Good morning, ladies and gentlemen. Thank you for standing by. Welcome to Ocular Therapeutix Interim 10-Month data update from the ongoing U.S. phase I clinical trial of OTX-TKI for the treatment of wet AMD. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker host, Donald Notman, Chief Financial Officer. Please go ahead, sir. Thank you, Livia. Good morning, everyone, and thank you for joining us on our conference call to discuss the interim 10-month results from our U.S.-based phase I clinical trial of OTX-TKI for the treatment of wet AMD. The press release that we issued on Saturday and the slide deck with the interim results can be accessed on the investors portion of our website at investors.ocutx.com. Leading the call today will be Antony Mattessich, our President and Chief Executive Officer, who will also be joined by Dr. Rabia Gurses Ozden, our Chief Medical Officer, and Dr. Peter Kaiser, our Chief Medical Advisor, Retina. Following our prepared remarks, we will open the line for your questions. As a reminder, on today's call, certain statements we will be making may be considered forward-looking for the purposes of the Private Securities Litigation Reform Act of 1995. In particular, any statements regarding our regulatory and product development plans as well as our research activities are forward-looking statements. These statements are subject to a variety of risks and uncertainties that may cause actual results to differ from those forecasted, including those risks described in our most recent quarterly report filed November 7th with the SEC and our annual report on Form 10-K filed on February 28th, 2022 with the SEC. As a reminder, the slides being presented in today's call by Dr. Peter Kaiser are available on the company's website under the Investors tab, Events and Presentation, Investor and Corporate Presentations. I would now like to turn the call over to Antony. Thanks, Donald. Good morning, everyone. Before handing it off to Peter to take you through the presentation, I just wanted to say a few words that we believe that this data means for Ocular Therapeutix and more importantly, for patients suffering from VEGF-mediated retinal diseases such as wet AMD, diabetic macular edema, and diabetic retinopathy. In the case of wet AMD, it is well known that the vision gains seen when starting treatment are not maintained over time in the real world. The main reason for this is the lack of compliance caused by the injection burden of current antibody therapies like Lucentis and Eylea. In the real world, patients tend to miss necessary injections for a variety of reasons. wet AMD patients tend to be elderly and can find it difficult to get to retina offices on a four-eight weekly basis, so appointments are missed or delayed and permanent vision loss occurs because of the damage caused when the medication wears off and the disease process returns. In the case of diabetic retinopathy, where patients are generally of working age, the lack of urgency from the fact that the disease may not have manifested yet and finding the time to get treated on a frequent basis create real compliance challenges. In this population, the result is that patients are not treated and frequently progress to more severe vision-destroying disease before seeking treatment, making diabetic macular edema a leading cause of blindness among the working age population. In short, we believe the promise of a drug like OTX-TKI is not only about convenience but also about saving vision. If we can move durability from the current frequency of injections of four-eight weeks and maybe at the outset three-four months to 10 months and beyond, we believe we can keep people on treatment and preserve vision. Lastly, it is important to understand that OTX-TKI is a different paradigm than typical antibody treatments. Existing treatments like Lucentis and Eylea are bolus injections where a large amount of antibodies, well above the amount needed for immediate treatment, are injected into the vitreous and those antibodies are eliminated from the vitreous until they drop below therapeutic levels, allowing the disease process to restart. Extending intervals is done by making the antibody larger and slower to eliminate or just by jamming more antibodies into the eye with each injection. Either way, you're still treating a chronic disease with pulsatile dosing. OTX-TKI is different. OTX-TKI is designed to deliver a continuous dose of axitinib, a potent inhibitor of VEGF, keeping drug concentrations above therapeutic levels for extended periods without the drug peaks or troughs of pulse dosing. We believe that these results bear this out and demonstrate that we are keeping therapeutic levels of axitinib at continuous levels in the vitreous for the duration of the study. If OTX-TKI works as it's designed to, it should work as long as we keep adequate levels in the vitreous, which our hydrogel technology allows us to do. This new paradigm will allow physicians and patients the comfort of knowing the drug is always on board, like a security blanket, and can hopefully demonstrate that there is less variability in the retina over time, and more importantly, that vision gains from anti-VEGF therapy are maintained in the real world. What's next? We believe we have our proof of concept in wet AMD and by extension have gone a long way toward proof of concept in other VEGF-mediated retinal disease, given the impressive durability of OTX-TKI. Importantly, we also have a working formulation. We believe we are ready to enter our first pivotal trial in wet AMD as soon as the third quarter of this year. We've scheduled a Type C meeting with the FDA to discuss the pivotal study design within the next few weeks. We've also mentioned that commencing this trial is subject to financing, and we are considering a range of non-dilutive or minimally dilutive funding options, but we have a strong preference to go forward through a potential strategic alliance. We've also stated our intention to begin a phase III program for diabetic retinopathy in the first quarter of 2024, assuming positive top-line data results from our ongoing phase I clinical trial and subject to a follow-up meeting with the FDA. The diabetic retinopathy program is a separate program and with much more modest resource requirements than wet AMD. Consequently, our plan to commence the first pivotal trial in diabetic retinopathy in the first quarter of 2024 is not contingent upon a strategic partnership. We believe both wet AMD and diabetic retinopathy could be blockbuster applications for the product profile we are building with OTX-TKI. We have a very valuable asset and we believe a very clear plan going forward. Without further ado, I'll pass the baton on to Peter to go over the 10-month data. Peter? Thank you, Antony. As was mentioned before, the slides I'm presenting are available on the Ocular Therapeutix website for viewing. It's my pleasure now to present the U.S. clinical trial results we just presented at the Angiogenesis meeting, which show the up to 10-month interim analysis. Next slide. As was mentioned previously, there are forward-looking statements and this presentation discusses an investigational product which are in development. The efficacy and safety profiles have not been established, they have been not approved for marketing by the FDA. Next slide. I'm now on slide three. The OTX-TKI is a hydrogel proprietary polymer matrix combined with axitinib, which is a multi-target tyrosine kinase inhibitor, specifically with high selectivity to all the VEGFR as well as PDGFR receptors. We look at the VEGFR2, which is the most pathologic, the one that causes leakage in angiogenesis, it has the lowest IC50 versus all other current clinical TKIs in development. This is injected as a rod through a 25 -gauge or smaller needle into the vitreous. It completely bioresorbs over roughly six to 12 months. Next slide. We're on slide four to remind everybody about the U.S. phase I study design. This enrolled patients with age-related macular degeneration with subfoveal choroidal neovascularization that has been previously treated with anti-VEGF injections and in the investigator's opinion, has controlled fluid. Patients are then randomized to one of two treatment arms, either the OTX-TKI arm, where they receive the OTX-TKI at baseline a month later than the aflibercept injection, and then are followed on a monthly basis for rescue. The rescue criteria are shown at the bottom. The most important rescue criteria is since this is a phase I clinical study, the investigator had the option to treat the patient at their discretion. In addition, if the patient lost more than 10 letters of vision from, on the ETDRS eye chart, or if they had evidence of more than 75 microns increase on the OCT of their central subfield thickness, combined with a five-letter loss of visual acuity or the presence of new macular hemorrhage. The control arm was aflibercept dosed on label every two months. Next slide. It's important to understand matching in a small study such as this, we were able achieve very good matching in terms of baseline visual acuity, central subfield thickness, age, et cetera. Next slide. We are now on slide six, and this shows the swimmer plot. There are some very important things to note about this. First of all, these are not patients who are not receiving injections, as shown on slide left in the pretreatment. These are patients who are receiving extensive anti-VEGF injections, a majority on a monthly basis before being enrolled in the study. If you look at the OTX-TKI arm, the majority of rescues were at the investigator's discretion. These are the purple squares, and only a few patients at the month eight and beyond actually met any rescue criteria and were treated according to rescue criteria. Three patients overall. This leads to a treatment reduction up to the 10-month time point of 92%, a dramatic reduction. Next slide. If we look just at the rescue-free subjects, these are patients who didn't require any rescue, we previously reported at the seven-month time point a 73% reduction, or rescue-free duration, and we're pleased to report now at the up to 10-month interim results of this study, we have the identical 73% of subjects being rescue free up to 10 months. Next slide. We are now on slide eight. This shows both the visual acuity and the OCT results of the clinical study. There's several very important things to note about this slide. First of all, if you look at the visual acuity outcomes and the OCT outcomes versus a basically gold standard control of aflibercept dosed every eight weeks, there was essentially no difference in visual acuity outcomes at month 10, 0.3 letters lost in the OTX arm and in the aflibercept arm, 0.8 letters lost. If you look at the retinal thickness, essentially no change. - 1.3 microns in the OTX and - 4.5 microns in the aflibercept. That's essentially within the error of the machine. The other thing I want to point out is aflibercept was dosed on label, so every two months. As Antony mentioned earlier, if you look at slide bottom, there's that seesaw pattern that we've seen in pretty much every clinical study with Eylea, showing that some of those patients are having a lot of fluid fluctuations, visit to visit, depending on if they received an injection or not. In contrast, the OTX-TKI arm shows a very stable, OCT result. Fluid fluctuations are kept to the minimum. In addition, at the end of the study, so we're looking at the eight, nine, and 10-month time points, we see the OCT actually improving over time with an uptick in the visual acuity at those same time points. Finally, if you censor the rescue subjects from these analysis, the visual acuity and OCT results are the same. Next slide. Since this is a phase I clinical study, the most important outcome for investigators is safety. We're pleased with the safety up to 10 months, with no reports of drug-related ocular or systemic serious adverse events in either arm. If we look at adverse events of special interest, including elevated intraocular pressure, retinal detachment, retinal vasculitis, and implant migration into the anterior chamber, this was not seen in any of the patients in the OTX-TKI arm. There was I patient in the aflibercept arm that had elevated intraocular pressure, this was judged as a moderate adverse event. In addition, as previously described in the OTX-TKI arm, one patient had acute endophthalmitis. This occurred after the mandated aflibercept injection at month one, was deemed to be not related to the study drug, but instead related to the injection of aflibercept. It resolved with standard treatment, which is intravitreal antibiotic injection. This same patient developed a moderate adverse event of a cataract after the acute endophthalmitis, which is shown here. The safety at month 10 was very similar to the safety at month seven, and so far shows good results. Next slide. We're on slide 10 now, which is the concluding slide, shows that this phase I clinical study at U.S. clinical sites in patients with previously treated neovascular age-related macular degeneration comparing OTX-TKI versus standard, gold standard aflibercept injections every two months. In the OTX-TKI arm, the safety was generally well-tolerated. As I mentioned, there were no drug-related ocular or systemic adverse events, and adverse events of special interest for a TKI polymer were not seen in the OTX-TKI arm. Importantly, no subjects to date have dropped out of the clinical study in either arm. We're very excited about the efficacy that has been shown now. Recall that at the six-month time point, 80% of patients were rescue-free. Now at the up to 10-month time point, 73% of patients are rescue-free following a single OTX-TKI injection. The visual acuity results in the OTX-TKI arm were stable and comparable to aflibercept dosed every eight weeks. We showed a very clinical meaningful reduction in treatment burden up to the 10-month time point of 92%. Next slide. This concludes my remarks of the U.S. phase I clinical study. I now turn it over to the operator to take your Q&A. Thank you. Ladies and gentlemen, as a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, press star one one again. Please stand by while we compile the Q&A roster. First question coming from the line of Jonathan Wolleben with JMP Securities. Your line is open. Hey, good morning. Congrats on the data. Thanks for taking the questions. Maybe two for me to start and then a follow-up if I can. Can you let us know the reasons for the three per protocol rescues later on in month eight, nine, and 10? Also there's some discussion of the dissolution of the hydrogel over the weekend at Angiogenesis. Can you give us an update on, you know, what the dissolution rates look like and the consistency, and then an update on any of the formulation work that you previously have discussed? Sure. I think, Peter, you want to handle the first question on that? I'm in. I'm gonna punt the first question to Rabia. I'll take the second question. Yeah, you take it. Rabia, you go first, and then Peter, you follow up. Sure. The, those, rescues were per the visual acuity changes, and also the, you know, like, they were per criteria is described, and those were visual acuity changes. I can actually just quickly go over the, you know, the solutions, if that's all right, and then Peter can add. Sure, go ahead. Sure. Okay. The, what we have seen in Australia data, we have a very, you know, our implants are very programmable. Only temperature and water contact would affect the resorption of the implant. Again, for the data we have seen from Australia so far, we have seen a very consistent start of the resorption of implant at around eight months. There may be individual differences, but we expect that would be still the case in most subjects. Currently, the trial is still masked for that and, we will have this data available at the end of the trial. Peter, would you like to add more? Sure. I've spoken with several of the investigators, both in Australia and in the U.S. studies. What they see as basically there's bioabsorption of the hydrogel and release of the axitinib is basically some white particles, very similar to what we'd see with, say, triamcinolone. This is very different than, say, intraocular inflammation, which is something we'd be very concerned about. These particles are released, as Rabia said, roughly at the eight-month or so time point, and then within a month or two are completely gone. Interesting thing is, you know, we're talking about a polymer here that should be bioresorbing anywhere from six to 12 months. We're starting to see it really around eight months. To me, looking at the clinical trial results as a clinician, you know, we want to kind of see patients start to get rescued in any study of this sort, because that would show that the drug is wearing off and the disease is indeed going back to being active. When I start to see rescues in eight, nine, 10-month time points, that doesn't bother me. In fact, that's what I kind of would expect to see in any trial with a polymer releasing any sort of drug. If basically there were no rescues, that would concern me, because that would indicate that maybe these patients didn't need any treatment at all. So we hope to see that over time in any study with a polymer. Is there any changes necessary to the formulation then that you'd like to get done before starting the next round of studies? Mm-hmm. No, we clearly have a formulation that works. You know, we've mentioned before that we're working on an additional formulation that would have a higher release rate. Given what we've seen with the results of the current formulation, we have a workable formulation and certainly one that we would wanna bring into phase III development. Fantastic. Just one more from me before jumping back in the queue. The diabetic retinopathy trial, you know, any sense when we could see some interim data from that, perhaps sometime this year? As we're thinking about the translatability from wet AMD to DR, you know, any sense of how what we've seen with visual acuity or retinal thickness translate to diabetic retinopathy severity score? Just getting a sense of what expectations should be, either in this first phase I or moving forward. Rabia, you wanna do the first one and then Peter sort of follow up on the second? John, would you mind I wanna understand your question very clearly. Would you mind? Yes, Rabia. Just when we might see some interim data from the ongoing phase I. Ongoing phase I, U.S. phase I, you mean? Diabetic retinopathy study. Oh, okay. Which is currently enrolling. Okay. Okay, yeah. It is currently enrolling, and we're gonna, you know, just, we are thinking now is, seeing, the, interim results by the end of this year. Taking your second question, which is, you know, how much can we use the data from both the Australia and the U.S. clinical studies and sort of extrapolate that to diabetes? Well, you know, it depends on mechanism action of a drug, whether you can extrapolate. For us, the mechanism action is targeting downstream activation of the VEGF receptor. We have two clinical studies, one in patients who are been previously treated, but more importantly, treatment naive in Australia. This study, which we just showed, the U.S. study, shows good activity in macular degeneration, which is largely VEGF-driven. Diabetic retinopathy is also largely VEGF-driven, as been shown with both the Eylea and ranibizumab approvals for the treatment of diabetic retinopathy. For us, the extrapolation is pretty easy. Obviously, we're not gonna move forward until we have some results from our phase I clinical study in diabetic retinopathy. As a clinician and as a scientist, the MOA between the two are very similar, we would hope to see a similar result. Got it. That's helpful. Thanks again for taking the questions and congrats. Yeah. I wanna add one thing to your question about the axitinib showing a terminal burst at about eight to nine months. To me, speaking with the investigators, in addition, looking at the results, basically, when you have that free axitinib, we're seeing a bump in both the visual acuity, and a reduction in retinal thickness. In a way, one of the things that we were concerned about was what would happen with the axitinib when released, and what we're finding is it actually is working great in these patients sort of the tail end of when the polymer's around. It's actually disappearing, but we're seeing improvements in our patients, not the opposite. Thank you. One moment, please, for our next question. Our next question coming from the line of Dane Leone with Raymond James. Your line is open. Hi, guys. This is Sean on for Dane Leone. Congrats on the update. Actually, to put a finer point on the point that Peter just made, perhaps difficult to quantify, but do you guys think that you are kind of confirming that you're seeing this bolus release and have an elevated vitreal effective concentration of axitinib kind of at that like eight-10 month time point? How are you thinking about that going forward, in terms of maybe potentially conferring a more durable effect, due to that accelerating release towards the terminal dissolution of the insert? It seems like you guys are now leaning more toward this formulation, potentially due to this effect, conferring more durability. kind of just to clarify, you're still going forward with the new formulation in terms of development, but you're thinking more about the current formulation moving toward the phase II-III and kind of how does that affect timing on the phase II-III? Well, I'll handle the first part. I mean, Or the last part. We're lucky enough to have, to know that we have a formulation that works. One thing that does seem to be suggestive from the data is that more axitinib is better. The formulation that we have currently in development actually increases the daily release rate of axitinib, so in the earlier periods, you'd get a higher concentration of axitinib. You wouldn't have as much drug at the end of the life of the insert, so there may be some effect on the durability. We really have, you know, two things to really choose from here that, you know, a higher release rate with potentially less durability, although we're well beyond the period that we thought we would be initially, speaking about, you know, eight months and longer. Initially we thought we were gonna go about six months. It is, we are definitely in the realm of standard-setting durability. We intend to bring both of these doses forward, and we will decide later on which one we want to bring to market or both, depending on which indication suits which formulation better. It's kind of an embarrassment of riches because we have the potential for both. Neither one are on the critical path in terms of being able to start our wet AMD in the thirdrd quarter of this year. We've had great progress on the backup formulation, so we believe that that will be ready in time, for that trial to begin. We're in very good shape. Your specific question's around the PK and what we're seeing in the trial, clearly we don't get human data on the PK in the vitreous. We have now collecting data on when we can see the insert go away or the hydrogel bioresorb, and then when the drug clears. That all appears to be around the eight-month time that we see the insert, the hydrogel bioresorbing, and then the, you know, nine, 10-month period where we see the drug clearing. In some ways, we're not surprised that our month seven results were the same as our month 10 results because we are keeping axitinib in the vitreous at the same or higher levels than the earlier treatment. I think the interesting part is gonna be the month 12 analysis, where we see patients who are no longer on high levels of axitinib in the vitreous to see how long it takes the disease process to restart. I think we would kind of expect that to be highly variable, just like it is with the current anti-VEGF treatments, that it takes a while for the disease process to restart. We would expect in that 10-12 month period to have a number of patients with fluid starting to return to the retina because they no longer have axitinib at therapeutic levels in the vitreous. I don't know if either Peter or Robbie wanna add anything to that. No, I think you said it well, right. You know, we sort of have two formulas that we could take forward and plan hopefully to take forward. As Antony mentioned, you know, one of the things that's very interesting about this formulation is its longevity. One of the things that's interesting about the new formulation is sort of the higher levels early on. What we don't know and what we don't, we can't tell you at this point is what we're planning to do in terms of phase III, phase II-III. One of the things the FDA usually requires is oftentimes two different drugs. It's not out of the question to be able to go forward with either this or the other one. I'm very excited about the results of this, especially in the later tail points. You know, basically, this drug is working up to month 10. I can't wait to see the final 12-month analysis of the full study. Yeah. Thanks. That's helpful. If I could have just one quick follow-up. How are you guys thinking about those two formulations in terms of patient populations? It seems like maybe it could be, you know, more amenable for certain distinct patient populations. How does that just inform those phase II/III as well? Well, I mean, you know, I don't think it's two populations, and we certainly don't plan to bring two drugs to the market that, you know, we're gonna figure out which one's the better of the two. As Antony said at the beginning, you know, this basically gives us options. Many companies will be like, "Well, you know, we'll just take this one forward." We have a couple to see which one's the best. I don't think in the future we'll be like, "Okay, we'll use this formulation for these patients and this formulation for other patients." We're only gonna take one forward to the finish line. I think if I can also add, is that, again, none of the formulations are at critical path. This one is ready to go into pivotals, and we mean to move this one to the pivotals. The other one is needed, if needed, would be added as well. Otherwise, you know, just wanna clarify, none of them are at the critical path to start a phase III, a pivotal trial in Q3. Thank you. One moment, please, for our next question. Our next question coming from the line of Joseph Catanzaro with Piper Sandler, your line is open. Hey, guys. Congrats on the data, and thanks for taking my question. Just wanted to follow up maybe first on, Antony, your comments on the 12-month time point and follow up. It sounds like that data point is gonna tell us more about the disease and less maybe so about TKI, but maybe you can correct me if I'm wrong, and just speak a little bit more to sort of the data points you're gonna get and what it'll inform you with regards to TKI and perhaps even the formulation. Then on safety, ocular AEs went up from, I think, 10-16 from seven to 10 months of follow-up. Maybe you could help contextualize those a little bit in terms of whether there were any trends or specific AEs observed in more than one patient. Anything along those lines would be helpful. Thanks. Yeah. I don't know if we wanna handle the safety elements first. Rabia, you wanna talk about the safety results? Sure. When we look at the safety, this is an ongoing trial, as you know, just go through the trial, of course you expect your adverse events to be increasing in the number. We have not seen any safety signal noteworthy to, you know, just head on, you know, like all of the safety is you expect from a retinal trial with intravitreal injection. That's why it's an expectant, you know, phenomenon to see that they are increasing. None of them are noteworthy at this point. Yeah. To handle the first part of your question, I mean, just sort of think about it in terms of what we know and what we don't know. I mean, what we do know, given the trials that we've had in both Australia and the U.S., is that when you deliver axitinib through our hydrogel in the vitreous, you can get rid of fluid, so it actually can work to decrease fluid in patients that have active fluid in the retina and in naive patients. We've also proven that it can extend durability, when axitinib is present in the vitreous. This is a brand-new mechanism of action in the treatment of VEGF-mediated disease, and it's an intracellular point of efficacy, so we're not working in the extracellular space. It has to get inside of the cell in order to be able to bind to the receptors. Working with a number of drugs that have an intracellular mechanism of action, it's very difficult to tell without clinical data, first of all, how much you need in order to get inside the cell. That's why we chose such a potent TKI because even though you may have a very high concentration in the surrounding tissues, you may have a much lower concentration intracellularly. The other thing that is what we don't know, which we'll find out moving forward, is that once you get inside the cell, how long it stays in the cell and how long it will take that when the drug is no longer visible or apparent in the environment outside of the cell, how long it takes for the disease process to regenerate. As I mentioned earlier, my guess would be that it's going to be highly variable, that some patients may last quite a bit longer than you would expect. I would imagine a larger number of patients will start seeing fluid return within a relatively near time point of when the drug clears from the vitreous. I don't know if Peter or Rabia wanna add a little bit to that, but it's gonna be a very exciting data point than at the 12-month time point. Yeah. I don't want people to think that we're expecting to see this onslaught of rescues in the next two months before the final results of the phase I study. To me, when I start to see some evidence of the polymer wearing off, I expect that. What we don't know is what Antony just mentioned, the axitinib is intracellular. It's preventing downstream activation. It's still present in many patients at 10, even 11 months. We may not see any change in rescue at all at the 12-month time point. What I'm saying as a clinician and as someone who does a lot of clinical studies, it wouldn't surprise me either. Okay, great. That's helpful. I could just ask one quick follow-up. Appreciate that some interim DR data expected later this year. What length of follow-up will that represent? Maybe if I could ask it differently, what's the earliest you believe you could start to see some separation from placebo in that setting? Thanks. Maybe I can just start answering and Peter could add. The study is, you know, initiated in December last year and, you know, enrolling currently. Of course, you know, the enrollment, depending on the enrollment, our expectation is to hit five to six month data, you know, if the enrollment goes away. That being said, you know, just, that's, we're gonna see how that goes and make the right decision to look at the data. As you know, the data is masked. This is a masked trial. Peter, do you wanna add, you know, like the separation? Yeah, it's hard to say, you know, what the separation would be. You know, we know the results of the anti-VEGF studies for both Eylea and for ranibizumab. Know that in those studies, the patients were receiving injections either every month or every other month. In the first six months, they were receiving injections, even in the Eylea study, much more frequently. It's really hard to kind of divine up what it will be. You know, to me, I'm really hoping to see good results and especially with the longevity that we are seeing in the AMD studies. You know, the idea of having a drug that lasts 10+ months in DR is incredibly exciting as a clinician. Okay, great. Thanks for taking my questions and congrats again. Thank you. Thank you. Our next question coming from the line of Chris Howerton with Jefferies. Your line is now open. Hi, everyone. This is Kambiz Yazdi for Chris this morning. Congratulations on the data. Couple questions from me. How will you consider CMC optimization and specific formulation in the light of your interest to do a strategic alliance, potentially around the wet AMD program? As a second question, how receptive are ophthalmologists to prescribing TKIs, and what patients would OTX-TKI be best utilized in? Thank you. I'm not sure I got all of the second part of that question. I think the CMC issues are pretty clear. As we talk about a strategic alliance, we know nobody does what we do. We're the only company that's able to use these proprietary forms of hydrogels and be able to put drug in them and have them last for the time and elute at the rate that we need to for the period of time that we program them for. We would handle all of the CMC related issues. We would do all of the manufacturing. There may be a possibility of transfer, but there's nobody who could teach us anything about what we're doing, and we would really have to start a whole new platform with whatever partner we work with if there was a desire for them to manufacture. I don't know if anybody else on the line caught the second part. It sort of felt like there was a little bit of a message delay issue. My apologies. I'll just ask it again. How receptive are ophthalmologists to prescribing TKIs and what patients would, maybe best utilize in for OTX-TKIs specifically? In what disease, DR or AMD? AMD. In AMD, you know, it's interesting. These results, combined with our Australia results, are very exciting. You know, I don't think any TKI would completely replace anti-VEGF injections. My thought as a clinician would be I would give a patient my anti-VEGF du jour, basically get them controlled like the patients in this study, and then put the OTX-TKI on board and watch the patient over time. You know, one of the nice things we hope to have in the future is home OCT, which would be sort of perfect if you think about it for this, where we would have the home OCT. We'd put an OTX-TKI on board and basically as the patient starts to notice a change in vision or if the home OCT starts to show that fluid is returning, that's when we would bring the patient back in and either redose with an OTX-TKI or give a basically a fill-up of anti-VEGF to get to keep them stable. I would see that us using this to maintain the vision and OCT findings long term. As you know, almost all real world studies in wet AMD shows a really nice improvement with the anti-VEGF, but that tails off over time because of both physician and patient burnout to the injections. And this really solves that because we could use the injection to maintain the vision and OCT like we just showed in this study. It's a straight line across as opposed to a declining line, which most real world studies of anti-VEGF have shown. Excellent. Thank you so much. Appreciate the answers. Thank you. Thank you. Our next question coming from the line of Yi Chen with H.C. Wainwright. Your line is open. Hi. Thank you for taking my question and congratulations on the data. Given the fact that the drug performed well in patients that does not have excess fluid as screening, would you be able to speculate how the drug could perform in patients with active disease and excess fluid as screening? Whether you do have a plan to pursue the population of treatment-naive patients in the future? Thank you. We don't need to speculate. We've actually studied it. Our Australian trial was in patients with active fluid. We've used it as monotherapy in patients with active fluid, which no other TKI company has done. We actually have data in that population, and are very confident that we can be effective in eliminating fluid. I don't, I guess I don't understand where the question comes from. We certainly do not plan to exclude patients with fluid in future trials. As Peter mentioned, we do see the TKIs as being used to take controlled patients and have them maintain control. But we are certainly not afraid of patients with a little bit of fluid. Does that mean your future pivotal trial will enroll both treatment-naive patients as well as treatment-experienced patients? Well, clearly we have to discuss with the FDA what that pivotal looks like. I mean, clearly you also would want to ensure that there's a bit of a unanimity of the type of patient that goes into the trial, so you don't get confounding results. I think it'd be premature to speculate on exactly what the entry criteria would be for our pivotal trials. Okay. Thank you. Thank you. One moment please for our next question. Our next question coming from the line of Caroline Palomeque with Berenberg. The line is open. Hi. Good morning. Thank you for taking the question. Just a quick follow-up on the clinical trial design for the phase II/III, and I understand, maybe it hasn't been finalized, but just wondering in terms of the endpoint, Are you planning to go out with the nine-month data? Can you just talk a little bit about that? Then just switching over to the business side, I'm wondering if you can just discuss maybe your ideal strategic alliance for this program. Thanks. Yes. maybe I can take this question and Peter can add after me. In regards to endpoint, there is an FDA-accepted endpoint of visual acuity. It's a mean visual acuity at month nine, is an FDA-approved endpoint. This is, that's why we are absolutely excited with our results, you know, showing the nine-month and 10-month visual acuity being very similar to aflibercept. Again, as Antony, you know, noted that we have an FDA meeting coming up, a Type C meeting, and we are gonna have discussions around how its clinical trial design should be. Again, as noted before, none of the populations are out of, you know, just, we're going to discuss all and make an agreement with the FDA how that population should look like and going forward with the endpoint. Yeah. Concerning the other part of your question about the ideal strategic alliance that we would have. I mean, as a company, we realize what we do well, and we realize what we will need help with. I mean, we are very good formulators. We're very good clinical developers of ophthalmic products. What we do not have an ambition to be is a global commercializer of the products that we make. The ideal partner would be a partner that would have global reach, that would be able to sell, commercialize OTX-TKI in all markets of the world. And that clearly is a fairly small list of companies that we can all probably name off on one hand that would have the ability to do that in the ophthalmology space. We are having conversations with all of them. We've been very open that we realize the enormity of the market that we're about to go into. We also have been very public about our displeasure with the current stock price that we have. I wouldn't expect any massively dilutive raise to be the way we fund our way through this program. As we take on particularly wet AMD, that is a very resource-intensive indication to get. Diabetic retinopathy much less so. In order to embark upon that program in wet AMD, we would want to be able to assure that there would be funding all the way through to the end of that program. By far our most preferable way to move forward with that will be with a strategic alliance with a partner who would take on the responsibility of the funding of those phase III programs, and then, of course, the commercialization of the product globally. Thanks. I could just ask a quick follow-up. In terms of funding, how are you thinking about the cost of the trial, particularly the phase II/III? Well, sort of a wet finger in the air, looking at wet AMD all the way to NDA, which is two pivotal trials, is probably a little north of $300 million in total investment. Looking at diabetic retinopathy, with two pivotals, two NDA filings is somewhere north of $60 million, depending on the FDA's feedback on what that trial should look like and whether we would need to be a two-arm or three-arm trial. Clearly one of them is far more digestible than the other when we look at it from a funding standpoint. Like I said, we realize that we're entering a very big league with a very important product that has multi-billion dollar potential. We would want somebody who knows how to do this, partnering with us going forward. Great. Thank you. Thank you. The last question in queue coming from the line of Georgi Yordanov with Cowen. Your line is open. Hi. Thank you so much for taking our question, congratulations on the update and on the data. Just to clarify. Well, just the clarifying one on our end. As we try to understand the clinical and the regulatory path here, specifically for wet AMD, maybe can you just first confirm that you need to run two pivotal phase III trials? Is the idea to run those sequentially, meaning, you'll wait for the results from the first pivotal until you initiate the second one? Yes. Oh. Yeah. Once again, it is premature to speculate- Mm-hmm. what the trials would look like because we are very, very imminently about to discuss those designs with the FDA. We are definitely planning to do the pivotals, in tandem with each other and not sequentially, which radically brings in the time to NDA filing for both DR and for wet AMD. Yes. Mm-hmm. You mean, sorry, just to confirm, you mean like the two pivotal for wet AMD at the same time? Yes. Got it. Perfect. Concurrently. Yeah. I mean- Super helpful. Yeah. Exactly like Antony said, the one of them may start, you know, a quarter or so after the other one, just for the operational reasons. They would be done at the same time. Got it. In terms of, just a follow-up, question on the baseline patient characteristics, maybe can you just talk about, you kind of alluded to that, but how close to the real world, were the patients that were enrolled in this trial? Also, would you expect to enroll a similar patient population in those pivotal trials? Do you think, the FDA requirements would kind of like push it to a slightly different patient population? Well, we're gonna have a meeting with the FDA to discuss these types of issues. Our guess is, you know, basically similar to other clinical studies in this space. For instance, the Port Delivery System and REGENXBIO are both in patients who were previously treated. So we have precedent from the FDA as to what they want us to be studying. We would expect it to be very similar to this cohort of patients, so previously treated patients. You know, towards the original. One of the questions earlier about treatment-naive. One of the reasons that treatment-naive is difficult at this time is there's so few treatment-naive patients to enroll in a study, so it takes forever. A study where you have previously treated patients, so the Port Delivery System for instance, enrolled very quickly, because, as a clinician, I have thousands of these patients sitting around getting injections every week. It's very easy to enroll that type of study and very quick to enroll that study compared to, if we were to do treatment-naive. This is great and super helpful. Congrats again on the data. Thank you so much. Taking the questions. Thanks. Thank you. Thank you. I'm showing no further questions at this time. I would now like to turn the call back over to Mr. Antony Mattessich for any closing remarks. Great. I wanna thank everybody for joining us early on a Monday morning after the Super Bowl, so I hope everybody's in clear enough thinking in terms of understanding the enormity of this data and the Q&A that we've just had. What I hope that people can expect from us moving forward is increasing clarity on exactly what the pivotals will look like for both diabetic retinopathy and for wet AMD. The other thing I think is really important to stress is that we have been very clear about our dissatisfaction with the current level of the stock price as it is. We certainly have no intention of funding the programs that we see going forward with a painfully dilutive raise at the levels which we are right now. The one thing to expect is greater clarity. The one thing not to expect is a painfully dilutive raise at the levels where we currently are. We believe we have a number of funding options, with a preference toward a strategic alliance, but there are a number of other levers that are possible to pull that are non-dilutive or minimally dilutive that we feel we have very good line of sight on. I would say watch this space and I hope everybody is excited as we are about the difference that this can make with patients suffering from VEGF-mediated retinal disease. Thanks everyone for attending today. Ladies and gentlemen, that concludes our conference for today. Thank you for your participation. You may now disconnect.