Good afternoon. I'm Serge Bélanger, one of the senior healthcare analysts at Needham. I want to welcome you to our 22nd annual healthcare conference. For our next session, we're going to be talking with Clearside Biomedical, and we have the company's CEO, George Lasezkay, with us today who's going to give us an overview and talk about the recently unveiled phase II-B trial design called from the ODYSSEY trial. I'll hand it over to George, and you can give us the overview. All right. Thanks, Serge. Appreciate being invited to be part of the Needham Conference. It's our pleasure and privilege to be here. Let me just take you through just some very brief slides about the company, and then we'll get into what we recently announced yesterday, which was our plans and our design for our phase II-B trial with our tyrosine kinase inhibitor axitinib in wet AMD patients. During this presentation, I may be making some forward-looking statements and please keep that in mind, and if you can read quickly, read this slide. Just as an overall view of the company, the company is based on our versatile therapeutic platform for delivering drugs to the back of the eye, our SCS Microinjector, using proprietary drug formulations to target the suprachoroidal space. We really have a two-pronged strategy. One is to develop internal products in our internal pipeline for development where we can, generally based in small molecule suspensions. Our first FDA-approved product was XIPERE, was approved in October of 2021, currently being commercialized in the United States by Bausch + Lomb. They've applied for approval in Canada. We also have a Pan-Asian partner in Arctic Vision conducting phase III trials in China, as well as phase I trial in diabetic macular edema. Our lead clinical development product is CLS-AX, which is a tyrosine kinase inhibitor, axitinib, recently completed a phase I/II-A study, dose-escalating study in wet AMD. We reported on those results in early February of this year, where we saw a significant reduction in treatment burden, an excellent safety profile, and encouraging data that allows us to move phase II-B, which we now plan to initiate this quarter, and it's a trial by the name of ODYSSEY in wet AMD patients, a clinical trial that will be looking at the duration of maintenance therapy with CLS-AX. The other part of our strategy is to develop external collaborations for pipeline expansion, and I'll talk briefly at the end of this presentation about our partners, REGENXBIO and Aura Biosciences. First, let me just go with the summary of our OASIS data that we reported earlier this year. Excellent safety data at all doses and at all time points. No serious adverse effects, no dose-limiting toxicities, no inflammation, and no AEs related to intraocular pressure. We were able to maintain stable best corrected visual acuity and mean central subfield thickness in our patients. In the extension study, which is the most relevant to going on to phase II-B, we saw greater than 77% reduction in treatment burden when comparing treatments in the study versus an equal period of time prior to enrolling in the study. Importantly, 67% of the patients in the extension study went six months or greater without requiring retreatment. 50% actually required no retreatment even at the six-month time point. We were encouraged that they could even be a longer duration than six months. All of this was very encouraging for us to design and initiate the phase II-B clinical trial, which I'll talk about now. We released this, the details yesterday. phase II-B trial will be in treatment experienced participants with active disease on enrollment. It'll be a randomized, double-masked, active controlled multi-center trial in wet AMD patients. We're looking for those patients that are treatment experienced but not treatment subresponders. We're trying to find those treatments. We want to make sure that on enrollment, they have clear independent reading center confirmation of persistent active disease but have shown some responsiveness to prior anti-VEGF treatment. There'll be two arms, total of 60 patients with a two-to-one randomization, 40 patients in the CLS-AX investigative arm and 20 in the control arm. The control will be aflibercept dosed on label with in both groups receiving three loading doses of aflibercept over three months. The control group will be then dosed every two months on label with aflibercept. The CLS-AX arm will receive a first dose on the second load of aflibercept and then will be dosed no less, no more frequently than every 12 months, or excuse me, every 12 weeks, and will definitely receive at least one dose at 24 weeks or six months. We'll do disease activity assessments on weeks 12 through 32. Total length of the trial will be nin months from the first CLS injection. The supplemental treatment criteria will be the same for both arms. various decreases in BCVA, increases in CST, or new or worsening vision threatening hemorrhage due to wet AMD. What we're looking for here is we're not powering this study to be a non-inferiority study, nor are we powering it to be a superiority study. We are running a trial here that we're going to estimate what our best fixed dosing regimen would look like going into phase III. We want to maintain BCVA, we want to have a determination, we believe we'll have enough with 40 patients in the investigative arm to come up with a very good measure of what our fixed dosing frequency should be going into phase III that will allow us to maintain BCVA in a similar fashion to the BCVA in the control group, using aflibercept. Why have we done it this way? First of all, we Based on the recent FDA guidelines for wet AMD drug development, we reevaluated our initial thought of comparing ourselves to faricimab and decided to go back to using aflibercept. We're very comfortable with aflibercept as our comparator. We think that using aflibercept as our comparator will better position us and better inform us regarding phase III trial plans. We're going to treatment experienced patients versus treatment naive and versus treatment resistant or subresponders. We think this is a much larger population, allows us to enroll quicker. Based on the KOL input that we've had, this is the group that the KOLs were most interested in finding a better maintenance with less frequent maintenance therapy. This is what was most interesting to them, and we agree with that, and that's why we're going to focus on this treatment-experienced group of patients. It also, by the exclusion criteria, we will minimize the recruitment of sub and non-responders to anti-VEGF therapy. As I said, our main goal here is to determine the duration of CLS-AX that will maintain CST and BCVA similarly to on-label EYLEA. We're going to look at that, and we're going to come up with a plan to go into phase III with a fixed dosing schedule of CLS-AX that we think will be an advantage to patients on longer-term maintenance therapy. The 36-week duration will provide us all that necessary data, both safety and efficacy data, to plan and initiate a phase III program at the conclusion of the ODYSSEY phase II-B trial. This slide gives you kind of a visual overview of how we plan to conduct the trial. We've tried to simplify it to eliminate a lot of the sham injections. It got quite complicated. Basically, you see that we're doing a three dose, three monthly doses of aflibercept in both groups. On the second dosing of aflibercept, they will be randomized into the CLS-AX group versus the comparator group. The comparator group will get a sham second injection, and the investigative group will get their first dose of CLS-AX. From that point on, beginning at week 12, we will conduct disease activity assessments to determine the need for any supplemental treatment. Participants in the CLS-AX randomized group will be treated no less than every 12 weeks and at least every 24 weeks. Participants in the aflibercept comparator group will be dosed every eight weeks unless supplemental therapy is required in between those two, you know, planned fixed injections. That kind of concludes our discussion of the details of our recently announced trial. What I would tell you is that we plan to initiate this quarter, and top-line data will be available in third quarter of 2024. Final note on our collaborations. As you can see, again, going back to our two-pronged strategy, our internal developing strategy is the CLS-AX with our ODYSSEY trial phase II-B. our external collaborations are the second prong of our strategy you can see listed here. We have a very good relationship with REGENXBIO, who's now partnered this program with AbbVie to deliver AAV-based gene therapy. Their RGX-314 program is into the suprachoroidal space using our SCS Microinjector for both wet AMD and diabetic retinopathy. They're currently in the sixth cohort of both of those phase II trials, and hopefully they will have a readout on both of those cohorts before the end of this year. Aura Biosciences, another good partner of ours with the virus-like drug conjugate. They've abandoned their intravitreal approach and are exclusively trying to treat choroidal melanoma with our SCS Microinjector injecting their drug product into the suprachoroidal space. They've announced that they will begin their phase III trial sometime early this year and have had very good results. Finally, at the bottom, our commercial partners, Bausch + Lomb, as I've mentioned, with XIPERE for uveitic macular edema in both U.S. and Canada, and Arctic Vision, our Pan-Asian partner, conducting its phase III clinical trial in China for uveitic macular edema, and they've just completed a phase I trial in diabetic macular edema in China as well. We're really excited about this. We continue to execute on our plan of developing our own internal products as well as partnering with those collaborators that have capabilities and technologies that we cannot develop on our own. As you'll see in the final slide here, our catalyst for this year, I've already mentioned the CLS-AX catalyst of we've reported our phase I/II-A, we will initiate phase II-B this quarter, and the data will be available next year in Q3. We'll be at all the major scientific presentations, meetings, and presentations this year. Then I've mentioned all the partnering programs and all their activities that are coming up this year with REGENXBIO completing their phase II clinical trials and Aura initiating their phase III clinical trial in choroidal melanoma. With that, Surge, if you have questions for me, I'm glad to take them now. Well, thanks for the overview. Sure. I guess my first question is just on the suprachoroidal administration. How well is it understood by the physician community in the ophthalmology space, you know, the differentiation between suprachoroidal versus intravitreal and the other administration or delivery routes, you know, how it differs in terms of safety tolerability and how it targets the drug to the actual tissue? Okay. Well, I think there's a couple of ways to approach answering that question. I think the reception certainly, the feedback that we've had from our clinical investigators like REGENXBIO and Aura Biosciences, as well as our commercial partner, Bausch, has been that the physician level of comfortableness and acceptance of the injection procedure itself has been very good. The training goes very well. It's a fairly simple training. The reception by the physicians has been great. There's a lot of interest in it. Every time there's training, especially by Bausch at meetings, they have more people wanting to be trained than they can train on-site. That's gone very well. We've had no reports of any difficulties or issues of any significance. We've injected several thousand times now clinically without any real difficulties, any real physician pushback, as long as they follow the training. The training is actually fairly simple with a couple of practice injections as long as the physician holds it perpendicular to the orb and injects over about five to seven seconds. Usually, there's no issues with that, which is a little different than intravitreal. As to the importance of putting it into the space, we found that we focused on small molecules, insoluble small molecules. Others that are in that same space have going intravitreally have had to put them in hydrogels, bio-erodible devices, and whatnot. We don't need to do that. Our formulation is fairly straightforward, very easy to formulate, and it goes into the suprachoroidal space, which is behind the visual field. We don't have to worry about floaters, we don't have to worry about snow globe effect. The other reasons why people are having to put it into bio-erodible devices and hydrogels is to keep all those insoluble molecules together out of the visual field and allow them to dissolve slowly and then try to get to the retina. We're right against in the back, we don't have to worry about any of those kind of problems of creating snow globe effects. Plus, we don't have to worry about any of that circulating drug in the vitreous going to the anterior chamber, affecting the cornea, etc. We think it's safer, it's compartmentalized, and we put it in that suprachoroidal space, and it acts almost like a drug depot itself. Rather than having a hydrogel or some other bio-erodible device, we just plant it behind the retina, and it sits there, and it stays and slowly dissolves there. The formulation is easier, the administration is simple, and we feel very good about it. The other thing I would say about the suprachoroidal space is what has been seen in gene therapy is that gene therapy delivered intravitreally has, I'm sure as you realize, has been problematic. It's caused a fair amount of inflammation that the varying degrees from manageable to less than desirable. The subretinal is obviously the best place to put it because it's an immune privileged space. The subretinal there's a big surgical procedure, you have to do a partial vitrectomy. That's good if it's one and done, but if it has to be repeated, that'll be a difficult situation. Mm-hmm. Where we found gene therapy in the suprachoroidal space is it causes much less inflammation. The experience so far is it's been much less inflammatory, much more manageable to deliver gene therapy into the suprachoroidal space than in the intravitreal, through intravitreal means. Hopefully that's kind of an overall answer to your question. No, absolutely. We're excited. We think it's a very important alternative route of delivering therapeutics to the back of the eye. Yeah. On the CLS-AX program with the OASIS data that you presented earlier this year, curious what kind of feedback you've gotten so far physician community, or maybe it hasn't been presented yet, and it will be at ARVO? Mm-hmm the retinal meeting. Yes, it's just beginning to be presented at various meetings. There'll be a presentation at ARVO. There'll be one at ASRS. Generally the feedback we've gotten from the KOLs that we work with and our scientific advisory board has been very encouraging. We need to do more, obviously. I mean, the phase I/II-A study was not a double-blinded study. It was just a you know, it was a safety study. We were looking for some markers of biological effect, which we think we've seen pretty clearly. We've had more, I think, you know, we've looked at all the individual OCTs. We really do see kind of a timing of we can see the biological effect come, and then we can see it slowly go away. We're really clear that it's having a biological effect. The question is really gonna be more important going into ODYSSEY when we're doing a completely randomized double mask, you know, a controlled trial, is can we show that but with differing dosing frequencies, we can have similar clinical outcomes to the standard of care, which is EYLEA to every two months on label? You know, that's gonna be the real test for us. The data has been very encouraging. We've been very, the KOLs that we've talked to have been very supportive of us moving forward. We've reviewed our trial design with many of them, and they've made some suggestions, and they're very excited about participating. Well, what I can say is out of basically a phase I type of trial, safety trial, we got a lot of good data on efficacy and duration that encouraged us to go into a more robust phase II controlled and double-blinded study. We're encouraged by that. Yep. You mentioned earlier, the patient population between OASIS and the ODYSSEY trial are gonna be vastly different. In OASIS, you had some of the more difficult to treat treatment experienced patients. Is that fair to describe it that way? The very difficult treatment experienced patients were in OASIS. Yeah. We knew. We selected them purposely. We knew they had disease, we knew they were difficult to treat. We wanted to see in that population whether we had something that was worth exploring further. We believe that was the case. Mm-hmm. In ODYSSEY, we debated between treatment naive and treatment experienced. Based on a lot of input, the scientific community, we decided to go with treatment experienced. The way we're doing this is we're not looking for the sub-responder population that we saw in the OASIS safety trial, but we are looking for patients who have been diagnosed rather recently, have demonstrated some response to anti-VEGFs. We're trying to not include non-responders. We wanna include people who require treatment. When they're enrolled, we wanna make sure that they have all the markers of active disease. We wanna see that they have fluid but under control or responsive to anti-VEGFs because we do not wanna be enrolling patients that may not actually require any treatment. They may not have fully active disease. What we don't want to do is put them in and then get a false sense of security that our drug is actually doing something when some of these patients may not have required treatment anyhow. We wanna make sure we're getting people who require treatment but are not what we saw in the first trial that one of our investigators called anti-VEGF addicts. You know, they responded, but they needed to get it very frequently. Yeah. We're looking for people like that respond to it but should do fine on the control group, we wanna compare ourselves to the control group and basically say, "Can we produce similar outcomes from the control group but with far less frequent dosing?" That's really our goal. Okay. That'll set us up for a nice phase III trial where we'll have a fixed dose going into a phase III trial and be very robust in a phase III program. Given where the market has evolved to, the anti-VEGF market, I guess, I mean, and VABYSMO, I'm including VABYSMO in there, what's the ideal duration for a product like CLS-AX? Well, let's look at what VABYSMO's label was. You know, we know, and this was our original trial design, we knew that over 50% of those patients needed, after 4 loading doses of faricimab, four monthly loading doses of faricimab, 55% of them, by their own numbers, needed to be retreated within three months. Okay? We didn't feel like that was a big bar to jump. That was a very high bar to jump over. Even with EYLEA HD, where people give us that comment, "Well, what about EYLEA HD?" From what we understand, they're applying for they've quadrupled their dose, and instead of at 2 mg every two months, which is what we're doing at on label for this trial, they're going to 8, but their duration, they're asking for every 3 months-4 months. They've quadrupled their dose, but they haven't quadrupled their duration. What we're looking for is something in ours. We'll be very happy, and we believe we're going to have a reasonable degree of success to achieve things that are 5-6 months out. I think if we're in the 4-6 month category, but more leaning towards 5 and 6 months, I think we'll have a very interesting product. That we could say to most people in this thing, in this kind of treatment group that we'd be looking at, they have the opportunity to be treated as infrequently as twice a year and still have good maintenance. That's what we're hoping to get. That's what we think we have the potential to achieve. ODYSSEY will show us whether our beliefs are valid. Yeah. you described the dosing regimen is gonna be Well, CLS-AX is gonna be compared to the current approved dosing regimen of EYLEA. Yeah. In ODYSSEY. You did mention it's not powered for non-inferiority or superiority. Correct. Mm-hmm. On the primary endpoint, what kind of differences will you be looking at? Well, we'll be looking within a certain band of BCVA. You know, we're gonna try to be within, you know, maybe one line of BCVA or letters of BCVA on our mean BCVA versus the comparator group, and see if we can do that at nine months. We're in very similar BCVA. We're not gonna end up with a p-value. What we're doing is doing this to guide our planning for phase III, where we would be dosing a we would be enrolling enough patients to run a non-inferiority trial. Okay? The expectation that we're gonna come out of this with non-inferiority with a p-value of less than 0.05 is that's not the right way to be thinking about what we're doing. We're doing something very similar to what EyePoint is doing. We're trying to get an estimation of what our duration looks like. Yeah What our capabilities are, what the possibilities are for us. If it's as good as we hope it will be, then we'll have a very good idea how to run a non-inferiority trial in phase III against a fixed dosing of CLS-AX versus a comparator. Okay. Hopefully that's clear. Based on prior clinical trials, what's the expected BCVA gain in the EYLEA group in this kind of patient population? Well, I. You know, I. We expect that they're gonna come in with a certain BCVA already that we hope to maintain. We hope that over time on this every two... They're not gonna gain too much over time. Okay? Yeah. I can't really answer that question. I wish I could, but I won't. I'll defer on that. No, no. That's fine. I just think that as they come in, our goal is to see. We would expect them to basically stay about the same, and hopefully we can keep their entry BCVAs stable with less frequent dosing. Yeah. We think by doing it the way we're doing it, with following on-label with the three loading doses, to the extent there's a gain, the gain would be equal or very similar in both groups. We don't wanna get one of these things where the comparator gets way out ahead of us, and all of a sudden we have this big gain in the comparator group, and it screws you. Yeah. We're trying to treat them equally on the entry into the trial by dosing both groups with three three-monthly loading doses, which is on label. If there is a pickup because of the 3 loading doses as they come into that more aggressive kind of aflibercept treatment, from what they were doing before, because of the randomization, it'll kind of even itself out. Yeah. That makes sense. Yeah. I mean, like you described it's a being evaluated as a maintenance treatment. Yes ... ideally to maintain the BCVA gain that's achieved. We really think that's where tyrosine kinase inhibitors in general fit is in a maintenance therapy much less frequent dosing to maintain the same kind of gains over time. You know, in long term, you know, we know that over time, there's a significant number of patients with the traditional anti-VEGF therapies that start to their actual gain from when they started on therapy to a couple years later, they start to lose that improvement over time. We're hoping, because we have a slightly different mechanism of action, blocking receptors instead of binding with the circulating VEGF, we think that maybe over time there could be an advantage to us that that kind of gain that's achieved is more able to be maintained rather than lost over time. Okay. You know, again, we're a pan-VEGF inhibitor, so they're just picking up one. They're just a VEGF-A. There can be this overexpression of C and E, and what we're trying to do is we're trying to block over time, the effects of any overexpression of the other VEGF in the other VEGF that's being produced. You know, it's kind of like they're great for acute, we might hopefully be better for maintenance. Once you complete phase II-B, next step will be moving to phase III. Yes. most likely have to conduct two separate phase III trials at kind of the standard path? That's probably most likely the outcome. Yeah, sure. Yeah. Since you're conducting the phase II-B against EYLEA, most likely you would go with EYLEA as a comparator also in the phase III? I would think that's probably the case. The question is, what would the FDA's guidance be at that point in time? Their draft guidance says, you know, go against EYLEA or LUCENTIS. Right now, that's what's in the draft guidelines. We know in conversations with them that there's just not enough safety data on faricimab right now. Mm-hmm. I don't know that faricimab wouldn't be an eligible comparator in the future. If it is, we could easily go against that. We've wanted to do that now, if it was more acceptable as a comparator to the agency, we'd probably consider one against that and one against EYLEA. Even at that time, you'd have to figure out, do you need to go against high-dose EYLEA, yes or no? Is that gonna be a comparator? All we can go on right now is what we know based on the draft guidelines, and the draft guidelines are pretty much, you know, LUCENTIS, EYLEA on label the way... Yeah ... it exists now. you know, we'll be very mindful and very attentive to the how the draft guidelines get finalized, and hopefully they'll be finalized when we're approaching the end of our phase II-B trial so we can better plan in accordance with what the final guidelines will be. Sure. Assuming everything goes well in the phase II-B and the phase III, product gets on the market, what role do you envision that CLS-AX could play? I would imagine first line treatment would still be the anti-VEGFs, and then second, third line is that where we could see CLS-AX come in? Well, again, what we're positioning it now for is maintenance right now, okay? That's what we know. It's hard for me to answer the question too, that's too far in the future. I would say certainly, I would think newly diagnosed patients would depending on this, their state, how they're diagnosed, and how severe their disease is when it's diagnosed, I would think would still be needing anti-VEGF in the way we see it today. You know, whether it, biosimilars, you know, the generic Avastin, whatever it is, would probably be needed if their disease was significantly advanced when they're first diagnosed. I would probably be indifferent to any of those approaches where I think tyrosine kinase inhibitors are going to play a role is after that diagnosis, after their initial stabilization, if you put them on, hopefully that's where we end up is we're the preferred maintenance, longer term maintenance therapy. That's not to say that we couldn't find a subgroup that might be able to be treated initially with a tyrosine kinase inhibitor. That could be the case maybe in a diabetic retinopathy patient. If you're talking about wet AMD, I would think what I know now is I would think it's probably after the acute intervention, you would go to maintenance therapy with TKIs. Yeah. That's where I think it would be. I mean, I think, hopefully, you know, retinal physicians will have a number of things to choose on in the near future, choose from in the near future. kind of like mixing your drug therapies in cancer. You know, different combinations of things, different patient subpopulations. I'd see us as, hopefully in the future, one of the preferred choices for maintenance, for sure. Again, looking ahead, where else do you think a TKI inhibitor like CLS-AX could be useful out beyond wet AMD? Does DME or diabetic retinopathy also make sense for such a mechanism of action? I think it does. I wish I could do studies on all of those diseases. I can't. As you know, some of the other people that are in the space, in the TKI space, of, you know, Ocular is doing a DR trial, and EyePoint is has talked about multiple trials. I think anything that's VEGF responsive could be a place where the TKIs could play. I do think so. Again, it's a combination. Do you need to have the standard anti-VEGF intervention first and then go to maintenance? If something is less symptomatic initially, could you start somebody on a TKI and never need to have the intervention of, you know, on EYLEA or LUCENTIS? That's possible, again, that'd have to be studied. Yeah. You know, that has to be studied. You know. Certainly conceptually or, theoretically, a TKI should have a place in those diseases. Yeah. We only have a few minutes left, so maybe- Okay ... you wouldn't mind just giving a financials overview of the company ahead of starting the ODYSSEY trial. All right. Well, we ended last year at about, it was $48 million, around $48 million in the bank at the end of last year. We have sufficient funds now to get us through Q2 of next year. We have enough money to get this trial going. We are going to have to raise some money either through non-dilutive or dilutive equity raise to some extent to bridge that small gap that we have between Q2 and getting the trial results in Q3 and having a little bit to go past Q3. We do have a little bit of fund funding that we have to take care of, but we think it's very manageable. It's not very large, and we're very confident that we can do that. Either by a combination of non-dilutive and dilutive or just a straight equity raise, we're very confident we can get enough to complete the trial and have sufficient runway past the Q3 2024 top line results. Great. Yeah let's wrap it up there. Okay ... thank you for spending time with us this afternoon and giving us an overview of the company and the phase II-B trial. Okay. Well, always great to be with you, Serge. I thank you for your time and appreciate Needham having us as a participant. Thanks. We appreciate it. Okay.