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spk02: Good afternoon and welcome to the BeLight BIO 2022 Full-Year 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. 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 lifestyleadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the BeLight website following the event. I'd now like to turn the call over to Tom Lin, Chairman and Chief Executive Officer of BeLightBio. Please go ahead, Tom.
spk09: Thank you, Tara. Thank you, everyone, for participating in this earnings call. I'd like to take this opportunity to give you an update on our current overview and milestones. So we are currently going into 18 months into a 24-month open-label Phase II study. which will be presenting that data at Arvo by end of the month. At the same time, we are also halfway. We recruited 41 subjects out of the 90 subjects into our global phase three study, and we are expecting interim readouts by mid-2024 next year. We recently met with the FDA to request that we increase the sample size from 60 to 90, The reason being that after analyzing very promising 12 month treatment data from our phase two, we ran some simulations and we worked out that if we increase the sample size to 90, we would have more data going to the interim and that will give us a very good chance of meeting that statistical significance for efficacy. We've also initiated our global phase three trial in geographic atrophy, secondary to dry AMD, which is expected to start enrolling subjects by mid-year this year. So with the interim analysis coming up for the phase two, the 18-month data, we feel that this will probably give a very good reference to what the study will look like for our phase three. Okay. Next slide, please. So the market opportunity is that To date, there's still no treatment for Stargardt's disease. And currently there's about 30,000 subjects, 30 patients in the U.S. with Stargardt, and currently there's no treatment. In terms of AMD, it is still a very large population globally, and this is still arising given the aging population worldwide. As you can see on the graph on the right, The graph shows that with more advanced age, the more advanced the AMD gets. And at the stage of AMD, we all know about the wet AMD, the market, about $10 billion a year. But geographic atrophy, we expect this to surpass the wet AMD market. Even though there is the anti-compliments that are getting approved or with a palace that's approved, we still think that there is still a very good, there's still a need given there is still a non-invasive form of treatment such as oral therapies, which we think would surpass the market for AMD. Next slide please. So I'll hand it off to Nathan to go through the scientific slides.
spk01: Thank you, Tom. Hello, hi, Nathan Monte here with CSO for the company. I want to talk about the mechanism of action of Tim Larabant. Before I begin that, I want to preface by saying in both these diseases that we're interested in intervening, Stargardt's disease and geographic atrophy, they're both associated with the toxic and actually cause retinal cell death in tissue. These toxic byproducts are derived from circulating vitamin A. What our approach is, is to reduce the entry of retinol into the eye as a means of reducing the bis-retinoids, these vitamin A byproducts that would cause retinal disease. Penlarabant, our orally available once a day drug, competes with native vitamin A, retinol, or binding to retinol binding protein 4, and reduces or limits the amount of retinol entering the eye. When this happens, the BIS retinoids, which are formed from retinol, also are reduced because there is a reduced amount of retinoids traversing through the visual cycle. In Stardust disease, this is the primary culprit of vision loss in these patients is the formation of A2E and related BIS retinoids. In geographic atrophy, these molecules accumulate as well, but for a different reason and from a different origin. It's because of a dysfunction of the retinal pigment epithelium. I'd like to now show you clinical presentations of what these diseases look like. On the top, you have a series of images, retinal photographs from a patient with Stargardt disease. And on the bottom series of images, you have a patient with geographic atrophy. We're looking over about a similar same period of time, roughly four and a half years in each patient. What you can appreciate if you compare the baseline images to the last images at 55 or 57 months, is that in both cases, the autofluorescent area you see around lesions, which are these bright areas of tissue you see surrounding the lesion, they actually spawn the new dead retina. So wherever the autofluorescence is, that is where the lesions grow into. the autofluorescence spans centrifugally, and the dead lesion, that black retina, follows. So this tells us that the autofluorescence precedes lesion growth in patients with Stargardt's disease and geographic atrophy, and that an approach to reduce these bis-retinoids by limiting retinol should be effective to preserve vision loss in these patients. Next slide, please. I'm showing now our clinical development pathway, starting with our first patient population, that is our adolescent Stargardt patients. This is, of course, after conducting our requisite SAD and MAD studies to establish safety and tolerability of this drug. In the Phase 1b2 study, we enrolled initially 11 Stargardt subjects and determined in those subjects in the one-month Phase 1b that a 5-milligram dose was effective to drive the retinobionucleotide level down to roughly more than 70% from baseline. We enrolled those subjects then into an open-label two-year phase two, and we added two additional Stargardt subjects for a total of 13 subjects participating in the ongoing two-year study. I have one-year data, safety and efficacy data, to share with you today from this phase two study. We've also initiated, as Tom mentioned, begun recruiting for our phase three adolescent Stargardt study. Out of a total of 90 subjects, we've recruited roughly 42 subjects to date. This is going to be a randomized double-mass global study. primary endpoint will be looking at the lesion growth rate. Secondarily, we'll be concerned with best corrected visual acuity. We are also now initiating a phase three trial in geographic atrophy. This, again, will be a two-year study with a similar trial design to that of Stargardt's in that the same endpoints are the same, same treatment duration, and there will be an interim analysis at one year, except this study will have 430 subjects randomized in the same manner as the Stargardt study with two to one favoring Tenlaribat. And you can see looking forward around 2025 to 2026, that is when the earliest timing we would have for an NDA filing with a promising phase three study in Stargardt's. If our phase three study is not that promising, of course, the FDA may requires to write another clinical trial. However, they have given us uh words that they would take our data under review after the first phase three pending really good lesion results and a stabilization of visual acuity and then certainly after 2026 would be when we start looking for planned completion of our g study and commencement of a second phase three study next slide please i'd like to now share with you some pre-clinical i'm sorry some clinical proof of concept data that tell us that Reducing retinal delivery to the eye would have an effect on slowing lesion growth. In this particular study, this was done in GA patients. This study was done when I was CSO for another company called Serial Therapeutics. It was conducted approximately 13 years ago, and the data was published. The reference is shown at the bottom of the slide. In this study, I used a drug that was not designed as a retinal binding protein for antagonists. This drug is called fenretinide. Fenretinide is a synthetic derivative of vitamin A. It was developed as an anti-cancer drug, but it has the side effect of reducing retinol delivered to the eye because it binds to RBP4 in the same way that our drug does. However, because it's a retinoid and because it's a weak binder, it's not expected to have great retinol binding protein for antagonism. However, I repurposed it for that purpose anyway, just because it was the only thing available to establish a proof of concept to address the question, would reducing circulating retinol entry into the eye have an effect on slowing lesion growth. This is a two-year study, placebo-controlled with two treatment arms, 100 milligram and 300 milligram. What we found at the end of the two-year study was that patients that got to a profound reduction of retinobinding protein for at least 70% or more had a statistically significant slowing of lesion growth. The data you're looking at on the right-hand side of these histograms show the lesion growth rate in placebo, that's the black bars, and you can see in those subjects, the lesions grew roughly 50% larger relative to baseline. So over two years period, they grew 50% more in size. Whereas patients that achieved this reduction of RVP4 of 70% or more had a 25% expansion of lesion growth rate, representing a 25% treatment effect on the expansion of lesions over two years. You can see that subjects in the 300 milligram arm who did not achieve at least that 70% reduction of RVP4 did not have any meaningful change in their lesion size growth, and they are comparable to placebo. Another important point, outcome of this study, was that those patients who achieved that greater than 70% reduction of RBP4 also had an improvement in visual acuity in the sense that they stabilize after 12 months. So if you look at this plot on the lower right-hand side, you will see those dark green bars stabilize after 12 months at about six letters lost. Meanwhile, the placebo group and the other 300 milligram subjects who did not achieve the RBP4 reduction of 70% or more lost anywhere between 11 to 12 letters over two years. such that at 24 months, we had a two-line gain, relatively speaking, in the group that achieved that significant RPP4 reduction versus placebo. The unfortunate thing in this study was that because of the limited bioavailability and lower potency of fenretinide, only one-third of subjects in that high-dose cohort demonstrated that significant reduction of RPP4. And again, that is largely because of the reduced bioavailability of fenretinide, We asked that this treatment, that this drug, it is an oral drug, be taken with a high-fat meal at dinner to improve absorption. Possibly two-thirds of the subjects in the high-dose arm did not comply after about 12 months, and we can see that from the retinal binding profiles, they actually inflected upwards, which showed us they were not taking their drug as prescribed, but that one-third of subjects that did in fact comply had a very profound reduction of RVP4 and had this profound reduction of lesion growth and a stabilization of visual acuity. Our drug, tenlaraband, is also an oral once a day, but it has much greater bioavailability than fenretinide and a much greater potency. You can see here the comparison. Tenlaraband binds RPP4 with an affinity of two nanomolar. Meanwhile, fenretinide binds with a similar affinity as the native ligand retinol at 200 nanomolar. So this means we have 100-fold greater potency, a greater bioavailability, and it's not a retinoid, so it has a better safety profile. Next slide please. I'd like to now enter into this discussion with some of the lesion growth rate data we had from that ongoing open-label Phase II study. But before I get there, I'd like to first describe to you what lesions we're actually looking at. There are two types of lesions I showed you in the previous image. There's an autofluorescent lesion, which is the first, the earliest lesion that is formed in the back of these patients' eyes. And again, this is because of the bisretinoid accumulation. So you're looking here at a subject with Stargardt's disease who has just the autofluorescent is rescuable tissue. It is not atrophic dead retina. But you can see that over 12 months, this autofluorescent lesion grows approximately 0.45 millimeters square per year. The point here is that these autofluorescent lesions are not stable. That is, they continue to expand, and they certainly never regress. Next slide, please. Here is a similar image of a patient that has both lesion types, both the autofluorescent lesion as well as the atrophic retinal lesion. So if you look at baseline, that black and demarcated area with the blue outline around it, that is atrophic retina, which ophthalmologists refer to as definitely decreased autofluorescence. That tissue is not rescuable. But to the right of that tissue, that zone of autofluorescence that you see, that speckled area, that is where the dysretinoids are. That is rescuable tissue. However, if you look at the 22-month image graph now, what you see is that lesion, that DDF lesion, has expanded tremendously from 0.82 millimeter square to 2.09 millimeter square. At the same time, the QDF lesion size, that is the autofluorescence lesion, has shrunk, relatively speaking, from 1.53 to 0.45. But if you look at the data more carefully, what you can see is it's only because that autofluorescence, sorry, the dead retina lesion has expanded into the autofluorescence zone. It's not that the autofluorescent lesion has shrunken necessarily. In fact, if you look at the perimeter, it's actually expanded outward a little bit, but the dead retinal lesion has occupied its area significantly. The point being here is that the dead retinal lesion grows tremendously in compromising the autofluorescent lesion size, and the dead retinal lesion, the DDF, is our primary endpoint. So, With that background, I now want to go into our phase two data, where we're looking at these autofluorescent lesions, the QDF, as well as the atrophic lesions, DDF. I should mention that in this open-label phase two, these 13 subjects, adolescent Stargrip subjects who were participating, had no DDF lesions at baseline. So we asked two questions. One, what is the time for transition from an autofluorescent lesion to a dead retinal lesion? And two, once that dead retinal lesion forms, How rapidly does it grow? We want to compare both those values to natural history. All the zeros you see at the baseline at phase one and the phase two are because there were no DDF lesions, no dead retinal lesions. But at six months into phase two, you see one of the 13 subjects transition to a lesion. This was striking to us because based upon natural history from the extensive PROVSTAR studies, we would have expected of these subjects to transition from QDF to DDF, yet we only have one of 13. At the one-year time point, we still have not another subject transitioning, just that same subject number 11 going from 0.32 at six months to 0.44 millimeter square bilateral lesion growth in both eyes. When we do the cohort mean for growth rate at 12 months, we get a very, very small growth rate of 0.03 millimeter square per year. In order to more faithfully compare our data to natural history, We looked at one of the prospective cohort studies of childhood onset star guards published by an author named Giorgio in 2020. And what they looked at here was the combined growth rate of the autofluorescent as well as the dead retinal lesions. So the DDF plus the QDF. And they saw a lesion size of 0.69. That's the growth rate for that combined lesion size. When we do that same measurement in our cohort of subjects, we only see a growth rate of the combined lesion of 0.26, representing a 60% reduction in the lesion growth rate of the combined QDF and DDF lesion size. Quite profound. Another piece of confirmatory evidence is that if we just look at the QDF lesion growth from the one-year data below, you will see that the QDF lesion in our subjects had a mean growth of 0.23, whereas the natural history predicts something closer to about 0.5. So here we're seeing about another 50% reduction in growth. So we believe we are seeing two things, two positive outcomes. One, a slowing of the transitioning from the autofluorescent lesion to the dead retinal lesion. And two, once that dead retinal lesion forms, we're seeing a slowing of the growth of that lesion. And both of these effects are consistent with the MOA that I described to you earlier. Next slide, please. I'm now presenting to you some of the safety data from the one-year Phase II open-label study in adolescent Stargardt subjects. I'll start this by telling you that there have been no systemic safety AEs whatsoever, no severe AEs or SAEs reported, and no AEs requiring discontinuation from treatment. Furthermore, there have been no clinically significant findings in relation to vital signs, physical exams, or cardiac health. What we see are two anticipated features of the drug, which we want to see because they are telling us we're having the intended biological effect on the retina. The first is called chromatopsia, which is an aberration of color vision. This happens when patients transition suddenly from a very dim environment to a very bright environment. This activates cone photoreceptors and they will require a chromophore to mediate that light response. because chromophore will only be slowly supplied to coneflow receptors. There is a delay in the time for them to adequately respond to bright light, and they will show they will misfire and electrically present into the visual field artificial hues of color. In this particular study, we're seeing more reports of xanthopsy, which is a yellow hue of color in the visual field. It has been reported as mild and transient. and all patients are dealing with it quite well. No one is really complaining about it because once patients understand how to transition from lighting environments to mitigate the severity of these AEs, they can manage them themselves. Same thing for delayed dark adaptation. Delayed dark adaptation is the manifestation of rod photoreceptors These are photoreceptors in your retina, excuse me, that mediate dim light vision. So when patients transition from a very bright light to a very dark environment, that activates rod photoreceptors. And once again, Promofor will only be slowly supplied to rod photoreceptors during tenlaraband treatment. The delay in the timing to fill up those rod photoreceptors so they become maximally sensitized to dim light is called delayed dark adaptation. And it's on the order of five to 10 minutes. most patients who have this disease, as well as geographic atrophy, have delayed dark adaptation. So they're mostly asymptomatic because they cannot discern the pharmacological addition of delayed dark adaptation on top of their own intrinsic disease cause delayed dark adaptation. Night vision impairment is a more severe exacerbation of the DDA, and this particular subject lasting out to 20 minutes, that is the delay in the ability to accommodate to dim light, and the increasing error score on the FM100 is a more severe manifestation of the xanthopsy. So again, a more prolonged manifestation of that hue of color in the visual field. But once again, no subjects have left study because of these, and we want to see these AEs because they are telling us we're having the right biological effect on the retina. This is a pharmacologic profile to show you the pharmacodynamic effect of our drug on retinobinding protein 4. Again, this is data from the phase 1b, our dose finding phase where we had the 11 adolescent Stargardt subjects. You can see here a 5 milligram daily dose drives the retinobinding protein 4 down to more than 70%. Over at least a three to four day period, we're not showing you all the data points here, but by the third day of dosing, they're actually at 70% or more reduction. And they stay reduced as long as we give them daily dosing until we withdraw the drug. And then during that period of drug cessation, you can see a very nice rapid reversibility of the pharmacodynamic effect. So we see a very rapid onset for reducing RPP4 and a very rapid offset. Having a nice reversibility effect is a good thing to have should there be any untoward effect of the drug during long-term treatment. This is now the clinical trial design overview for our Stargardt study. In the middle, you have our Phase II trial design, which I've already described to you, so I won't belabor that point. But if you look to the far right, this is our Dragon study, our Phase III study for Stargardt. I mentioned before that in our open-label Phase II, none of these subjects were required to have DDAF lesions, but in our phase three pivotal study, they will be required to have that because this is the endpoint, and we will need some measure of lesion size at baseline to compare subsequent lesion growth rate over the ensuing two years. Of course, it will be a global study, double-blinded nature, 2-1 randomization favoring tenlaribet, as I've mentioned, two-year duration with one-year interim analysis, and we'll be looking at the same efficacy measures that I told you about, looking at the bed retina growth, the GDF lesion growth as the primary endpoint. Secondarily, we'll be looking at autofluorescence, that is the QDF lesion, also be looking at vision, as well as retinal anatomy by spectral domain optical coherence tomography, and we'll also be measuring light sensitivity of the retina by microperimetry. I mentioned there is an interim analysis at one year, and at the bottom, you can see the key exclusion criteria. We will have very specific lesion size cutoffs, and that's because prior Experience has taught me that lesions of a larger size do not respond to these early intervention therapies because the disease has gone too far. I will now explain and provide for you our trial design for the phase three study in geographic atrophy. Before we began designing this study, we wanted to make sure that we had the right dose. Subjects who are elderly, GA subjects are typically larger, you know, they're heavier, higher BMI, of course, they're older age. And natural history shows that those two things predict a higher RBP4 level in blood. So I was concerned that we would have to use a higher dose above five milligram to achieve the same pharmacodynamic effect that we saw in the Stargardt subjects. We did not have that problem. So here you're seeing the pharmacodynamic profile from a five milligram dose in these older subjects with higher BMI and higher age range. And you can see we get about a mean reduction, about 80%. That was exactly what we saw in the Stargardt subjects. And then when we withdraw the drug over a 14-day period, you can see a return of that RBP4 value back toward the baseline value. This is our clinical trial design overview for geographic atrophy. Geographic atrophy has the endpoint that we're... is slowing the lesion growth rate. So both in Stargardt's disease and in geographic atrophy, we are looking at the exact same endpoint with the exact same imaging modalities that I showed you earlier, those retinal imaging that shows you the autophorescence as well as the dead retina. We'll be targeting patients with small lesion size for the reason I just said earlier. So this is another differentiator for our treatment effect. In addition to oral intervention once a day, we're looking for patients with early stage disease because these molecules that we are targeting actually are the earliest incipient molecules that start retinal atrophy. So we believe that if we can get to these patients early enough, we can actually halt their disease process and they would never be at risk of losing any vision loss as long as we get them at the right stage. We'll be doing this both for Starburst disease as well as geographic atrophy. And of course there's broad potential for this being an oral once a day therapeutic that is really going after the earliest causes of diseases that we believe this could be going into intermediate stages, such as intermediate AMD. We'd have to work out the biomarkers for efficacy there, but there certainly is a pathway forward. As I said before, we think in general with these chronic diseases where you have to have treatment for years to decades of your life, an oral once a day therapeutic will be a much more tractable approach than, for instance, For instance, an injectable intravitreal therapeutic into your eye. Next slide, please. Okay, again.
spk08: Thank you, Nathan. So in 2022, our R&D expenses increased 1.5 million from 7.4 million in 2021 to 8.9 million in 2022. The increase was primarily due to an increase in wages and salaries due to our R&D team expansion and increased share-based compensation expenses. Our GNA expenses increased by $1.6 million from $2.4 million in 2021 to $4 million in 2022, which was primarily due to an increase in professional service fees and also an increase of our DNO insurance expenses and increase of wages and salaries. In terms of cash, we received $38 million IPO net proceeds in 2022, and as of the year end of 2022, we have cash of $42.1 million. which can last until end of 2025 and is enough for us to complete a phase two and phase three startup shop if we do not spend any money on GA. However, considering the promising data that we have seen in the third time phase two study, in our own phase two study, and the market potential of GA, we do want to start GA phase three trial with the limited contractual liability in certain countries that we already received wrong interest from the PI and the sites, such as in the US and Australia. And with that, we will have cashed runway until end of 2024 and be able to complete phase two STAGA disease trial and obtain the interim result of the phase three STAGA disease trial. And we expect to only expand the GA study to more countries when we secure more funding. With that, I'll turn it back to Tom.
spk09: Thank you. So the key anticipated milestones for the year in Q1, we've initiated the Phoenix phase three study in GA. We've also enrolled 42 subjects into the Dragon study. And I believe that by I think this month is probably about six and six to 10 subjects that qualify for the study and So that will bring up to 50 by the end of the month. For Q2, we have our presentation that we will be presenting the 18 month treatment data for the phase two for Stargardt's disease. And shortly after that, we have a tail event to discuss this 18 month phase two efficacy and safety data for Stargardt's disease. We also expect to initiate enrollment for the Phoenix phase three study. in GA by late Q2. And then the second half of the year, we'll have the top-line 24-month Phase II treatment data, which we'll be expecting efficacy and safety data for the two-year study. We'll complete the enrollment for the DRAGON study by end of the year. with the recruitment rate picking up, we should be able to reach that target enrollment by end of the year. With this, this ends my presentation, and I'll hand it off to Tara to moderate the Q&A.
spk02: Great. Thank you, Tom. At this time, we'll be conducting a question and answer session with our speakers. Please hold for a brief moment while we pull for questions. So our first question comes from Bosma Radwan from SVB Securities. Please go ahead, Bosma. Bosma, you might be on mute. All right, we'll go to the next question. So our next question comes from Jennifer Kim from Cantor Fitzgerald. Please go ahead, Jennifer.
spk04: Hi, thanks for taking my question, and this is a very helpful update, so thanks for that. I have a few questions here. First, I know you talked about the reasoning for increasing the size of the Stargardt trial to 90. I just want to clarify, is that to increase the probability for a successful outcome for the study overall, or is this thinking that it could increase the probability of a positive readout at interim. And then related to that, does the mid 2024 interim assume, I know you said enrollment completion by the end of the year, but can you remind me if that mid 2024 interim, is that a one year interim readout based on the total patients?
spk09: Thanks. Yeah, so thanks. Thanks, Jennifer. So the first question was on Sorry, you asked three questions over there. The first question, what was the first question I asked?
spk04: Oh, just the rationale behind increasing the size.
spk09: Oh, yeah. So it's actually for both. So number one, that increases the probability for interim and for the final final. If we missed out on the intro, but we still have a positive trend. that gives us a pretty good opportunity for the final analysis as well. So actually it's for both.
spk04: Okay. And then the timing of the interim in mid-2024, how does that work with, so is it the enrollment completion is year-end and then the interim?
spk09: Yeah, so we would have majority of the patients completing 12 months by that time. I know some patients will be in the six months, will be six months, but the first quarter or one third of patients would have 18 month data by then. So on average we'll have 12 month data. Okay. Majority of patients. Yeah.
spk04: Okay, great. And then my second part of the question is for Phoenix. Is there a way we can think about, I guess, the pace of enrollment when you start out in those specific targeted countries and then how that will ramp up once you, I guess, expand into other sites? In terms of numbers, is there a way to think about that?
spk09: Yeah. So we started off in Europe, recruiting patients in Europe. So the first batch or the bulk of patients come from Europe.
spk08: She's asking about Phoenix, so it's a GA study, not a startup.
spk09: Oh, sorry, sorry. So what's the question again regarding GA study?
spk04: Since the GA study, I think you said you'll target enrollment in specific countries and sites, and then later down the line, you'll expand it to other sites. So is there a way to think about enrollment before and after?
spk09: So since global study, we're starting with U.S., uh and and then we work ourselves um to um globally to other sites as we um complete our financing so we can have um open about 50 sites globally okay uh and then of those 50 sites how many sites come from uh i guess that first um that first those first steps in general I think it's evenly spread. I don't have the list of sites right here in my hand, but I think it's evenly spread between U.S., Europe, and Asia.
spk04: Okay. That's helpful. All right. Thanks for taking my questions, guys. Thanks.
spk02: Thanks for the questions, Jennifer. Our next question comes from Lachlan Hanbury-Brown from William Blair. Please go ahead, Lachlan.
spk06: Hey, this is Lockland for Tim Lugo. We noticed that you've recently increased the upper age limit for enrollment from 18 to 20 years in Dragon. I was just wondering if you could talk about the rationale for that, I guess also the rationale for how you chose the original age bracket of 12 to 18 and then why you've expanded that.
spk09: Yeah, so Nathan, you want to take the question?
spk01: Yeah, let me just go ahead and take that. So initially, Lockland, the age range was really sort of capped off by the uh ODD designation and the rare pediatric disease designation because they categorize adolescents of um up to 18 years of age and so for those designations we kept that age restriction for the phase two the open label phase two but after going to the agencies of ODD and the RPD office we found out that as long as you don't completely transition outside of your adolescent patient range to just primarily get adults and try to get a indication for adults then you're fine, you still have the ODD status. So the real rationale for adding the 19 and 20 years is from investigators that have reached out to us and told us that they have subjects at their sites that would meet all qualification criteria for inclusion except the age range. So we wanted to do two things. One is to satisfy these investigators and get those patients into study. And two, it helped us reach that additional 30 subjects we wanted to get you to go from 60 to 90. And it didn't hurt. any of our orphan drug or RPD designations in the FDA or EMA.
spk08: Thanks.
spk02: Thanks for the questions, Lachlan. So our next question comes from Yi Chen from HC Wainwright. Please go ahead, Yi.
spk07: Thank you for taking my question. Just to clarify, could you give us some additional coloring on the enrollment criteria in terms of lesion size QD and versus DD in the phase three Stuttgart disease trial? And also, could you give us the same for the upcoming GA phase three trial as well in terms of enrollment criteria of the lesion size?
spk01: Yeah, good question. Thank you. I'll go ahead and take this. So for the start of our disease study, actually for both studies, what we know Dr. David Artesani, M.D.: : Again, based upon prior clinical experience is that lesions above a certain size and that roughly is greater than 10 millimeter square. Dr. David Artesani, M.D.: : are not that responsive to this type of treatment, we knew that from the fed right night study, we also knew that from the recently failed. Dr. David Artesani, M.D.: : boat to study with a mixture stat where they found that their starter disease patients didn't have any treatment effect, but when they did a. Dr. David Artesani, M.D.: : post hoc study and looked at patients that came in with smaller lesions at baseline they had a 40% treatment effect. So we know, and there's other published data that show that lesions that are larger grow slower. I know there's some contention in the field about if that's actually the truth, but I'm convinced by the data I've seen in the literature that larger lesions, whether you have Stargardt's disease or you have geographic atrophy, they just grow slower. So we're capping off the lesion a small size of 0.05 millimeter square. and the upper size would not be any greater than eight millimeters square. Those will be the size ranges for DDF lesion. We have no requirement for QDF lesion size whatsoever.
spk07: Okay, so are the patients in the ongoing phase two trial, is the requirement the same for the patients in the ongoing phase two trial and the phase three dragon trial?
spk01: No. In fact, that's one of the big differences is that those adolescent Stargardt subjects in phase two did not have any DDF lesion at baseline. And we're sort of, again, this was more proof of concept. So we want to see if our drug is having an effect on the conversion from the autofluorescent to the DDF lesion. And also, what is the growth rate of the lesion once it actually happens? In phase three, these subjects will be required to have a measurable DDF lesion of at least 0.05 millimeters square in order to enter the trial again, because we have to have a baseline measure of atrophy as a sort of a reference point to measure subsequent lesion growth.
spk07: I see. And what's the requirement for the dry AMD patients?
spk01: Going to be the same lesion size range.
spk07: Okay, got it. Thank you.
spk02: Thanks for the questions, Yi. So our next question comes from Bruce Jackson from Benchmark. Please go ahead, Bruce.
spk03: Hi, good afternoon, and congratulations on all of the progress. I have a follow-up question on the PHOENIX trial, the phase three for AMD. You're going to start enrolling during Q2. How long do you think it's going to take to enroll 430 subjects?
spk01: So my prior experience tells me 18 months to 24 months.
spk03: Okay, great. That's all I've got. All of my other questions have been answered. Thank you.
spk01: Thanks, Bruce.
spk02: Great. Thanks for the question, Bruce. So our next question comes from Yonzi from B. Riley. Please go ahead, Yon.
spk05: Thank you for taking our question. I have three of them. First, Nathan, can you share additional color regarding the change of enrollment for Stargardt disease? What was the assumption you used for the statistical analysis?
spk01: Yeah, so you mean for the initial 60% or is this that one?
spk05: Yeah, so from 60 to 90 patients, and you mentioned that the interim analysis will have a better chance to reach statistical significance.
spk01: Right, so when we initially targeted 60 patients for enrollment, the treatment effect that was postulated there was a 35% treatment effect. We felt that was a little bit too robust, given, you know, so even though we saw very positive data at six months and one year, what we wanted to do was really compare, be more conservative, and so we used the treatment effect that to GA study, which is roughly about a 25% treatment effect. So with that treatment effect, a lower treatment effect, again, being more conservative and optimistic, even though we believe we're going to have something greater than that, we wanted to power our study with much greater power. And so we posited a lower treatment effect, which of course triggered a higher sample size, a larger sample size to meet the power of at least 80% with 90% confidence. and of course an alpha of 0.05.
spk05: Got it. That's very helpful. And the second question, Tom and Haoyuan, can you remind us your thinking around the strategy to develop GA programs?
spk08: Well, I think, you know, in terms of the strategy, we would be more, you know, looking for our income result on the startup trial, and then we will be open to maybe find a partner for this entire pipeline i think it's going to be uh hard that you separate the two indications even it's the same drug so it's more likely that uh if we find a partner they're going to take over both indications and i think for the potential second ga trial that probably will be run and paid by that pharma got it and my last question is regarding the fda's requirement on save check
spk05: Can you remind us how many patients are required to be enrolled in the phase 3 trial for GA, of course, adjusted by the duration of treatment?
spk01: So this question is really on a case-by-case basis. The hard sort of line, if you will, that the FDA takes, because they have a hard requirements for the safety database. So their requirement for a safety database, which is really the only requirement you have to have, in addition to showing statistical significance in your trial. So for the safety database, the agency wants at least 300 subjects at or above the intended clinical dose for at least one year. And that doesn't mean it has to be your indicated patients. It can be any patients with any ophthalmic disorder, just so long as they have some ophthalmic disease. So you can use those patients to establish a safety database. In terms of what you put into your phase three, the agency does not ever opine that maybe you don't have enough, or maybe you have too little, or sorry, too much, because it really is the sponsor's decision. You have to understand what the agency is looking for in terms of statistical significance and the safety database. So those are the two requirements that we look to, and everyone should know that we're a very cautious and conservative company. All of our trial designs are vetted before the agency in type C meetings before we solidify and move forward towards recruiting.
spk05: Got it. That's all my questions. Thank you for taking our question.
spk01: Thank you.
spk02: Great. Thanks for the questions, Jan. This concludes the question and answer session for today's call. I'll now turn it over to Tom for closing remarks.
spk09: Thank you, everyone. Thank you for your time and your interest in the Starlight and AMD program. Look forward to everyone keeping up to date with our data, with our presentation and our KOL meeting. Haoyan and Tara will send out the invites and the information regarding these two events. And thank you again.
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