All right. Great. Hi, good morning, everyone, and thanks for joining the Clearside Biomedical session. It's our pleasure to have George Lasezkay, President and CEO of Clearside. Charlie, I don't see here, but Victor Chong, who is the Chief Medical Officer and Head of R&D, and it's great to have you all here. Clearside's got a great platform and a great strategy, so maybe, George, you can give us a quick overview of Clearside, the platform and the program, both proprietary and partnership strategies, and then we can launch into some Q&A. Sure. Thanks, Annabelle, and thanks for inviting us to be part of the conference today. We really appreciate the time. Since its inception, you know, Clearside's focused on delivering therapeutic agents to the suprachoroidal space. We're a pioneer in that space. We have developed a proprietary injection procedure and device that we're very proud of. It's worked, it's safe, it's reliable, and it's effective to deliver a variety of different entities into the suprachoroidal space. Early on in, at least, I've been the CEO since 2019. Early in that tenure, we established a few validating partnerships, one with Aurora Biosciences and another with REGENXBIO, to develop a suprachoroidal delivery in areas where we did not have any expertise. One was for a viral-like drug conjugate to treat a choroidal melanoma. The other was a gene-based therapy of REGENXBIO that went after a variety of retinal diseases. Those were areas that we did not have any expertise other than we could help them deliver the drug to that space. We also did a commercialization partnership strategy with Bausch + Lomb and Arctic Vision, in the Asia region for our first approved product, FDA-approved product for suprachoroidal delivery, and that was XIPERE, which is triamcinolone into the suprachoroidal space. We did not have the ability to do commercialization of that product, so we partnered that. We think all of these partnerships have really been validating that other companies found interest and utility in delivering drugs to the suprachoroidal space. One other final note on Arctic Vision, they've recently partnered with Santen Pharmaceuticals, the major ophthalmology company out of Japan, to commercialize that product in the region, in the Pan-Asia region. As I mentioned, the device itself is proprietary. We have a very strong intellectual property portfolio in and around the device, the use of the device, the manufacturer and design of the device, as well as the use of delivering drugs to the suprachoroidal space through that device for a variety of disorders. Finally, we've taken, and this will be the bulk of probably your questions for the rest of the time. For Victor, we developed CLS-AX, which is axitinib for wet AMD, delivery into the suprachoroidal space. We successfully finished phase II-B, our Odyssey trial. We think we have a phase III-ready product with flexible dosing, with the duration of a TKI, but the flexible dosing of a biologic. We're very proud of that, and we're currently looking and having discussions with additional potential investors, as well as potential strategic partners, for CLS-AX, so we can continue its development, through phase III and onto commercialization. Great. Thanks for the overview. Maybe, you know, before we get into the program, for those that are not as familiar, can you talk about the benefits of injecting into the suprachoroidal space of the eye, its advantages, its disadvantages, and whether with XIPERE being on the market, you've gotten greater acceptance of this? I know that there's been some who are skittish about injecting into that area of the eye, but it seems that they're getting more and more experience, and you're getting more and more partnerships related to that delivery mechanism. Maybe you can just go into that a little bit. Sure. I'll let Victor take most of that, but I will say that, as people use XIPERE, they've been very excited about the results that they've seen. It's performed better in terms of duration and effect than was predicted by our pharmacokinetic models. Once the physicians become comfortable with the procedure, they found it to be very accessible, very easily used in their practice, and very acceptable for them from a practice point of view. I'll let Victor really address the bulk of your question. Yeah, thank you very much, George, and thank you, Annabelle, for having us. I think that, you know, the thing to think about is that for most people, we're probably familiar with intravitreal injection. Intravitreal injection, you get all the way inside the eyeball. Then suprachoroidal is, instead, instead of going all the way, you're injecting a drug into the suprachoroidal space, which is kind of like in the coat of the eye, you know, in such a way. I think it's, from that perspective, it's less invasive because it didn't go through all the way. But it's as easy as an intravitreal injection, and it's an office-based procedure, it's not a surgical procedure. I think that, like what you said, just like any new procedure, I still remember when we were first doing intravitreal injection, people are skittish about it, as you said, using that term. Now it's really a routine thing. I think that is the same thing with suprachoroidal injection. When you have never done a procedure before, when you're doing something slightly similar but slightly different, you take a little bit of time to learn. We discovered that it only takes two or three injections that you'll be very good at it. After two to three injections, you know, recent survey, more than 93% of the people think the procedure is easy. I think from our point of view, the acceptance is increasing. We have more than 100 peer-reviewed publications in the last few years and over 15,000 injections using our injector in patients. I think we believe that without our partner, we are moving to phase III in diabetic retinopathy and us into wet AMD, and it will become a mainstream procedure. Finally, one of the biggest benefits probably is that because it doesn't get all the way into the eye, there will be no risk of endophthalmitis, which is one of the major, potential complications of intravitreal injection. Great. That's helpful. So just getting into CLS-AX now, outside of this mode of delivery, can you tell us how your TKI stands out from others in development, maybe how it compares to some of the new anti-VEGF compounds that are out there, Vabysmo or Eylea? You have a wide range of durations right now that came from your phase II. So help us frame that in terms of what's available today and what's in development, as well. Yeah. Yeah, I think that, you know, we can, you're absolutely right that we can separate two types of competition. I think one type of competition is the current TKI in development from our competitor. They are going for a six-month duration only, and then you need rescue in between. Again, we do know wet AMD patients have different, kind of durability for the drug that we use, and not everyone can get to six months. That is kind of like something that we think that our molecule is significantly better from that perspective, the flexibility to counter the variability of patients. Comparing with the more recent approval, now, obviously recent approval also had that flexibility of one to four months, but we are going after three to six months. Again, that increasing the durability would also help us in the marketplace. It's just two different types of competition, but we believe that we are competing with the potential market leader of the future, Vabysmo and Eylea High Dose. Got it. Maybe just on that point, can you review your phase II data and tell us what you pulled out of your phase II that sort of describes some of these differentiating features? I know a lot of people try to compare across trials. Maybe you can even talk about some of those features where you can't really compare, and get a good sense. Yeah, I think a mid-trial is always difficult, but I think that we can look at the science point of view that, you know, well, which TKI have a better TKI in terms of, lower IC50. I think we believe that axitinib has a much lower IC50, so it has a much better efficacy potentially. And then when you're actually looking at our redosing or, comparing with our competitor rescuing criteria, that we have not only we have more active patients, but we have the easiest criteria to redose. Despite that, we are very, very similar to Ocular, and we're even slightly better, to EyePoint in terms of that, reducing, need, you know, up to six months. I think it's also important that we are the only company that did not have any ocular SAE at all, and some other companies do have ocular SAE. Most importantly, I think that we have redosed at least once in almost every patient in our phase II. I think that we know how patients behave after redosing with our own drug. Unlike our competitor, who went straight to phase III, I think there is a risk for going to phase III when you never redose, but we have redosed and we learned from that. Okay. Maybe just on that point, some of your competitors are looking for six-month durations, as long as nine months, as long as twelve months. And you're, it's pretty clear that you're looking for, you think the sweet spot is three to six months. So maybe help us understand those differences. Like, why, why do you think that's the right sweet spot? You know, the view that maybe the superficial view is that, you know, the longer duration, the better. Is that not the case? Maybe just help us frame that. Yeah, I think that, you know, we have talked to a lot of KOLs that people do not think that more than six months is needed. However, that, you know, from a label perspective, you can always use less frequent than what your label said. I think that is something that, you know, people thinking about that, oh, could you go for longer? If your label says three to six months, then yeah, of course you can go longer, just like Eylea that is supposedly every two months, and you can obviously do less frequent. I think that is from a label perspective that we believe that that flexibility makes sense. When you're talking about that, some people say more than six months, but they are talking about, you know, superiority trial, which is something that we have never seen since the first approval from Lucentis way back. I think that is some, you think that in the regulatory world, that when anything which is not standard has an increased risk. That's why we went for the gold standard non-inferiority design, and also very similar to the recent approval. It had been brought to our notice by the agency that if you need rescue, and especially when the rescue is near the primary endpoint, i.e., short about a year, this would be considered as a treatment failure by the agency. That could increase the risk of regulatory failure. We took the approach that, using a design that was just approved quite recently with Vabysmo and Eylea High Dose, allowing the flexibility of different frequency, and then we were not expecting any rescue. Similar to the phase III of the most recent approval. I think from a regulatory point of view, we are using a gold standard methodology. Annabelle, let me just add one thing. I think that we have to make sure it's clear that we think six months is the right sweet spot. It's not that we're trying to have three to six months, but we're able to redose those patients that don't make six months. We think the vast majority of patients will make six months on our therapy. The advantage of our drug, as Victor has explained, is for that minority of patients that don't make six months, in our case, we can redose them. For the minority of patients that don't make six months on our TKI competitors, they need to be rescued with standard of care. It's not only a regulatory risk, but it's shifting back and forth between drugs. We look at ourselves more like a Vabysmo, like High Dose Eylea, that the goal really is six months, and we think the vast majority of patients should make six months based on our data so far. It's just if for that small group that are, that are difficult, if not impossible to identify at the start of therapy, we get to redose them with our own drug rather than rescue. Okay. Got it. Maybe can you, sorry, can you talk about that, that criteria for the retreatment? I know it differs, the criteria for retreatment differs, I guess from trial to trial. Can you just remind us what that is, just so we can sort of be able to frame a little bit better, in terms of why you had some people, you know, retreating at some four months or at five months or at six months? Yeah, so I think that, you know, there is criticism by clinicians that, even in Vabysmo and Eylea High Dose, the criteria are something that they probably wouldn't use in the clinic, and they certainly come, you know, when they complain, but talking about that, well, it's a design that which is artificial. I think that we have talked to a lot of people, and we think that, you know, again, certainly there was a recent publication suggesting that intraretinal fluid, which is fluid inside the retina, are more important. And again, for me myself, I, in my clinic, I would take that more seriously as well. I think that, you know, we would be separating intraretinal fluid and subretinal fluid rather than just a CST change or just an OCT change. I think that will be closer to what people are using in the clinic. A lot of our KOL supported that idea. Our design are much more real world from that perspective than what they were more traditionally used in, in that treat and extend on everyday practice. Okay. Got it. Can you just remind us how long is your phase III, the way you've designed the phase III trial? How long will the trial be and how many points of readouts will you have and what might you learn from this trial that you're not going to learn from other trials? Yeah, so I think that, just like most, just like basically all regulatory trial that you need to be two years, at least that in one of the two phase III studies, we are aiming to do both studies to two years. We would have a short running, loading phase period, you know, about four months, which is again, you know, consistent with that we want to use in Eylea to load, the, the newly treated, treatment-naive patient. So overall, it's about two years and three months from that perspective. The primary endpoint was set with the agency at around, 52 weeks from baseline. And 52 weeks is partly because that, we would like to have two cycles of our drug. Going for six months, two cycles is 48 weeks. The key primary readout is at 52 weeks from baseline, and then the study duration is two years. Okay. Got it. There are going to, there's, I guess there's a, after the 12 weeks, there's going to be a check on the patients every four weeks thereafter. At some point, if all these patients do not last six months, you're going to start having a bifurcation of the different arms that get treated every four months or every six months. How should we think about all those different arms? Are you going to have different powering for the different arms? Does it get exceedingly complicated or am I thinking about it incorrectly? Yeah. That's really a great question. I think there is a bit of a confusion to a lot of people. Again, if we are going back to Vabysmo and Eylea High Dose for that matter, they had a two- to four-month label, but they're still one group. I think Eylea High Dose is slightly more confusing. They had a so-called Q12 arm and a Q16 arm. If we're going back to Vabysmo, it's probably closer to our design. They are really one group. So CLS-AX is one group, but then have different dosing frequency for different patients, but it's from the original sample population. We discussed with the agency, it's not a sample group, it's just one group of CLS-AX versus the comparator group, which is Eylea on label. That statistical modeling is almost exactly the same as what you will see in Vabysmo from that perspective. The agency fully accepting that. That was the approval from that perspective. It's not different group, but it's really that because we understanding what AMD patient have variability and that variability of frequency, we then using our drug in different frequency and just like what we're doing in real clinical practice from that point of view. It's not really different group. However, you know, what you were talking about is that, slightly different from Vabysmo, we optimize our study. Because some people do say that, well, our plan, the study seemed to be a bit smaller than, say, Vabysmo. I think that there's two reasons for it. One is that we know that for non-inferiority design, the variability would potentially kill your study. We have talked to the agency that we know that from the previous, preview data that, you know, patients that who have poor vision, who have thicker retina, they are more likely to have variability in the study. We eliminate them, but it's a relatively small number of people that we eliminate. I think that we talked to the agency, the agency understand our reasoning and accepting our proposal. Furthermore, we are using a four and a half letter margin, which is actually what the agency agreed with us on. Unlike that, Vabysmo were using a four letter margin, for instance. Okay. Got it. Got it. I'm just, and just on that point, can you just, I know we were talking about the variability there. This is a treatment-naive population. Can you just help us understand the inclusion and exclusion criteria, that might be different from the other trials? You mentioned how you optimize this population with patients who have thicker CSTs. Is that because they are poor responders? Just trying to make sure that we understand how this might affect the trial outcomes. Yeah. I think that we are not necessarily talking about so-called poor responder or non-responder. I think that was a misconception from that perspective. We're talking about patients that we knew that have high variability of results. I think that is slightly different. It so happened that from past understanding of record that, you know, when you've got a very thick retina or when you've got very poor vision, your result or your number of letter gain have a much higher variability. We showed that to the agency and agency staff that, yep, you know, those variability is not needed to be allowed to be included in the study. I think that's the kind of something that we are not selecting a population specifically other than reducing the variability for our study. Okay. Got it. Got it. I just want to make sure people understood that. Now, when you talk about retreatment, how do you define when a patient needs to be retreated? Is it also similar to the other trials that incorporate rescue, or is there some variation there? Yeah. I think that, number one is that we are very different from the other TKI trial because they are rescuing and we are, rescue is really a rescue, because we solve our problem or the variability of patient in terms of frequency that, you know, to the different duration. Again, we have also heard a lot of criticism that, at least from the agency as well, that even in Vabysmo and Eylea High Dose, the dosing frequency going up and down even before primary endpoint. We understood from the agency that making that label discussion much more complicated. On our type C discussion with the agency, we selected to think that, you know, we only test it once. Once you test it once, then we're using that same dosing frequency for the rest of the year. I think that is something the agency really liked, the idea and supporting our decision on that. I think that also has good implication for the real world because I think that would also allow us to actually use that, you know, to be in clinical practice. I know that patient, physician might not want to, which I understand, but they have that flexibility is the term. I think that we have additional data at the same time that will allow the physician to go from extending from three months to four months to five months to six months and so on. I think that flexibility is what physician want and it is what physician like. Got it. Got it. So as we're talking about this, can you, everyone's got a different, it seems like everyone has a different ideas of what the FDA treatment guidelines are or FDA guidelines are on the design. So how do these studies align with the guidelines? FDA has made a big deal about not wanting masking. There's been some problems with Eylea HD. So maybe you can talk about that, the FDA guidelines a little bit and help us understand that. Yeah. I think the FDA guideline is a guideline and also that one that people talk about is the draft guideline in particular. There was some confusion on that guideline that we have cleared with the agency. The agency always maintained the discussion about that what is important is adequate masking. I think that was more important. I think that there was a confusion about, you know, so-called sham injection or, or on and so on. Again, you know, if you read the document, sham injection was never discussed at all. I think there was a little bit of confusion about what people were talking about to actually people that actually have read the guideline. Also, that there's a confusion about the comparator. Again, if you're going for a non-inferiority design, the guideline was very clear. You can only use Lucentis or Eylea. There was no other option per se. I think that, you know, I would certainly encourage people to go back and look at the guideline. Indeed, earlier this year I gave a talk in one of the conferences to explain the guideline in detail, which that presentation is in our website. I think there is a lot of confusion. The agency have been very clear to us, you know, that a non-inferiority design with good masking is the way to go. Any other design have more regulatory risks, particularly on treatment failure. They take it very seriously. Rescue, even a small number, can lead to non-approval. We really pushing very hard to go for the solving the problem of variability of patient using variable dosing and variability to give us the label that we can use in clinic. Finally, that we would not expect rescue. We don't have treatment failure. Right. And then one last question for you, George. Any progress on how we're going to be funding these trials? We're continuing our outreach program to strategic partners as well as potential investors. We have engaged a number of people in discussions and we're hopeful that we can soon have an idea of how we can have CLS-AX advance into phase III and be paid for. We're continuing, we're looking at all different options, combination of investors and potential strategic partners, strategic partners alone. We're having those outreach and those discussions as we sit here and talk. Excellent. Okay. We're out of time now, but thank you very much for giving us that overview and helping to clarify a few of those points. Appreciate the time. Thank you again, Annabelle. Appreciate it very much. Take care.