Good morning, and thank you for joining the H.C. Wainwright 4th Annual Ophthalmology Virtual Conference. My name is Yi Chen, and I'm a healthcare research analyst at H.C. Wainwright. We have the privilege of having the following panelists join us today on our panel discussion on the evolving therapeutic landscape of age-related macular degeneration. Dr. Jay Duker, President and CEO of EyePoint Pharmaceuticals; Dr. Victor Chong, Chief Medical Officer of Clearside Biomedical; Dr. Ram Palanki, Executive Vice President of Commercial Strategy and Operations at REGENXBIO. And Mr. Wesley Jackson, President and Chief Scientific Officer of Valitor, Inc.; Mr. Robert Dempsey, President and CEO of AsclepiX Therapeutics; and Dr. Alan Franklin, CEO and founder of ForwardVue Pharma. And last but not least, Dr. Mark Breazzano, Clinical Assistant Professor at SUNY Upstate Medical University. Welcome to the panel. Dr. Breazzano, could you please give us a brief introduction of yourself and your practice? Absolutely. Thank you for having me. So I'm an exclusively medical and surgical retina specialist. So my practice, I just finished in a high-volume private retina practice, and I'm still maintaining a clinical assistant professor at the local medical school, and will be transitioning to full academic practice, in two weeks, actually. In this practice, it's very high volume. I was seeing about, anywhere from 60-85 patients a day. Some urban, but primarily, suburban and rural setting. And I was doing this, 100% of the time, 5 days a week. And happy to go into the specifics of different profiles of patients and things, but definitely, a high proportion of age-related macular degeneration patients. Would you give us an overview of the current treatment paradigm for wet AMD in your practice? Yeah, absolutely. It probably differs a little bit from what I've heard with colleagues elsewhere. We do have a lot of relatively Eylea usage in our practice, compared to faricimab. But there is a good amount of faricimab or Vabysmo as well. But, you know, there is a substantial usage of Avastin, Lucentis, and as well as Cimerli, is actually increasing the last few months as well. Okay. And what are the main benefits of using faricimab versus aflibercept, and are there any disadvantages associated with faricimab? Yeah. So, faricimab certainly has been shown with trials to potentially be a better treatment than Eylea for many indications, or at least non-inferior, if not superior. There were some subtle disadvantages. The absence of the prefilled syringe, I think, was a pretty substantial deterrent for many of us. Now, the risk for things like endophthalmitis or infection inside the eye after an injection are certainly not very high, fortunately. You know, there have been other sort of less controlled studies that have demonstrated that the more steps you involve in terms of having to prepare and then deliver that medication does not significantly increase that risk. So, but it is exciting. faricimab, they did just get approved for that prefilled syringe, so that preference may be evolving and change quite soon. I believe it's coming out this fall. So, that I do anticipate that to change. Thank you. As you mentioned, Avastin and Lucentis, what percentage of patients under your care still use it? Mm ...... Avastin and Lucentis, and what's the reason for that? Mostly it's driven by insurance, I would say, is when we would go to Avastin. I think more and more often, step therapy is required. It is interesting, you know, how step therapy changed. You know, as soon as Eylea HD was approved, you know, there was a double-step therapy to get to Vabysmo. So that's the other reason why, you know, faricimab was also limited. But as soon as Eylea HD was approved, then all of a sudden, double step for Vabysmo was not necessarily needed anymore. So, you know, there's some of these insurance schemes that kind of happen. But yeah, going back to the Avastin part, a lot of it is that insurance. This particular practice is the main game in town, and so we have all comers, Medicaid as well. So, you know, the less represented, the more socioeconomically disadvantaged, those with lower insurance types, obviously, it's going to be a little bit harder to get branded medication. Uh. So that certainly influences it. And then Lucentis, you know, it's a small percentage. Avastin's pretty substantial. I would probably say, certainly not as substantial as the branded medication, so maybe, I would probably say 20%, maybe even 30% are Avastin. And then, Lucentis is small. I would say maybe 5% or similarly 5%. And those are usually just for the, you know, diagnostic codes where you can't get Eylea or something like that accurately. So we're talking, you know, secondary CNV to central serous choroidopathy, for example, which can sometimes look like age-related macular degeneration, and depending on how you code it, you might be able to call it AMD. And we're learning more and more, you know, the VRM group out in New York City... I'm sure even Jay Duker's group here, you know, in Boston, has published a lot on these sort of variants with wet AMD. They overlap with polypoidal choroidal vasculopathy, pachychoroid disease, and whatnot. So, yeah. From your perspective, what could new treatment options offer in the future to improve patient outcome? Sorry, what was that first part again? I mean, what do you wish new treatment options to offer to- Mm ... improve patient experience and outcome? Yeah, I mean, yeah, you know, I think the durability, not only the efficacy, but the durability and really getting that sustained treatment, I think would be very helpful, especially for our patients that are traveling more than 100 miles every visit to come to our clinic and get treatment. In some ways, you know, even an alternative mechanism that can help shut it down adequately. You know, if they're coming once every 12 weeks, you know, every three months, I don't think that's that bad. Mm. You know, trying to convince someone to do that versus someone who gets an every 6-month treatment, I don't know. At that point, you know, it's less frequent than a... You know, once you get to every six months, it's like going to the dentist. Every 3 months, you know, that's less frequent than going to the barber. You know, I think once you get to that far out, that's great. But really, we have these patients that have, you know, every four, five, six, seven, eight weeks, and they're traveling quite far. I think that is an unmet need. And fortunately, you know, most of our patients are not in that category, but there's a lot of them that are. Mm-hmm. I think, you know, that durability combined with that sort of efficacy, I think, would be helpful. Got it. Got it. Thank you. And, Dr. Palanki, we know that REGENXBIO is developing a subretinal gene therapy, RGX-314, to phase III trials for wet AMD. Could you tell us its mechanism of action, and what are the technologies involved in RGX-314? Yeah, absolutely. So that's an adeno-associated vector that's transplanted in the subretinal space surgically through the vitrectomy. And you know, it is certainly invasive. It is very hard to get patients into that trial. And you know, they're very, very stringent criteria, which is understandable because you know, you're trying to-- you know, you want to be able to show a significant result. Yeah. But yeah, in terms of that mechanism, you know, the thought is that hopefully it can sort of you know, give a sustained delivery of the angiosuppressant medication on its own and would hopefully reduce that burden of treatment long term. The issues with it, again, is that invasiveness, going to the operating room. You know, I'm sure we're all optimistic that it could, you know, come to market and be helpful for us. But, you know, we still have a little bit to go before we find out more and whether it will be viable. I don't necessarily think, you know, just from a logistics standpoint, anytime you're talking about surgery, you know, assuming that that particular visit is when you sign that patient up, they still have to go to the operating room. They still need to be seen post-operatively day one, usually week one, month one, typically. And so I'm just not sure, at least in the short term, how much you're actually saving in terms of patient visits. So that's, that's kind of one of my hesitations with something like that. Whereas if you have... You know, as soon as you get an anti-VEGF injection, the next time you're coming back is in a month, assuming you don't have anything going on with that other eye. Dr. Palanki? Yeah. Thanks, Mark, for setting the stage for me. I think you've kind of talked about the mechanism of action. So the subretinal therapy, maybe we should start with the overall 314 program. So we have two routes of administration. Victor's on the call, too, so we actually use their technology for an in-office approach. So we started this program really back in the day, where the product profile that came out of subretinal was the earliest, and it showed safety and efficacy that we got really comfortable with and carried it into a phase III program. And as part of that process, we also partnered with AbbVie for the overall program, where AbbVie actually shares about 2/3 of the cost, and we share one-third of the cost to execute the program. Today, as it stands with the subretinal program, we are in the midst of our phase IIIs. We're on track to submit our BLA by first half 2026. The product is not too far from getting to patients after a lot of effort that has gone into developing the asset itself. Some data and perspective, if you look at our phase II and II data, we now have up to 4 years of data, and even extending up to 5 years, and we see 50% of patients going injection-free and almost an 80% decrease in post-treatment injection burden. I think that's really where the value is in terms of being able to sustain a treatment impact on a therapeutic basis. More importantly, these patients are gaining vision. I mean, if you go back to our phase I and phase II data and you examine the type of patients we had, these were really severe patients that were getting very frequent treatment for almost 5-7 years previously, and they got treated with 314, and now we have up to 4 years of data that suggests that we're able to sustain vision on an improvement basis, where we saw almost a 2-line increase in these previously treated patients. I think... That is the power of sustained therapeutic treatment, where once you have a protein that is solving for the cyclic troughs and peaks of what we see with intravitreal injections, even when you get those incremental durability aspects, when you're able to control the disease on a consistent basis, I think you actually prevent the microscopic damage that's happening within the retinal tissue, and that leads to sustaining vision ultimately over a long-term basis. People talk about treatment burden a lot, but I think the real unmet need that exists in patients today is actually sustaining their vision over the long term. So I think a lot of these treatment options we're developing right now are focused on solving for that problem, and the winner will be the products that can solve it on a long-term basis, on a consistent basis, and have the right safety and efficacy. And to Mark's point, you know, we saw that, you know, as a subretinal therapy, there are few limitations in terms of how many patients can access the treatment, so we also went into the in-office option as a life cycle management aspect to develop 314 in the suprachoroidal space. And coming into the last earnings call, we even announced that we are now accelerating our DR program, going into end of phase II in fourth quarter and potentially starting a global pivotal program as a one-time injection, which I think solves for a global, global health priority. Where if you can stop these patients from progressing to vision-threatening complications, and our data suggests that with a one-time treatment, at 1 year we saw almost a 90% decrease in that, risk reduction towards developing vision-threatening complications. Okay. Kind of the overall program today and where we are. Okay, thank you. Dr. Jay Duker, EyePoint is developing DURAVYU, and the drug is about to enter two phase III trials for wet AMD pretty soon. Could you tell us its mechanism of action and the proprietary technology involved in it? Sure. Yeah, thank you very much for inviting me, and, congratulations on putting together such a diverse and excellent panel. So our lead asset is called DURAVYU. It is a small molecule tyrosine kinase inhibitor that's called vorolanib, and it's in our proprietary sustained release technology that we call Durasert E. TKIs in general offer a new mechanism of action for VEGF-mediated diseases. They block the receptor intracellularly. Vorolanib in particular is a selective and patent-protected TKI, and it has excellent activity against all of the VEGF receptors, which means it should block all isoforms of VEGF. In addition, vorolanib also has activity against PDGF, which should lead to a beneficial anti-fibrotic effect, and this new MOA in the treatment of wet AMD can work with existing therapies. So, what is the clinical efficacy observed so far at 6 and 12 months? So the clinical efficacy so far has been excellent. We performed two clinical trials of DURAVYU and wet AMD. The phase I trial was called the DAVIO trial, and the phase II trial was called the DAVIO 2 trial. We're not all that imaginative, I guess, with naming. Both trials showed excellent safety, efficacy, and tolerability. And in the DAVIO 2 trial, we enrolled 160 patients, and they were randomized to one of two doses of vorolanib, either approximately 2 milligrams or approximately 3 milligrams, and that was versus an on-label aflibercept control. The primary endpoint of the phase II trial and the primary endpoint of our pivotal trials is non-inferiority change in visual acuity, against the aflibercept control. And in DAVIO 2, this was measured at month 8, which represented six months after DURAVYU was injected. The study was relatively small, only 160 patients, but despite the size, we achieved the endpoint with high statistical significance. In addition to that, all the secondary endpoints were also reached, including no safety issues, approximately 80% or more reduction in the treatment burden. About 2/3 of the eyes were supplement-free up to month 8, and we had very good anatomic control as measured by OCT. Overall, the clinical results in wet AMD have been excellent. How do you expect DURAVYU to fit into the current treatment plan? Well, again, that unmet need of longer durability without sacrificing vision and anatomy is really something I think doctors and patients would like, because it gives them the flexibility to go longer between visits. So we're develoPing DURAVYU as a maintenance therapy. We would expect after a series of loading doses of any of the ligand blocking agents, retinal specialists would then introduce DURAVYU into their wet AMD patients in an effort to maintain the visual and anatomic gains that were achieved by the load. This should significantly reduce the visit and the treatment burden. Based on the phase II data, if these trends continue in the phase III and the drug is approved within every 6-month dosing regimen, it appears that about 2/3 of wet AMD patients could be controlled with DURAVYU alone. The other one-third that required supplementation had supplementation given at a significantly reduced interval than what they had treatment going into the study. So, a rescue or a supplement treatment in this setting of use of DURAVYU is not really a failure of DURAVYU necessarily, 'cause the overall goal here is to reduce the treatment burden. Got it. Got it. Dr. Victor Chong, we know that Clearside is developing CLS-AX in a phase IIb trial, also for wet AMD, using the suprachoroidal delivery. Could you tell us its composition of matter and the technology used to provide sustained drug delivery? Yes, thank you very much for having me and joining today. Well, our main drug from the TKI point of view are very similar to what Jay had mentioned earlier, that this is a tyrosine kinase inhibitor that will block all the VEGF receptors. So I think from that perspective, it's very similar. And instead of an implant, like what Jay had mentioned about in his company's technology, we are injecting drug in the suprachoroidal space. And by injecting drug in the suprachoroidal space, that using a relatively straightforward suspension, that we can actually keep that drug in that space and slowly releasing the molecule into the retina. So I think it's something, similarity to EyePoint, technology, and, it's really something that, from our point of view, that we would share, some of the benefit that Jay mentioned already earlier. But again, you know, as a company that we are the leader for in suprachoroidal space, I think Ram has already mentioned earlier that, you know, we partner with them, on gene therapy development, but also that, we have partnership with, other company, in say, ocular oncology as well. Got it. And so what is the clinical efficacy observed so far from CLS-AX? Yeah, so we are a little bit behind EyePoint. We are still ongoing on our phase II study, and that is due to come out the result in about a month's time, in the end of Q3, so we don't really have all the data yet. However, that on our phase I data suggesting similar result that, you know, one-third of the patient will need some form of rescue, but then about 2/3 that can get to six months without requirement of additional anti-VEGF. However, our phase II is very different. Instead of EyePoint or Ocular Therapeutix that are using rescue between the treatment or in fact, after the first treatment in the phase II, we will be able to redose with our own drug. So I think that, like Mark mentioned earlier, that, you know, there is patient that require very frequent treatment, and there's also patient that can go longer. And I think that the way that we think about it is that, we would have the flexibility that potentially that those patient who are on around 4-6 weeks will get to us, about every three months. And then for those who are already three months or so, that they may get to us for every six months. So I think that is a slightly different approach. Instead of using another anti-VEGF biologic, but we will be almost, like, replacing Eylea high dose and faricimab in that end, but extending further out. I think that is kind of like the conceptual idea of flexibility as well as the efficacy, that durability that most physician want. One point I mentioned that by Mark, about endophthalmitis, I think that is, luckily, that it was very rare. However, that because suprachoroidal injection, we are injecting outside the blood-retinal barrier, so in theory, there would be no risk of endophthalmitis. Now, again, we probably can't prove it at this point, but at least that we now have more than 10,000 injection without a single case ever reported. But it kind of biologically makes sense that because you are injecting on that space, then any bugs that you get in the choroid, immune system will protect the eye. Got it. Thank you. Mr. Dempsey, we know that AsclepiX is developing AXT107 for wet AMD too. Could you tell us its composition of matter, any, the proprietary technology involved to provide sustained drug delivery? Yes, and thanks again for this opportunity. So obviously we're based out of Baltimore and Johns Hopkins, in which the original technology came out of Peter Campochiaro's lab. And we're developing a first-in-class novel integrin regulating peptide that we believe targets multiple pathways, including the inhibition of VEGF-A and C, obviously reducing neovascularization. Also promoting Tie2 activation, which we believe could lead to reduction in vascular leakage, as well as inhibiting vascular inflammation by preventing NF-kappa B-mediated inflammation. From a standpoint of composition of matter, we believe it's very strong and gives us some unique advantages in this space. Right now, it's through 2039, with the opportunity to extend based on our clinical development program. From a standpoint of the technology, actually, we're not using any specific technology, polymers or PLGA implants to achieve our durability. It really is intrinsic low aqueous solubility of AXT107 utilized in a micro particulate suspension that we believe will result in the in this durability. In addition to some of the other folks on the line, we are delivering into the suprachoroidal space, which we believe will also provide some additional durability from that perspective. So that's a quick little overview of where we are. Obviously, we just announced back in May that we had completed enrollment of our first-in-man trial, and obviously, we're gathering the data as we speak. Got it. Thank you. Dr. Jackson, Valitor, we know, is developing VLTR-559 for wet AMD. Could you tell us its mechanism of action and the proprietary technology involved? ... Yeah, of course, and thank you for this opportunity to present with this panel. We developed VLTR-559 using the platform technology that we have at Valitor called multivalent polymer conjugation. What it enables us to do is take multiple copies of a drug modality, conjugate it along a single-chain biopolymer, and then use that biopolymer to really define the pharmacokinetic properties of the drug. For VLTR-559 specifically, the biopolymer we're using is hyaluronic acid, and it's conjugated to a single-domain anti-VEGF antibody, giving us the kind of minimal protein unit we need for the specificity of the anti-VEGF mechanism. We view that as the gold standard, and we really want to be able to bring the existing benefits of anti-VEGF therapy to patients with a substantially greater durability. The hyaluronic acid itself is kind of the core component that gives us the ability to offer these durability benefits. It's a really unique biopolymer with some great biophysical properties that enable it to really take on these huge hydrated structures. After injection in the back of the eye, it really does inhibit the just transport of our overall macular molecular structure and give it the opportunity to stay in the back of the eye, really absorb up the VEGF mechanism and enable it to provide that therapeutic efficacy based on our preclinical studies, we're looking at somewhere between six and eight months. So, you know, I think this is going to be able to bring a really substantial advantage in that existing anti-VEGF mechanism that will make a substantial impact for the patients Mark was describing, who really have challenges getting into the office, reduce the treatment burden and be able to sustain the therapy in a way that we're hoping also provides better long-term outcomes. Oh, has the drug candidate entered a clinical trial yet? No, we're still preclinical. We have a growing database that is giving us more confidence about the expected performance we'll see as we translate into the clinic. From a potency standpoint, the VLTR-559 has equivalent potency to the current anti-VEGF treatments that are being used clinically. And again, we'll really differentiate ourselves on the basis of durability. Based on our preclinical PK studies, we're expecting a half-life about 4x longer than Eylea. So, for example, a patient who's treated stably with every other month 2 mg Eylea, we're hoping to push those patients out to six or eight months before they need to be redosed with VLTR-559. Right. Thank you. Dr. Franklin, ForwardVue is developing a ORAI1 blocker for AMD. Could you tell us its mechanism of action and the technology used to provide sustained biological activity? Sure. And thank you again for allowing us to present our technology in, such a great platform and be with such a great panel. At ForwardVue, we're blocking ORAI1. I'm a vitreoretinal surgeon like Mark, a similar volume of patients. I've done about 60,000 injections, and as ophthalmologists, we try to treat vision first. And if you look at our wet AMD patients, two out of three do not get the three-line gain benchmark, and DME patients, one out of three don't get that three-line gain benchmark. And in other forms of medicine, hypertension, cardiology, oncology, they're all pleiotropic mechanisms. They're all getting treated with cocktail or multi-target therapy. ORAI1 is a multi-target receptor. It co-localizes with VEGF-R2, so we get the VEGF pathway, but it's also pretty tightly linked to the Wnt pathway. Wnt binding inhibits ORAI1, as our channel blocker does. So we hit two critical pathways associated with pathologic angiogenesis. The Wnt agonist was recently shown to outperform VEGF in clinical trials, although we're a preclinical company. Our asset, carboxyamidotriazole, outperformed VEGF by a factor of two in two different preclinical assays of retinal neovascularization. It's a small molecule, so we have it complexed in PLGA. We have a 60-day implant where it releases linearly, as Ram was talking about, so that you don't get the peak and trough. We have an implant that releases linearly over 100 days, with 30% of the API still left in the bioeffective range, so extrapolating that five to six month dosing. So we have a novel pleiotropic mechanism of action that's durable and appears very potent. Okay. Thank you. Dr. Breazzano, have you had any experience with any novel drug candidates being developed for wet AMD, and have you had any experience with suprachoroidal delivery? Great question. So, yes, I've been an active sub-investigator for multiple different drugs, including Vabysmo, which is now clinically available. Yes, so basically, yes, in terms of suprachoroidal delivery mechanisms, there's obviously an emerging treatment paradigm that I don't have quite as much experience with. There is also Opthea with the ShORe and COAST trials, so we have, you know, essentially another angiogenic suppressant medication to sort of piggyback what we currently have. And I do wanna clarify with the REGENXBIO, I think is very exciting how they also have the impressive suprachoroidal space approach as well to augment an otherwise great delivery system. I do think it's also exciting how the recently released data concerning the bioconjugation for the adeno-associated vector with these suprachoroidal delivery treatments. And so I think, as long as we can continue to work on and augment these approaches, I think we will have some promising methods of augmenting the way that we currently do treat wet AMD or neovascular AMD, to supplement or even complement, in some cases, replace for these particularly high-burden patients from the traditional intravitreal approach. Do you always use a single drug on a particular patient, or could the treatment be a combination of drugs? Usually it's monotherapy that I, you know, will typically treat. And then, depending on the response, insurance reimbursement patterns- Mm-hmm. ... and then, from that standpoint, that usually dictates moving on to another medication. Generally speaking, yeah, generally speaking, from that, that approach. How would you fit a treatment that can last six to nine months into your practice when they become available? six to nine months? Mm-hmm. Yeah, I think I would want to make sure, at least in the interim, you would observe relatively closely. I wouldn't necessarily want to do the treatment and have them come back in six to nine months, and then see how they're doing. So even if they're not getting treatment in the meantime, I would probably want to see them at least as frequently as every other month, just to ensure that there hasn't been reaccumulation of fluid. I do think there is... I mean, there is substantial evidence that, you know, you could potentially have—I mean, obviously, over-treatment is less of a concern than under-treatment, as we know from disparities in health, we know from lapses in care, all these sort of aspects. It is interesting that, you know, having a little bit of subretinal fluid can actually be protective for the retina- Mm ... than not. So, you know, we also wanna make sure that we are titrating, accurately the amount of medication that we're giving, too. So whether it's under or over-treating, under-treatment is certainly the bigger concern. I do think close monitoring, at least in the short term, would be- Mm ... helpful. Okay. Then once you get out from the six-nine months, then you could probably, you know, push out the monitoring visits further. Of course, this is certainly hypothetical. I mean, FDA recently approved several versions of Eylea biosimilar. Do you expect Eylea biosimilar to change the way you use the drug when they enter the market? I do think that, I do think it will be interesting, and it probably will shift a little bit. Some of it will just depend on the business side of the retina itself. I know a big influencer for a lot of practices tend to be sort of these kind of rebate programs and things of that nature, which I'm not 100% privy to at this particular moment. However, I do know there are some attractive things that certain companies will do for practices. I know Cimerli has begun to take quite a bit of a hold for Lucentis as a biosimilar, for example. And yes, there are several for Eylea that are arriving, and so I anticipate something of that sort will also happen. Right. And, what are the most important safety considerations when you treat a wet AMD patient? The safety considerations with wet AMD- Mm. ... the biggest one, as we touched on earlier, was endophthalmitis. I think that's the biggest. And of course, given what we've seen in the, you know, non-neovascular AMD landscape in the last year or two with Syfovre and Izervay, maybe less so, it's hard to say, we're worried about a sort of similar, inflammatory reaction, that's not infectious, but can be devastating as well. So I think from that standpoint, those are certain considerations that we always need to worry about. You know, and as we like to keep those numbers as low as possible, ideally within the one to-- of thousands of cases. And, depending on where you read, you know, that can vary anywhere from one in 2,000 to 10,000 or so. So, you know, you know, but generally, one out of several thousand at this point- Uh ... with a standard treatment. Thank you. Dr. Duker, what are the safety signals observed in the clinical trials of DURAVYU? Well, so far, there's really nothing significant. We've performed four clinical trials. A total of just over 190 patients have been treated with DURAVYU, and so far, we've had no reported ocular or systemic SAEs. When you look at the AE tables from the trials, they're generally mild, and generally those that would be associated with the injection itself or progression of wet AMD, which can still happen in these trials. So the safety so far has really been terrific. In addition, vorolanib had been previously studied as an oral agent in wet AMD. At the time, it was called X-82. So we also have a database of another 150 patients or so that were treated with oral vorolanib for wet AMD, and they had no ocular issues from a safety perspective as well. Database of well over 300 patients so far exposed to vorolanib, with nothing of concern. Certainly, there's been no cases of serious posterior segment inflammation, as Mark just described, as one of the worries in the retina community. No insert migration into the front of the eye, so far reported, and no cases of endophthalmitis reported in association with the injection of DURAVYU. Now, I have to say, and, you know, if we're doing injections in the eye, eventually that's gonna happen. It's kind of inevitable, but as Mark indicated, provided we're in the same ballpark as the other injections that are being given, the 1 in 3,000, 1 in 4,000, then it's not gonna be a concern in the retina community. Got it. Can you talk about the enrollment criteria for the upcoming phase III trials, and what's the estimate timeline for readout? So we are about to commence two pivotal phase III trials in wet AMD. The first is called Lugano, the second is called Lucia. Lugano is almost exclusively in the United States, and we expect to randomize the first patient in the second half of this year. So that's upcoming. The Lucia trial will be split between the U.S. and global, and we expect to enroll the first patient in that trial several months after the first trial starts. We've got a lot of activity going on to get these trials up and running, with well over 100 sites have now committed to being in the trials. The criteria is gonna be active wet AMD, either naive, meaning not previously treated, or previously treated wet AMD. The structure of the trial is similar to the phase II in that we will be against an Eylea on-label control, single dose of our drug. Approximately 2.7 milligrams of DURAVYU will be the dose that we're testing. As for the timeline, at this point, we would estimate top-line results from the trial somewhere in mid-2026. Got it. Thank you. Dr. Chong, could you talk about the safety signals observed in clinical trials of CLS-AX? And, what was the enrollment criteria for the ODYSSEY trial that's still ongoing? Yeah, I think there's some similarity to what Jay said, that, you know, because I think we are both using the TI, although with a different one. And we're using axitinib, just like what he said, that axitinib have been a systemic oncology drug for a long time, and we don't see any ocular effect. On our own drug that I've already mentioned that we have a approved the product, but it's a steroid. And again, multiple injection have been done, and that was shown to be safe and actually have no evidence of any endophthalmitis. And partly I mentioned earlier that is, was something that we think that could be a potential differentiation. And luckily, as I say, it is rare, but like Mark said, that was one of the things that most retinal specialists are most fear of. And again, about potential retinal vasculitis, again, SAM is a small molecule, is not biologic. The risk of this kind of vasculitis are possibly less likely, so that's always a potential benefit. But all these things are one in 10,000, one in 5,000, and it's probably quite difficult to be able to demonstrate in a good trial. And I think it's good not to see it is great. I think the similarity there for us is on our own trial that, you know, in particular, CLS-AX, that the number is still relatively small at the moment, but then we don't have any systemic or ocular SAE linked to our drug. And we are about to finish our study, so we have only a few more patients to close out. So, and then that's why we are kind of on track to the end of the quarter to present our top-line result. But so far, we don't have any concern from a safety perspective. How soon can you advance the CLS-AX into a pivotal trial? Yeah. So I think that it probably depends on how our fundraising is going. There's a reality that I think the other colleagues in the panel would know, that at the moment, we don't have enough money to run a phase III study. But again, to be fair, that we are kind of, you know, going to present our result at the end of this quarter. And I think that we're expecting that we would get the support of the investment community or partner with a strategic partner, and then we can basically get going. The expectation is that it's similar to most other company that, you know, from the point that you're fundraising to your start of your phase III, are probably around nine months to a year. I think to be realistic, you know, I think that you can look at other people, and it will be similar kind of timeline that we were thinking about. So, it'll be second half of next year. That is what we hope to, if we can achieve, funding, pretty quickly, after our phase II result. ... Yeah. Thank you. Dr. Palanki, are there any safety signals you observed for RGX-314, and what are the enrollment criteria for the ongoing phase three trials? Yeah, I, I think, you know, it's when you think about gene therapy, some of the concepts you have to think about is really important on the basis of route of administration. If you look at historical data and everything that's been done in the gene therapy space, it's always been shown that the subretinal space is the most immune privileged. And it's been consistent for us as we've gone into the phase III program. To date, the overall RGX-314 program, we have hundreds of patients that have been treated with the drug. We haven't seen any clinically significant or any SAEs related to the drug itself. So to date, the safety profile stays really strong. I think the differentiation in the subretinal program versus other gene therapy programs is also that, you know, we don't have any prophylactic steroids. So it actually proves to the point that that space is very immune privileged. And to date, to all the clinically concerning inflammatory events that the rest of the panel spoke to, or things like procedure-related outcomes on a AE basis, everything's been going as expected. So it's a pretty strong safety profile that continues to be the case, and as I said, we are in the midst of phase IIIs, and our plans are to submit a BLA by first half 2026. When the data actually reads out, we'll have a pretty clear view, but things are on track, and everything is pretty safe as it stands today. So the data will come out by the end of 2025? Yeah, I mean, it's, you know, if you backtrack to our BLA submission, I think that's a good estimation. Okay. Got it. Thank you. Mr. Dempsey, so for AXT-107, are there any safety concerns so far? As of today, which we're very happy about. So we recently completed enrollment of our phase I/2a clinical trial, as I mentioned, examining the subretinal administration of our new microparticulate presentation. This is an ascending single dose, first-in-human study, and basically, what we're trying to determine is the maximal tolerable dose. We're studying three doses, a low dose, a mid dose, and a high dose. And where we are right now, obviously, this is an open-label study. The study is currently demonstrating safety, tolerability, signs of durability, as well as a biological response across all doses tested. Looking at the timeline, we expect last patient, last visit in the first quarter of 2025, and at that point, obviously, we can, you know, release the data and get the completed study report to start sharing with the public. But as it stands right now, across these 15 subjects, you know, just the safety profile looks to be pretty clean. No remarkable findings to date. Thank you. Dr. Franklin, are there any safety concerns for or ORAI1 blocker, even in theory? There don't appear to be any safety concerns for ORAI1 blockers. Our molecule was initially a cancer drug, and it's been in 900 patients systemically, and there were some mild reversible side effects noted in cancer with systemic administration. Pre-clinically, multiple formulations in multiple species, we've seen no safety signals, both on anatomic measures and functional measures that include ERG and VEP. So we're pretty comfortable with that this is a safe molecule for the eye. Thank you. Dr. Jackson, any potential safety concern for 559? None that we're aware of. You know, we just started designing the composition for VLTR-559 early with safety in mind. I think we get to benefit from the extensive safety record of the anti-VEGF mechanism. The hyaluronic acid component has a long safety track record in the clinic as well. We've been looking for safety signals in all of our preclinical studies with ocular exams and tox readouts. And so far, we can report really quiet eyes, no evidence of ADA response in the ocular tissues. And everything we're seeing is giving us a positive outlook to the safety readout when we get to the clinic. Thank you. Dr. Breazzano, so when multiple durable treatment options become available for wet AMD in the future, what, how would you choose? What are your points of consideration? Yeah, absolutely. So, of course, patient preference is number one concern, but usually, the biggest factors, again, are gonna be that insurance issue. And then also, I generally think about things in terms of invasiveness. So, things that are certainly going to be the safest or have the least potential drawback, probably going to resort to first if the patient's willing. So, you know, if something's gonna take a few more visits to get the same amount of treatment as something else, that's gonna be a little bit more invasive. You know, I'll kind of couch that and let the patient sort of decide that part. But generally speaking, escalating from, you know, conservative management to surgical type approaches. But certainly there are exceptions to this. You know, there's certainly, you know, just in terms of other, analogies or metaphors, you know, like pneumatic retinopexy, for example, for treating a retinal detachment, which is less invasive than going to surgery, that's more commonly employed in different parts of the country, depending on who you ask as well. So at least for me, you know, I think that's sort of how I would sort of think about these things. And certainly, longer-lasting data, or more robust data, more experience, I think will also help feel more comfortable with newer medications. But again, you know, there'll be some variability. It seems that there is still a lot of hesitation, for example, with the non-neovascular treatments compared to the neovascular treatments right now, which is interesting. So it'd probably be a diversity of opinion. Yeah. Do you expect the treatment paradigm for wet AMD to change significantly within the next three to five years? I certainly do think so. I mean, I think just like we're talking about the arrival of the biosimilars, all these excellent treatment candidates that are on the horizon right now, I'm optimistic that I think it will change quite substantially. I would keep in mind, though, that many patients do have quite a sufficient response to treatment, and so they can. So in my particular practice, you know, I tend to go treat and extend with the current available medications, which basically means that you slowly extend out the treatments between each visit, and many of them can go, you know, 15, 16 weeks. So that's just a few times a year, and patients are content with that, and it can monitor that, and I'm comfortable with that. Others will do treat as needed, but bring them back very frequently, to observe for any response to treatment. So a lot of patients are able to do that. So we're really talking about the, that handful of patients that just can't. So, while the market, I think there is certainly, opportunity there, it is tempered a little bit by the fact that many people are still responsive, but it's still an unmet need, for sure. Thank you. I wonder if any other panelists care to comment on how do you expect the treatment paradigm to evolve in the coming years? Anyone can comment. Again, I think it's been well covered. I do think there's two issues that probably are worth mentioning. The first is home OCT, which is coming and almost here, I think, for some of us. And it's unclear how extensive it will be, but the ability to monitor fluid at home may make long intervals between injections more palatable. And the second issue is the whole thing about fluid. You know, when you use a short-acting anti-VEGF, any recurrence of fluid, you know there's no drug left in the eye, you've got to retreat. But with sustained-release treatments, like sustained-release TKIs and gene therapy, there's still drug on board. And so what we're seeing is there could be fluctuations in fluid that are not significant to the vision, and this will produce, I think, a paradigm shift in how retina specialists view a little bit of recurrent fluid when you've got true sustained release. I think- I think- I think there is so much heterogeneity in this disease and having all these options out there in the market. I think there'll be different types of responses that you're going to start observing in these patients. You know, with about 1 million patients being in the clinic that have different needs, I think all of these treatments are going to be adopted on a, you know, initiation of treatment through maintenance of treatment, through long-term management. They're all going to have their own set of ways fitting into the overall treatment spectrum because these are lifelong diseases for these patients. There are just lots of patients that need treatments like this. So there will be a huge treatment shift on how these patients are going to get managed on an individual basis that fits the phenotype. Thank you. And just to build on that, having done some market research about novel MOAs, the physician community is calling for that. And, you know, novel MOAs offer durability, will hopefully be accepted on the market. And I think we all saw, and we're surprised by the amount of interest that Merck showed with their recent acquisition of EyeBio. I mean, if there's any clear indication, it's the amount of money they spent to get a differentiated product with a novel MOA. And based on what I saw, I'm sure the panel can comment, you know, they didn't show durability in that study. Now, maybe that will come out in future trials. So I think the market is very interested in looking at novel MOAs, and I think that's really where we are right now. Thank you. Dr. Chong? Dr. Chong. Yeah, you may add that. I think if a physician, like Mark said, a physician quite often do treat the so-called treat and extend. I think that is still probably the mode for some time. I think that the future will be more segmented, that currently with Avastin, Lucentis, when Eylea up to recently with the new approval, I think there's a lot of similarity in those drugs and people using that just based on, kind of like Eylea extending a little bit longer than Lucentis, and now the Eylea high dose and faricimab extending a little bit longer than Eylea, to a certain extent. I think that we believe that, you know, I think treat and extend is still convenience for physician as well for patient. That, you know, our drug that we're able to provide a flexibility, we will actually aim to get a label, on, every three months to every six months. I think the flexibility will be helpful for physician to using our drugs similar to the current biologic, but potentially extending further. Like all the panelists have said, that, you know, AMD is, the patient are variable. They, some patients do need more frequent treatment, but yeah, on the same drug, and then, but using a different drug that they may last longer, but they may last from the four to six weeks, as I said, to the three to four months. I think that would be something that we will see. But there will be patient that, you know, might be more suitable for gene therapy, for instance, in particularly, they're potentially going to suprachoroidal space, that, you know, you are less invasive. Like Mark said, that invasivity is also, a price to pay. But I think potentially, suprachoroidal gene therapy would be another, key, key, play in the future. Thank you. ... I think, over the next couple years, we'll see all these, companies that are having a durability for, for anti-VEGF, and I, and I think that will really be helpful. Currently, in the trenches, I see a lot of wet AMD patients that have progressive degeneration during, treatment, and what we're doing in the here and now is we're doing both anti-VEGF and complement inhibitors to address both the, leakage and the progressive atrophy, which, to Mr. Dempsey's point, is ultimately we need better mechanisms that address both and address the subretinal fibrosis. I think. So over the next couple years, we'll see durability, we'll see treating with anti-degenerative medicine, plus, anti-neovascular medicine, but the real quantum leap will be from pleiotropic, targets. Got it. Got it. Got it. I just wanted to jump in quickly. I think being part of this panel is really exciting to see all the options and innovation that are coming to the market. VEGF seems to work really great for many patients, but it's the only game in town. So, you know, it'll be really exciting in the coming years to see new options coming for patients to really find what works best for them. Thank you. Dr. Breazzano, any closing remarks for our audience? Yeah, I think this is a great panel, and I'm really excited to be on it with all these wonderful companies that are bringing the new treatments to the horizon, and I... It's been wonderful, and I do agree, Jay brought up a wonderful point about home OCT. I don't think we're quite there yet with it, but it is exciting. Had some early work earlier this year with the home OCT, and, you know, once we get clear out some of those early snafus, I think, you know, that will certainly help assist in these long-term delivery devices to help reduce that burden of visits as well. Got it. Great! Thank you. I would like to thank all the panelists for an informative conversation and, our audience for participation. This concludes this panel discussion. Thanks again. Thank you. Thank you. Thank you.