All right, good morning, everyone, and welcome to Oppenheimer's 35th Annual Healthcare Life Sciences Conference . My name is Andreas Argyrides. I'm one of the senior biotech analysts at Oppenheimer, and today I have the pleasure to be joined by the management team from Clearside Biomedical, George Lasezkay, CEO, and Victor Chong, CMO. Quick intro here, background on Clearside: they're developing CLS-AX, a proprietary formulation of axitinib delivered through suprachoroidal space for the treatment of wet AMD. Following positive phase 2 readout of the Odyssey study in Q4 of 2024, the company now plans to initiate two phase 3 non-inferiority trials in the second half of this year. Clearside is also investigating small molecules for the treatment of geographic atrophy. Great to have you guys here.
Great to be here, Andreas. Thanks for having us.
Thanks, thanks. Maybe we'll start with George and an overview of the company, and then we can dive into some questions.
Andreas, you got us started with a good overview of the company. I appreciate that.
Yeah, of course.
We, you know, seriously, we look at ourselves as the proven leader to deliver drugs to the suprachoroidal space. Our SCS Microinjector, which is our proprietary injector that you mentioned, continues to provide safe, reliable, and repeatable delivery. We've done over 15,000 injections to date, clinical and commercial injections. It has a very good safety record, and it's working out very nicely. We've successfully navigated the drug-device regulatory pathway with the FDA as well. You know, we received the first and only FDA approval for a suprachoroidal delivery product, XIPERE, which is for the treatment of uveitic macular edema. I'm sure you know that. There is a significant and I think increasing interest among both the retinal specialist community and leading pharmaceutical companies in applying this suprachoroidal delivery approach to the treatment of serious retinal diseases.
We're quite happy with what we've done, quite proud of what we've done in leading the way in suprachoroidal drug delivery.
Okay, great. Maybe we can continue along those lines, and you can give us a sense of the benefits of delivering drugs to the suprachoroidal space.
At the risk of oversimplification, there's a couple. One, we believe that small molecules injected into the suprachoroidal space, it acts as a natural depot and creates the possibility of longer duration of therapeutic effect. Next, it also has potential advantages in delivering ophthalmic gene therapy with minimal inflammation, which has become very important and an area that people are really focused on now, delivering gene therapy to take care of retinal disorders. Thirdly, we think suprachoroidal delivery lowers the risk of infection. We have seen no risk, no endophthalmitis in our 15,000 injections, so we think there's virtually no risk of a dangerous condition of endophthalmitis by virtue of our injection procedure.
Okay, great. Before we get to Victor and him talking about the lead program, maybe you can give us a quick snapshot of the pipeline, your internal programs and external partnerships.
Sure. Again, briefly, what we do at Clearside is we internally, we're focused on small molecules and our small molecule pipeline. As you mentioned, we have CLS-AX, which is a small molecule axitinib. It's a phase 3 ready product for wet AMD that you and Victor will talk about in a minute. And we have two preclinical suprachoroidal candidates for GA, both small molecules. So we've focused internally on small molecules. On the other hand, externally, we've partnered our SCS Microinjector technology with established partners, most notably Bausch + Lomb, who's marketing XIPERE, and I mentioned XIPERE earlier, as well as AbbVie and REGENXBIO. They're going into phase 3 for diabetic retinopathy later this year with their RGX-314 gene-based therapy using our SCS Microinjector.
We have this internal program focused on small molecules, but we are partnering externally where it makes sense, both commercially and for development purposes, using our SCS Microinjector technology.
Okay, great. Thanks for that, George. All right, so moving to you, Victor. How is CLS-AX in wet AMD differentiated from the other TKIs in the space?
Good morning, and thank you for having me. I think that from our point of view, wet AMD had a relatively effective treatment. The main mandate is in duration. Yet, every patient is different, and even the same patient, even at different times of the treatment journey, is different. We believe flexible dosing is important. Physicians like to treat the patient with treat and extend to changing the frequency as needed. They do want a longer duration. What CLS-AX can do is we can be able to have the flexible dosing layer biologic using our own drug to repeat the dosing, but with the durability of a tyrosine kinase inhibitor, also called TKI.
Okay, great. Maybe you can provide a summary of the phase 2b results from Odyssey.
Yeah, I think that the phase 2b for us is to have two roles. One is somewhat to compare with our TKI competitor, but also learning from that to understanding how to design a phase 3. As a summary, as you say, that we enroll the difficult-to-treat patient. In particular, we have specifically required they have active disease. For that, even with our treatment criteria, reducing criteria are a little bit easier to reduce, and we're still achieving excellent results and with durability, if not similar or even better than our TKI competitor. We have stabilized the vision to six months. The most important, we are the only company in phase 2 that we have redosing with our own drugs already. I think that is an important feature that we show the positive safety profile with the ability to redosing with our own drug.
I think that's very important because that's an important learning for us that when we reduce a drug, we know that how what would happen. That gives us an advantage as we advance in CLS-AX into phase 3. We can certainly discuss the phase 3 program later on today.
Yeah. Maybe that's a good segue back to you, George. What are the next steps in the CLS-AX program? Have you had your end of phase 2 meeting yet with the FDA?
Yes, Andreas. We've successfully completed our end of phase 2 meeting with the FDA for CLS-AX in wet AMD. Our interactions with the agency regarding the phase 3 development program have been very positive and productive. We've had no surprises, no contingencies. We're completely aligned with the agency on a proposed phase 3 program design. The plan that we discussed with the agency is to run two concurrent pivotal trials, phase 3 trials, with a primary study endpoint at 52 weeks to ensure participants receive multiple doses of CLS-AX. The phase 3 trials are designed to support, as Victor's already mentioned, the flexible dosing. The phase 3 trials are designed to support that type of a label, combining flexible dosing of a biologic with the longer duration of a tyrosine kinase inhibitor.
Our goal in phase 3 is to produce the data that would support a label, allowing CLS-AX to be dosed between every three to six months. While we believe most patients will get to six months without need for retreatment, CLS-AX offers the physician the option of redosing with CLS-AX earlier if needed. That is why we like this flexibility. That is unlike the other TKIs in development that need to be rescued with anti-VEGF products. We plan to provide a more detailed update on our phase 3 program with our earnings call in March following the receipt of the official FDA minutes. Those are the next steps in the CLS-AX program.
Great. Yeah, March is around the corner. Back to Victor. The Odyssey subgroup analyses, they guide to selecting treatment naive patients for the upcoming phase 3 trial. How does enrolling this broad wet AMD population improve the likelihood of success?
Yeah, thank you for that. I think we have shared some more data last weekend in Angiogenesis about the two subgroup analyses in particular. I think one is that those patients just got our six-monthly injection with CLS-AX. Again, they were not undertreated because I think there was a concern that when you can last six months, they might be undertreated, but they're not. In fact, they did extremely well with a very stable visual acuity all the way to our nine-month study timeline, as well as the CST and the anatomy were perfectly stable. The other one is that, you know, we do know that some patients that on the day of performing a visual acuity test, sometimes they are not performing as good.
Again, you know, it's not an analysis that we say, well, if we take out those with this kind of like a visual acuity change, we've done no anatomy change. By taking out those time points, our results look even much better. Those are two analyses that we share, and then we kind of learn from that. Let me just quickly review what George already said. I think it's important for us to remind the audience that, you know, so far, every retinal trial since Eylea are two non-inferiority trials. The two trials are usually very similar. I think we believe that is important. I think certainly when we went to the agency, that is certainly what they encourage us to do.
The second is that talking about a comparator, and again, EYLEA would be used as a comparator. We believe that is what the agency documented in the guidance. Furthermore, we do appreciate that the non-inferiority study design, one of the biggest problems is variability. Sometimes people confuse about numerical similarity. You know, you hear people reporting that the two arms might have very similar mean gain of BCVA. But actually the margin is important. Sometimes people confuse about that. We do know that the margin can widen if you got more variability. I think that is also another thing that we have deliberately tried to select in patients to reduce variability in our study. That's important.
The third thing that we also want to emphasize is that I think, you know, if our audience need to remember one thing, you know, flexible dosing is a thing that is very, very important. In fact, that will be our key differentiator to other TKI programs. Flexible dosing would also, like the phase 3 design or the phase 3 study in the recent approval, like EYLEA HD and VABYSMO, that they do not have any rescue because by redosing, it is actually to adjust what I mentioned earlier, that wet AMD patients do have a different need at times. Therefore, you know, it is right that some people need a slightly more frequent treatment than others. We can do that just like the VABYSMO and EYLEA HD.
With that flexible dosing, we were not expecting any need to rescue. Rescue is an issue. The agency has told us that, you know, if you have rescue near the primary endpoint, that could be a potential problem and consider treatment failure. I think that is certainly something that we design our study from our learning that would not be the case. Going back to what you asked me from the beginning about treatment naive, again, we selected the phase 2 patients are the more difficult to treat, have a high dependency before treatment. As you might recall, those patients have more than around 10 injections the year before enrolling. Even in that group, we have a substantial amount of patients that can only need the CLS-AX in every six months.
I think that we believe that a general population will have even more people getting to six months. We also mentioned earlier that those who get to six months have stable vision and stable anatomy. I think that is what we hope to achieve. Furthermore, I think that CLS-AX has the flexibility and therefore can cover a wide audience similar to EYLEA HD and VABYSMO. You do not need to be specifically finding a group of patients that can last six months, but at the same time, so far, we would not be able to find those who need rescue earlier or who need redosing earlier.
I think that is also something that by doing that, adjusting the redosing rather than try to predict, you know, who would get to six months, I think that we are very important from that perspective. In summary, our phase 3 design is a non-inferiority, reducing variability by flexible dosing, and we will not expect any rescue.
Yeah, maybe I'll, and you touched on a couple of points that I was going to ask, but maybe we can, you can get into them a little bit more. I think one of the key differentiators for CLS-AX compared to the other TKI-based treatments is really around the flexible dosing. Maybe, you know, kind of if you can elaborate more on the real-world application to flexible dosing, and then also how this could play into, let's just say, you know, potential label differentiation as well.
Yeah, so I think that, as I mentioned earlier, the flexible dosing is what physicians do. I think that some of the audience might be familiar with treat and extend, but if I may just briefly mention about treat and extend, basically that you treat the patient, you know, once the treatment, once the patient seems to have stabilized, then you can extend the duration by a couple of weeks. You treat the patient again, and then you see the patient, and then, you know, a few weeks longer than the last interval. Coming back, that you're still looking good, and then you're extending further. By extending further, and then also that if you're looking less good or become unstable or become active, then you bring it, you wear it back. That's how we do things.
However, to do that in a phase 3 clinical trial is actually quite difficult. We appreciate the fact that the reality that our biologic competitor with the recent approval with EYLEA HD and VABYSMO, they do not exactly have this flexible dosing or treat and extend, but what they did was try to test for activity, and then over that following period, to have a similar duration when the eye was developing some activities. We are modeling from them that because what we have seen is that although the phase 3 design is slightly different from clinical practice, once the design, once the drug is approved, and also once the physician saw those results, they move those drugs into treat and extend mode.
I think that what is how we believe that our design are similar to the EYLEA high dose and VABYSMO design, but instead of looking at one to four months or two to four months, we're looking at three to six months. I think that is critically understanding that we couldn't really do exactly in clinical practice, but by learning from our key competitor that how they do the phase 3, and then modeling from them, and then we believe that when our drug approved, then physicians will be able to use our drug in treat and extend similar fashion as they were moving to EYLEA high dose and VABYSMO. That is completely different to our other TKI competitor in development. They so far are using it for every six months.
Every six months, and then again, you know, they either need to identify who can actually last six months or else that they might need rescue. I mentioned earlier that the agency do worry about rescue, and actually rescue could lead into a failure of phase 3 study. I mentioned earlier, again, that will be caused that we adjusted the need for patients by adjusting the frequency, so we do not expect any rescue. I think finally that George already mentioned that one of the key advantages of suprachoroidal injection is that, you know, we are injecting the suprachoroidal space in the coat of the eye. That would allow you basically not injecting into the eye, so we do not have this risk of endophthalmitis. Although endophthalmitis is a rare event, it is a devastating event.
We already have more than 15,000 injections, not a single case been reported. Biologically, we understand that when we're injecting drugs into that space, we're next to the choroid, and then the choroid immune cell will take out any bacteria, unlike that intravitreal injection where we're injecting into the vitreous. I think those are really key important. You know, comparing with our TKI, you know, because in the suprachoroidal space behind the retina, there's nothing floating around. Again, patients don't like something floating around inside the eye. I appreciate that in biologic that there was nothing floating around either. Again, your biologic are more likely to induce an immune response.
I think that we had potential multiple advantages over our biologic competitor that we do not even need to put in the fridge, but then comparing with our TKI competitor that we do not have anything floating in front of the eye.
Okay, great. Thanks for that. You mentioned EYLEA HD, and that continues to ramp, I think, more slowly than expected. How do you see this impacting the competitive landscape for CLS-AX?
Yeah, so I think that it's interesting that comparing EYLEA HD and VABYSMO, I think VABYSMO have a more flexible dosing frequency. As I mentioned, they are one to four months, and EYLEA HD is two to four months. That doesn't sound like a real difference, but I think that is to us is another important learning for us. I think I already mentioned that if anyone that listening, that flexible is really the key word for us. CLS-AX is aiming for a three to six months dosing frequency, as I mentioned. While our TKI competitor would be, you know, every six months. I think that flexible dosing is what physicians want and what I want as a physician, and we are trying to give them that.
I believe that the kind of the results that for the experience of EYLEA HD and VABYSMO are quite similar, but that flexibility seems to favor VABYSMO and leading to their market success. We certainly believe that when the time comes that when a physician wants to choose to use a TKI, they will choose the one that with the maximum flexibility, which will be CLS-AX.
Okay, great. Maybe we can switch some gears here and talk about the pipeline, how you're exploring small molecule approaches to geographic atrophy. How does your choroidal perfusion and inflammatory modulation strategy differentiate from existing therapies, and what's the expected timeline for a lead candidate?
Yeah, thank you for your interest on that. I think that geographic atrophy is really the next big frontier for in age-related macular degeneration. I kind of write a reminder audience that more than 50% of legal blindness in the United States still need to wet AMD, need to AMD. Partly is still under treatment of wet AMD, and that is why the CLS-AX is developing for longer duration, allowing more true real-world improvement on treatment of wet AMD. Geographic atrophy is still leading to a lot of legal blindness in this country, in the United States and also in the European country. Geographic atrophy, we are really fortunate that they're starting to have two treatments recently approved, but they need monthly injection, and they slow down the duration, they slow down the progression a little bit without a meaningful improvement of function.
Yet that they are both targeting the complement pathway. Now, I think that, you know, I don't want to blow my own horns, you know, like C3 is actually one of the molecules that my lab identified, you know, more than 25 years ago, and it was really rewarding to see that eventually lead to a treatment. However, that is important to understanding that complement is just one part of the story. We do know that geographic atrophy is actually more a choroidal disease, and the choroid is starting to affect the first, and we see that the choroidal perfusion to the eye is significantly worse in patients that with geographic atrophy.
Indeed, you can understand when you have less blood supply, you know, to the tissue, and when the retina has a very high metabolic need, and that leads to cells functioning less well, and then eventually dying. In fact, we believe that those poor perfusion areas start the complement activation with the inflammatory cells surrounding it. That is why, instead of targeting complement, which is the after effect, we are actually going to target the two areas that we believe can, not only by improving the blood supply to the choroid, potentially improve retinal function, because just later when you get a better blood supply to the tissue. Also, we have evidence to support that when you have poor choroidal perfusion, your lesion size grows faster.
It makes sense, you know, if you have less blood supply, things get worse faster. We believe that by providing better perfusion, the cell will not die as quickly or even stop dying. I think that is why we think that is an important area. The inflammatory cell is the same, that we have a lot of inflammatory cell around, and the inflammatory cell attacking the retina, you know, and leading sometimes that through the complement pathway, but also more than the complement pathway, there is other way that you can damage the cell by this inflammatory step. By moderating the inflammatory cell, we know a lot from immunology. That was actually one of my main research interests in the past, that, you know, your inflammation causes a lot of problems in cells.
In the old days, that inflammation are just steroids, but now that we can really target the inflammatory cell very specifically, learning, you know, from our other drug developers. Those are the two areas we want to focus on, and we believe that those areas are additional to the complement pathway. It's something that we probably can use together or replacing. I think that is really a main advantage that to select those two areas. We do know that many companies are over attacking complement. We actually can and have previously published that we can use suprachoroidal delivery of anti-complement as well, but we are now focusing on these two areas for the time being. As George mentioned, that suprachoroidal is great for delivering small molecules.
The reason that we believe that geographic atrophy is a choroidal disease, that we think that suprachoroidal is not just the, you know, is not just a way of delivering drug for geographic atrophy, and we believe that is the way that, you know, we caused by doing this full suprachoroidal not only safe, not only take a longer duration, but we got a very high concentration of our drug in both the choroid and the retina. I think that is why that we believe that those are excellent programs for our future. We expect to have IND opening next year.
Okay, great. You know, before I ask, or maybe George, you can chime in here for final comments. I think one, and this is a question from the audience, basically around suprachoroidal. I mean, maybe you can give us a quick way of dispelling some of the misconceptions of the injection, how long it takes, and the amount of skill it requires. I mean, you've done a good job in the past, but maybe this question from the audience is a good one to remind everybody how simple, somewhat simple it is.
I'm going to let Victor do the details on that, but there's always been this view that it's a complicated procedure, and there's also people that have thought that it's not that patient-friendly. Both of those are clearly not true. In their phase two data, we saw that there was virtually no problems, no patient complaints, virtually no complaints of any pain or difficulty in that sense. From a safety and a patient acceptance point of view, it's done fine. I'll let Victor comment on the complexity, quote unquote, the complexity of the procedure, which is really not an issue either. Victor, why don't you spend a minute or two on that?
Yeah, I think that just like any new procedure, there is a learning curve, but this is really something that multiple KOL have reported that maybe you need to do it twice, and then you'll be pretty good at it. The first time might be that you want to make sure that you know what you are doing. It's slightly different because it's slightly different that you need to know that it's slightly different. I think that's important, you know, for people to know that. Once you know that it's slightly different, then it's not difficult at all. There is a recent report to suggest that, you know, once you learn how to do it after two or three injections, you know, 90-something % of the people who are surveyed considered it to be an easy procedure.
I think that the key difference is it does take a little bit longer, and the position of the injector needs to be perpendicular, which is actually different from the intravitreal injection that we've been doing for years to point the needle to the back of the eye. In fact, this just needs to be perpendicular, which is not natural until you remember that. I think that from our point of view is that we are actually quite happy to take a challenge. If any physicians say this is difficult, let us know, and then we can teach them how to do that. Again, some people talk about that it's difficult, but they have never even tried.
Some people have done it without talking to us or learned how to do that and just give it a go on their own, but without reading it through. We believe that, you know, this is such a simple procedure, but then it's because it's slightly different. Physicians just need to think a little bit about it. Otherwise, you know, it's not difficult.
Yeah, just think we've had multiple external partners conduct multiple clinical trials. We've had 15,000 injections. We've had virtually no problems with it. The safety is on par, at least on par with intravitreal injections. As we pointed out, it has an advantage of no endophthalmitis. I might also point out too that there is a CPT code that has been granted in the U.S., and we get a physician get a slightly higher reimbursement for suprachoroidal delivery technique than they do for intravitreal technique. We think, look, once a physician does it two or three times properly trained, it's just not a big issue for the physician or for the patient.
Fantastic. All right, George, maybe I think we're close to time, but maybe, you know, want to wrap it up with any closing comments?
Yeah, I would just say that right now with the CLS-AX is our focus. Right now, we think the phase two data is very good. We've confirmed our phase three program with the agency, and we believe it's optimized as much as possible for success for the reasons Victor explained. We are well positioned to take on a strategic partner to help us continue to advance CLS-AX forward. As well, still, you know, considering additional partnering for SCS Microinjector platform while we continue to develop our internal pipeline. We are very enthusiastic about CLS-AX. We think it's a great proof of principle, great drug going forward, and definitely ready for phase three. That's where I'll leave it, Andreas. We are very enthusiastic and very positive on CLS-AX and the SCS Microinjector platform in general.
As are we. Okay, great. Thank you guys for your time, for walking us through Clearside and the lead programs here, and we're looking forward to updates for the remainder of the year. Thanks again, guys, for joining us.
Thanks, Andreas. Appreciate it very much.
Take care, guys.
Bye-bye.