This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk00: 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 coworkers, They found in 53 adolescent Stargardt kids, the growth rate of the combined lesion was roughly about 0.7 millimeter 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 millimeter 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 Prague Star. 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, ProgStart, 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 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 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 chromatopsy 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 eight 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 this findings we basically lost one subject to follow up at 12 months so out of 13 subjects we have 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 Phase 2 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 mg, 300 mg, 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 mg had absolutely no effect on lesion growth. what you're seeing here on this histogram shown on the left hand side in the black 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 had a very profound reduction of retinal binding protein for 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 RBP levels in these patients would inflect upward, indicating, in fact, that they're no longer having suppression of RBP4. 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 a hundred 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 a little bit of our phase three 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 pharmacogenetic profile as it did in younger subjects. So in these healthy adults, we're seeing about an 80% reduction of RPB4 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 to Larabette. 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, 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.
spk02: Thank you, Nathan. So as of June 30, 2023, we have $57.4 million in cash. And for the R&D expenses for the three months ended June 30, we had research and development expenses that was about $5.5 million. compared to $1.6 million for the same period last year. The increase was mainly due to the expense on the Phoenix trial and also the increase on the wage and salary due to our R&D team expansion. For the G&A expenses, again in Q2, we had G&A expenses $1.4 million compared to $0.9 million for the same period last year. And the increase is due to the increase in professional service fee and also the wage and salaries. The net loss was $6.8 million this quarter compared to $2.4 million last year for the same quarter. And about the key milestone, as Tom mentioned earlier, so we initiate the study this Q1, and we just got the first patient in this quarter. And we also fully complete enrollment for the DRAGON study with 100 subjects so far. And we expect to have the 24-month data by Q4 this year. And also, we expect to have the interim result from the phase 3 DRAGON study in Starler disease by mid-next year. With that, I'll turn it back to Sarah.
spk05: Thank you. At this time, we will begin conducting our Q&A session. For those analysts that are in the Zoom with us, please raise your hand to indicate you would like to ask a question. And for those on the webcast, as a reminder, if you are in full screen mode, you may need to exit it in order to see the Q&A portal. So with that, I'm going to open it up for questions from our first analyst, which is Basma Radwan from Leerink. Basma, you may go ahead and unmute your line.
spk04: Hi, good afternoon. This is Basma on for Mark Goodman. We have your question on the upcoming final readout of the phase 2 trial and start our disease. The 1st question is really what should we expect in terms of the efficacy at month? More specifically, I'm talking about the reduction of the. Lesion growth rate. Should we expect a similar level of reduction in the lesion growth rate to the level demonstrated at month 18, which is a 50% reduction when you compare it to the match controls from the Proxstar study? The second question, it's about the conversion from the QDAF lesion to the DDAF lesions. So at month 18, five out of 12 patients on tenlariband had DDAF lesions. versus nine out of 20 patients in the PROCSTAR study. What changes to these proportions should we expect at month 24? And the final question is about any updates you have about dropouts in the study. Do we still expect 12 patients for the time point at month 24? And I do have a couple of questions for the phase three dragon study, if you don't mind.
spk01: Sure. Nathan, you want to take this?
spk00: i'd be happy to if how yen can go exactly yeah exactly go here so the first question related to what we expect to see at 24 months if you follow these trajectories particularly for the ddaf um basically you're going to see the same thing basically add another the lines will continue to sort of track the same way so we'll get at least a 50 reduction we already know what the 24-month data look like um in in in progstar so it's going to go a little bit higher than where it is where it is now And of course, our DDF will inflect upwards a little bit as well. But this study is going to end in October, so basically two and a half months from now. I don't expect that there's going to be any significant change from these trajectories over the next two to three months. So I think what you're seeing here is a very good snapshot of what you can expect to see at 24 months. And in terms of the numbers of subjects, I don't expect we'll lose any additional subjects. Again, we lost one. out of 13 when we first started due to a lost follow-up at 12 months. No one has left because of any safety or AE concern. So don't have any real concern about that. Your other question was related to the conversion from autofluorescent lesion to the atrophic retinal lesion. And so I expect that probably by 18 months, I'm sorry, by 24 months, we should see at least two more subjects convert. Again, that's based upon the sort of run rate that we're going, but there will be a significant percentage difference, numerical difference in the percentage of subjects in ProgStar that converted versus the number of subjects in our study that's converted. Our study will show a lower number, which again is consistent with our hypothesis and our MOA that reducing the autofluorescence will then slow the transitioning of the autofluorescent lesion to the atrophic retinal lesion. So I think I addressed all three points, Basma, but please let me know if I've missed anything.
spk04: Thank you. That was very helpful. The one question we have about the phase three dragon study, it's about the inclusion criteria. So you do specify in the inclusion criteria lesion size to be within three disc areas. Could you provide more color on the rationale behind this inclusion criteria? I'm ready.
spk00: yeah so this this goes to our approach for early intervention so um i've done new number a number of studies in starburst disease and geographic atrophy one thing i've consistently seen and by the way all of the studies i've done in these diseases have been with oral therapeutics and either visual cycle modulators or rbp4 antagonists to sort of mediate the effect and so what i've seen consistently in these studies is that lesions that are smaller at baseline tend to respond better to these types of therapeutic approaches. And that's even been shown in natural history studies where you look at growth rate of lesions that are small versus large. You do tend to see faster lesion growth rates in lesions that are smaller than they tend to sort of slow down as they get large. And this term i'm using large and small of course is ambiguous but when i say small lesions i'm talking about lesions that are less than for instance five millimeter square and certainly nothing bigger than 10 millimeter squares anything bigger than 10 millimeter square is what i consider too large in fact that's where inflammation starts kicking in so it's important to know sort of the chronology of the pathology early in the disease course there's very little inflammation so when these early lesions uh how young could you go to the lesion comparison the qdf and ddaf yes here so so these qdf lesions that you're seeing here are really the the first lesions are actually going to convert right and and and turn into um the atrophic retinal lesion but once the lesion if you look at the left hand right hand side right now once that atrophic lesion gets too large there's nothing you can do to slow it down so the reason that we're specifying less than three disc areas is again based upon all the prior clinical studies that i've done and natural history studies in both ga and starters that show that smaller lesions respond better um to treatment and a sort of a real world evidence for that is data from the mix you step study um this is a study conducted by kubota pharmaceuticals or maybe even called kubota vision formerly AccuCella Pharmaceuticals is what it was, and they were advancing a drug called amixustat, which is an RPE65 inhibitor intended to do the same thing that we're doing, which is reduce the bis-retinoids. And in fact, it worked very well in animal models, but it's a very aggressive approach because it hits an enzyme of the visual cycle that's the rate-limiting enzyme. So anyway, they ran a phase three study with 194 Stargardt subjects, and they didn't reach their endpoint at two years. But in a post hoc analysis, what they found was that patients who came in with smaller lesions at baseline had as much as a 40% slowing of lesion growth. So that's a very, very important note for us, particularly in Stargardt's disease, because that's exactly what we're doing is we're recruiting subject with smaller lesions at baseline. We believe all this clinical evidence and scientific evidence tells us we're doing the right thing for these kids. So again, early intervention is the best way to stop these emerging retinal lesions that will eventually affect vision.
spk04: Great, thank you. That's very helpful.
spk00: Yes, thank you.
spk05: Thank you for the questions, Bosma. The next question comes from Jennifer Kim at Cantor.
spk03: Hi, thanks for taking my questions and congrats on the execution this quarter. Maybe to start off with Dragon, I believe the original announcement for enrollment completion highlighted 90 adolescent patients, and here it says 100 subjects. I was wondering, maybe you could provide any color around that difference?
spk00: Yeah, I'd like to do that if I could. I'm sure that was going to come up. But it's important to note that when we stopped the enrollment at sites, there were a number of subjects in the screening queue. We can't just turn those subjects away. So basically, although we stopped accepting new patients, the patients that were in the queue, which
spk01: about it. I think it was about 20 patients in the queue, went through screening, and of those subjects, approximately 10 qualified for
Disclaimer