteria at the bottom The phase three study that we call Dragon is actually enrolling. We're up to about, I believe, 58 patients out of 90 that we're targeting. These subjects will all have DDAF at baseline because, again, this is a pivotal study. It will have a placebo control, and we need some reference point for the endpoint, which is, of course, slowing the growth of the atrophic lesions. Of course, this will be a global study, Stargardt being an orphan disease. Hard to find these subjects, especially since we're going after adolescent subjects, not adult subjects. So thankfully, the enrollment is going quite well at this point. You can see the randomization here, 2 to 1 favoring tenleriband. two-year treatment duration with a one-year interim analysis. And of course, we're looking at the same efficacy measures and safety measures as we looked at in phase two. The inclusion criteria are a little different. You can see there at the bottom, we've increased the upper age range to 20. We've increased, we've also put in a size stipulation for the lesion size. So there is an upper end of the lesion, but that's not because Teleribet won't work with larger lesions, but in a two-year study that gives us the best opportunity to observe a treatment effect versus placebo. Next slide, please. So as I mentioned before, this drug targets retinol-binding protein 4, which is the sole carrier for delivery of retinol from the liver to the eye. Important to note that this protein is not needed for retinol delivery to other tissues of the body because they don't require RBP4. They lack a receptor that the eye possesses in sufficient quantity. So the eye has this dependence on delivery of retinol-bound RBP4. This is why this is a fairly direct, site-directed approach. You can see here that over periods of dosing in the ongoing phase two, up to 18 months, we're getting a sustained reduction of retinal binding protein form of at least 70% or more. The reason we target this particular dose is because of data from a precedent clinical study in geographic atrophy, where a different RBP4 antagonist was used In those patients, those subjects, it was found that subjects who got to at least the 70% reduction or more had a slowing of lesion growth. And I'll share that data with you as we move forward. And as I mentioned before, this dose, daily dose, is 5 milligrams. And you can see here approximate 80% reduction, mean reduction of RB24 throughout the treatment trial. There's no tachyphylaxis. That means rebounding of the pharmacodynamic effect. Next slide. Next slide. I want to now share with you some of the lesion data from our 18 month open label study, the phase two. But before we do that, I need to sort of give you an orientation for what we're looking at. We're looking at two different lesion types. The first one you can see here on the left is known as a questionably decreased autofluorescent lesion. You can see the boundaries there outlined in blue. this is what ophthalmologists refer to it as qdaf lesion it's visualized here as you can see as i mentioned by fundus autofluorescent imaging the important thing about these lesions is that they may be amenable to rescue because the tissue is not atrophic yet it is simply filled up with all of these autofluorescent bis retinoid compounds so it's on the verge of converting But if we get to it early enough, it's possible that we may be able to slow its conversion into dead retinal tissue. And we'll talk about that more in a moment. And now as we transition to the right, you can see how that autofluorescent lesion converts into an atrophic retinal lesion. This is what ophthalmologists refer to as definitely decreased autofluorescence. I refer to it as dead retina because that, in fact, is the indication of irreversible loss of photoreceptor cells. There's no coming back from that. So when investigators look at the growth rate, they look at it in a couple of different ways. One way is to look at the aggregate growth of both the autofluorescent and atrophic retinal lesions. That's referred to as decreased autofluorescence or DAF. Another way to look at the lesion growth is independently the autofluorescent lesion growth versus the dead retina growth. And of course, the dead retina growth is what the FDA is most interested in, in terms of a primary endpoint for efficacy. We look now to the literature to see if this data, the growth that we're seeing in our subjects is comparable to or less than or greater than something that's published in Natural History. And we look at a recent study published by Georgia in 2020, where they quantified in 53 adolescent subjects the growth rate of the aggregate that is the DAF lesion, the autofluorescence plus the atrophic. They see a growth rate of about 0.7 millimeters square per year. When we do that same analysis in our cohort at 18 months and analyze the data, we see a growth of about 0.28 millimeter square per year. This represents approximately a 60% reduction in the growth rate of the aggregate retinal lesions, both the autofluorescent and the dead retinal lesions, again, compared to natural history. Next slide, please. We now look to comparisons versus Prague Star. So if you're not familiar with Prague Star, this was an international effort by global retinal specialists and ophthalmologists to better characterize the natural history of disease progression in Stargardt patients. They looked at both adolescent and adult patients, but it was skewed more heavily towards adults. What we have in our cohort, our phase two cohort, subjects that are 18 years or less, and they have no DDAF at baseline. Well, it turns out subjects with that exact baseline characteristic were present in the ProgStar cohort. And when we look at the growth rate of lesions, both the aggregate lesion, the DAF shown on the left, and the atrophic retinal lesion by itself on the right, we see the growth rate fairly linear. That's the gray or blue line you see. That's the ProgStar data, roughly anywhere from about 0.8 to 1 a millimeter square change of those retinal lesions per year. And then we compare that to our data shown in the red line here, the DDF lesion on the left, the DDF lesion on the right. And you can see, if you look at the trajectory, there's roughly about a 50% reduction in the growth rate of the combined retinal lesion and separately the atrophic retinal lesion compared to ProgStar. So in the previous study, we had a 60% reduction in growth compared to natural history. Here we're seeing about a 50% reduction looking at both the primary endpoint measure as well as the aggregate lesion growth rate measure. Another important point to measure is that not all of these subjects converted to an atrophic retinal lesion. In fact, the majority did not. Seven of 12 subjects did not develop any atrophic retinal lesions at the 18-month time, but that's roughly 60% of the cohort. Next slide, please. we're looking at the visual acuity data we have what we we're very we're very happy to see this actually this shows a stabilization of vision most ophthalmologists who see um adolescent starboard patients tell us that we should be seeing a more significant loss of vision just based upon the natural progression of disease here we're seeing a stabilization we're not losing any more than about three letters over 18 months which is well within the test retest variability of BCVA. So really there's nothing to be said with respect to BCVA other than we are stabilizing it, which is almost a promising treatment trend. Next slide. Now we're talking about the safety data. So again, this is the 18-month safety data. We look systemically for AEs, of course, in these subjects because this is an oral drug. You would expect to be systemic side effects, but in fact, we see no systemic side effects whatsoever, no severe or moderate drug-related AEs reported, no AEs requiring discontinuation from treatment, and no clinically significant finding signs in relation to vital signs, physical exams or cardiac health. Very important point. And as I said before, this is a fairly site-directed approach. So what we're seeing are primarily two ocular drug-related adverse events, which we want to see. These are anticipated features of the drug, and they tell us we're having the intended biological effect on the retina. The first is a form of chromatopsia, which is an aberration of color vision. This happens when patients transition suddenly from a very dark environment to a very bright environment. This activates cone photoreceptors in your retina. Cone photoreceptors mediate bright light and color vision. So when you stimulate them with bright light or color, they want chromophore and because under our treatment regimen that chromophore will only be slowly supplied to the photoreceptors there's a delay in their timing to fill up and they will misfire during this period and produce these transient use of color in the visual field in this case yellow has been most frequently reported by our patients but you'll note most of the subjects are reporting this as mild no one's leaving study because of it and of course it's transient so it goes away after several minutes The other manifestation that we're noting is delayed dark adaptation. Again, an anticipated feature of the treatment. This is mediated by rod photoreceptors, which mediate dim light vision. So when patients transition suddenly from a very bright light to a very dim light, this activates rod photoreceptors. Of course, they'll need chromophore just as cones would in the bright light. They don't get it and they'll misfire during this period. They will not have their full dim light accommodation. So patients will wait several minutes before they can actually accommodate to that dim light. We have mitigating measures for both of these AEs. They simply are to slow patients' transition from extremes of lighting environment. So in the instance of chromatopsia, you slow your transition from the dark to the light. And in the instance of delayed dark adaptation, you slow your transition from light to dark. This is particularly important for elderly patients in our GA study. But again, all these AEs are mild and well-tolerated with respect to delayed dark adaptation. This is a manifestation of the disease process. So most patients can't even discern the pharmacological added delayed dark adaptation on top of their own intrinsic disease-caused delayed dark adaptation. Next slide, Hyun. So I mentioned earlier that we had clinical proof of concept from a different retinal binding protein for antagonists. I call this a surrogate molecule. I did this study when I was with another company approximately 12 years ago, trying to answer the question, would reduction of retinal delivery to the eye reduce lesion growth rate in patients with either Stargardt's disease or geographic atrophy? At that time, we didn't know much about Stargardt's disease. There was no regulatory path toward approval. But for geographic atrophy, there was. And in fact, that study was easy to do because there were lots of patients available. The drug used is called fenretinide. This drug was chosen. Because although developed as an anti-cancer drug, it has a side effect of reducing retinol-binding protein 4 in the circulation. Can you give me a click, Hayim? So as shown here, this is a synthetic retinoid. It was not designed as a retinol-binding protein 4 antagonist. It was designed as an anti-cancer drug. So I repurposed this drug in a phase two proof of concept study with 246 patients that had geographic atrophy, including a placebo control. So there was placebo and two dosing arms, a 100 milligram arm and a 300 milligram arm. I'd now like to show you the uh lesion growth data over the duration of that study we're not showing the 100 milligram cohort because there was no treatment effect whatsoever you can see in the black bars here the placebo growth from baseline grew 50 so basically a 50 increase in this area of the size of the lesions in those patients that got the placebo treatment In the 300 milligram group, there was something very interesting. There was a group of subjects that did not achieve a reduction of retinobinding protein 4 of 70% or more. Those subjects showed the same growth rate as placebo. But in the 300 milligram group, subjects who achieved at least a 70% reduction of retinobinding protein 4 or more had this profound reduction of lesion growth. approximately a 25% reduction over the two-year study. I do get often asked from time to time, how did we find out that this treatment effect occurred? Actually, at end of study, there was no treatment effect whatsoever. But in the interim analysis, we noticed a treatment effect, and I wondered, where did it go? And so I started looking at the pharmacodynamic data, and we saw that there was an inflection of retinol-binding protein 4 upward at the 12-month point. A lot of these patients either stopped taking it, or it stopped having a bioavailability effect in these patients. So the other point I want to point out is that at the 12-month time point, when we look at the visual acuity loss, again, we see a stabilization in those patients who had a treatment effect against lesion growth. So you can see here in those patients who had at least a 70% reduction of retinal binding protein 4, they had a slowing right about the 12-month time point. They didn't lose any more than six letters. In the meantime, placebo and those patients in the 300 milligram group that did not achieve that large RPP4 reduction, they lost as much as two lines relative to the other group, the responding group. So this is roughly a two-line gain. It's approximated. Does that be based upon looking at the difference between placebo and the treatment arm? We have a 25% slowing of lesion growth and a stabilization of vision representing a two-line gain at the end of this study. As I mentioned before, it's unfortunate this study, only one of every three subjects actually met this requirement for the retinobinding protein for reduction. And we believe that's due to largely the lowered bioavailability of the drug. We asked this drug to be taken with a high fat meal. A lot of elderly patients don't want to comply with that. So we didn't get a lot of good bioavailability exposure. The other problem was A fenretinide is not very potent. It has the same potency for the target as does the native ligand retinol. Our drug, Tinlaribat, overcomes all of the negative aspects of fenretinide. First, it has much greater potency, 100-fold greater potency than fenretinide. Two, it has much greater bioavailability, so it's much more water-soluble. Patients won't have to take this drug with a high fat meal. And thirdly, maybe even more importantly, it's not a retinoid, so it has a much cleaner safety profile and will be much more tractable for long-term chronic dosing in diseases like Stargrass disease and geographic atrophy. Speaking of geographic atrophy, let's talk about our phase three study design in GA. I mentioned earlier that the five milligram dose was effective to achieve the same pharmacodynamic response in both adolescent subjects as well as elderly healthy adults. You're seeing here a pharmacodynamic profile obtained from adults to match the higher BMI and higher age range of geographic atrophy patients. These volunteers took five milligrams daily, and you see a very nice profound reduction of retinol binding protein four following the initial doses. It stays reduced during daily dosing until we withdraw the drug. We didn't show you that in the adolescent patients, but it's true for them as well. When we withdraw the drug, the retinol binding protein four rebounds back toward the baseline, which is a nice effect to have the reversibility of the pharmacodynamic effects should there be any untoward effects with regard to safety or long-term dosing of tenlaraband. Next slide. So this is the clinical trial design overview for the phase 3 GA study that we call Phoenix. This endpoint is going to be exactly the same in Stargardt's disease. The duration is the same, same primary endpoint, same imaging modalities. The only real difference between these two studies, of course, is the indication, that being GA versus Stargardt's disease, and of course, the size. We're looking at approximately 430 subjects to be targeted. We're actually starting that enrollment actually starting this month and next month. This will be a global double-blind study, same randomization as we saw in the Phase III Stargardt study, 2 to 1 favoring tenlariband. As I mentioned, two-year treatment duration looking at exactly all the same primary efficacy measures that we looked at in Stargardt. And of course, there will be a one-year interim analysis. So with that now, I think I'll throw it over back to Hao-Yen so we can talk about the Q1 2023 financial results. Hao-Yen?