All right, good morning, everyone. Thank you for joining us at the Clearside Biomedical presentation. Happy to have George Lasezkay, our CEO of Clearside, as well as Victor Chong, our newly appointed Executive Vice President, Head of R&D. I believe you just have moved forward beyond the CMO role, correct?
Yes, thank you.
Okay, great. So, you know, Clearside obviously has the microinjector platform for suprachoroidal delivery for ophthalmic conditions, retinal conditions. And so, George, maybe you can give us a quick overview of the story first.
Sure. And thanks for having us this morning, Annabel. Always great to be at the Stifel conference. Well, as you know, we're in a very competitive set of situations with tyrosine kinase inhibitors. And we feel like we're positioned very nicely in that space. We have looked at using tyrosine kinase inhibitors into the suprachoroidal space. And we just completed our phase II-B Odyssey trial in wet AMD patients. And there's a couple of things that are really important to note as you look at us versus the other TKIs. One, we specifically tried to enroll patients with evidence of active disease. In other words, they had presence of fluid. And that was really important because the other tyrosine kinase inhibitor companies have not been so selective in their patient population. So this is a harder-to-treat patient population. We know they required therapy.
Secondly, in Odyssey, what we did that's different than the other ones is we did repeat dosing with our own drug. This is important too. Neither of the other two tyrosine kinase inhibitor companies have attempted multiple dosing yet. Yet, both of them are advancing into phase III. If you look at our data, our data is extraordinarily competitive with their data in terms of efficacy. There's no doubt that tyrosine kinase inhibitors have a biological effect. All three of the companies have shown that two-thirds or so of the patients can go six months after treatment without needing any kind of intervention. But what about that other third? There's a third of those patients that don't make that six months. Those are impossible to identify proactively.
So we thought it was very important to show that we can redose with our own drug for those patients that don't make six months. And that really distinguishes us, I believe, and I'm sure Victor agrees, that that distinguishes us from the other tyrosine kinase inhibitor companies. So what we've shown in Odyssey is that we've developed very, very competitive efficacy data in a harder-to-treat population than the others. And we've demonstrated that we can safely redose with our own drug, safely and effectively redose with our own drug, where the others haven't tried that. So if you sum the whole thing up, the way I look at it is we've attacked a patient population that's much more real-world in that it's patients that we know require therapy. And we've done it with the same degree, and we believe, in some cases, better efficacy data than our competitors.
We've done it safely. We've been able to retreat with our own drug. We've set ourselves up for phase III trials, where we can run a phase III trial that hopefully will produce a flexible dosing label of every three to six months, which will be very KOL or physician-friendly, very much a real-world kind of label that will gain us a lot of use in that competitive space.
Okay.
Okay, we just think we have the best approach to using tyrosine kinase inhibitors for wet AMD.
Excellent. So just let me ask you a couple of questions about the Odyssey trial and the way it was designed. And we have a bad habit of trying to compare cross-trials, which we know we shouldn't do.
It's okay.
But it's specifically about the design here. You dosed everyone got a series of aflibercept doses in the beginning. You dosed CLS-AX at the second dose rather than the third dose of aflibercept. Can you explain the rationale behind that and help us understand what that might mean for the first few months of efficacy?
I'll let Victor deal with that question.
Yeah, I think that at the time when we designed the study, when we had the first phase I study, some physicians actually tried to redose very early. And there's a little bit of uncertainty on that. And that was the reason to have one more on the aflibercept on that. However, when we moved to phase III, that might not be needed. And I think that we now have experience and data to support that we probably don't need that. And we certainly in Odyssey that we actually 100% get to month 12 and week 12, and more than 90% get to week 16. So I think that is just something that when you learn from phase I to phase II, and I think also that learn from phase II to phase III.
Okay. So by month 12 and month 16, we would not have seen any more aflibercept.
Yeah, week 12 and week 16, yeah.
Okay.
Yeah, so I think there's a little bit of confusion out there that when other TKI companies are rescuing, so when we put out our presentation as intervention free, because our first intervention is always CLS-AX, so I think that was a little bit of confusion with other companies.
Okay, great. And then can you just explain the differences between, I guess, your criteria for retreatment versus others' criteria for retreatment, and whether there were differences there that were meaningful when people are looking at the data?
Yeah, as you say, that comparing trial is always difficult.
Yeah.
I think that reemphasizing one point George mentioned, that our study needed the patient to be active. I think that's important. Our two competitors do not need to be active. In fact, Ocular has to be completely dry. Then when you're comparing the rescue criteria, actually all three companies are using very similar criteria on three criteria. Three of them are quite almost identical. But those three criteria actually less used. The most commonly used criteria, there was one so-called 100-micron increase. In our study, you only need once. As soon as you had 100-micron increase, then you will need to be redosed with our drug or rescue from other company. But our competitors either don't have that criteria, or you need to have that three times in two consecutive visits.
So imagine that in a monthly-based visit, that if you need thrice, in other words, that you will be automatically four weeks further. So if you're looking at our data, that you could imagine that using a criteria for our competitor, in our case, every patient will be moved four weeks further. So I think that would be really showing that our very competitive data set, despite our patients are active, and we actually still, on every time point, look like that we are achieving a similar ratio, if not better ratio.
And that 100-micron criteria, that's what's used in typical practice right now. It's not the letters or a change of five letters or a change of 10 letters.
Yeah, that's not really. I think that is something that was used at the time that when this study was done a few years ago, when considering that as a kind of limit that you really can't stop doing something. I think that in real practice, and actually that is what we already see in the current newly approved biologic, that when you seem to have an extension a bit longer in the trial, but in fact, in practice, it doesn't actually last as long. So I think that what we are thinking about is actually similar to what we have shared in the webinar with our KOL, that we might want to tighten up the criteria. And in fact, tightening up the criteria means that it might be easier to redose. However, that is actually more closer to clinical practice.
What might the criteria be?
We haven't actually decided exactly what, but if you're referring to actually a recent publication, published by a bunch of experts, to say that, well, how do we look at the redosing criteria and what people use and what I use as a physician myself? I think that I don't want to go into a lot of detail, but in the retina, the 100-micron is the overall increase, but in fact, we know that if you have fluid inside the retina, what we call intraretinal fluid, comparing with fluid under the retina, which causes subretinal fluid, they are pretty different, and certainly, that I wouldn't tolerate a lot of intraretinal fluid because they have fluid inside the retina and can cause more harm, and we actually found that subretinal fluid that can tolerate some of the subretinal fluid.
In fact, the presence of subretinal fluid could sometimes be helpful in the overall visual acuity. I think that we are thinking about separating those two things. In other words, that if you have an intraretinal fluid recurrence, we might want to start redosing. When you got a little bit of subretinal fluid, which we do in practice, a little bit of subretinal fluid, you might be happy to leave the patient alone. I think those are the criteria that we are thinking about, that using those biomarkers are a little bit more specific than 100 micron. 100 micron in subretinal might be less. 100 micron is too much. Even say 50 micron, 50 micron subretinal might be okay. 50 micron in intraretinal will probably not.
Is the FDA on board with this type of fluid? Has it ever been used in trials before?
Yeah, so I think that the agency has not really very focused on exactly what criteria you use. Actually, not on the label. I think that what we have seen from the more recently approved aflibercept high-dose and Vabysmo, they're also using very completely different criteria. So I think that we are comfortable with the agency that using this kind of a more even more specific, even more scientific, more clinical. I think the agency will not have any problem with that. However, that as we shared that we are going to have our end of phase II discussion early 2025. I think that was something that we'll go finalize with the agency.
Okay, got it. So I just want to go over some of the different numbers within Odyssey. You had the standard retreatment rate, whether it was four months, five months, six months. Then there was, and that included patients who were retreated regardless of whether they met the criteria. Some physicians treated earlier. And then there was the other rate that was a little bit higher if they actually retreated based on protocol. And then there was yet another set of numbers, which was based on the true ITT population. So what exactly, which number should we actually go by? What is the real number?
Yeah, so I think that we are trying to share data that shows how comparable with our competitor. I think that we know that we are among the three TKI companies mentioned that we are the last to share the data. So we're just trying to help the community to look at how we compare data and so on. So the first set of data that we originally shared, other than the criteria we mentioned that we are much easier to redose, are using almost identical criteria to our competitor who also had a bigger study. So if you're looking directly at our last four points of our timeline that we shared, with the last four points that shared with our competitor with a bigger phase II data, and despite that, I mentioned that our criteria is a little bit more easy to redose.
If you want to compare our so-called fit protocol data, and again, another competitor, even more advanced, that they also share that they have data that doesn't meet criteria. Doesn't meet criteria is not uncommon in this kind of trial because physicians sometimes want to treat earlier. The 100-micron is sometimes that people feel a bit uncomfortable, as I mentioned earlier, that we might want to tighten that up because physicians don't like it that much. So I think that, again, because our competitors also provide data that which is meet criteria and which is not meet criteria. So we're providing the not meet criteria data as well so as people understand that, yes, our number even looks even better. Almost more than 80% get to six months if using the criteria that you actually need to meet the 100-micron protocol.
And then finally, that the ITT, just again, some colleagues requested that. And in fact, the ITT number is absolutely virtually no different. It's within 1%. The concept of ITT and otherwise are just because the dropout rate is so low, so it doesn't really affect it. But some people asked for it, and then we provided it.
Okay, all right. That's important to know the dropout. What was the dropout rate? It was.
Yeah, up to six months is less than 10%. And up to nine months is about 12%-15% overall. In fact, the dropout rate is slightly higher in the comparable arm, in the aflibercept arm.
Okay, great. I want to drill down a little bit more on the retreatment that you baked into the phase II trial. So how meaningful is that for physicians to see that? Number one, I guess, how meaningful is that to bake it into the phase III trial? And what's the feedback that you got from the street? Or not from the street, from the medical community. We're the street on the medical community, given that none of the other trials had that retreatment option. They had more of a rescue option.
Yeah. Well, I think that the physician understands that better, seems to us. And the physician understanding that when you jump from phase II to phase III without ever redosing in your phase II, you're taking a very high risk because you don't know when you redose what might happen. So at least that we know what happened. And again, we learned from that. And I think that, as I already mentioned, tighten the criteria and also making the physician happy about it. And similar to what you mentioned, that where do we start our CLS-AX comparing with the loading phase. So all those things that we are big learning, I think phase II is a learning stage in my book. The community understands that. And somehow the street might not so much. But again, I think that is something that we want to try to explain to them.
Also, I think the understanding of redosing, the ability to redose, is something that physicians really understand. I think that for many years, including one of my previous publications in the academic world, that you couldn't really quite predict how a patient would behave in the beginning. The best way to predict is how they respond to treatment. And that is how that treat-and-extend comes along. And that is why that you can see how they respond, and then you see how that you can extend that patient. Extend means a slightly longer duration of treatment. And that is something that we really, how we practice. However, if you're using a rescue, if you are fixed dosing every six months, which some of our competitors are now, I should say some, or both, companies are using this six-month criteria.
The question is that how do you find the rescue. So in a clinical trial, you find the patient by seeing the patient every month. But that completely defeats the purpose of that you don't want to. You want to reduce the visit. I think that is something that really fundamentally different. Unlike what George said earlier, in our case, if we do a study design which is similar to the more recent approval of Vabysmo and Eylea high-dose, you can really move to a treat-and-extend. Now, obviously, in our clinical trial, they are likely to see the patient monthly. However, the design is to help us actually see how to move our drug into treat-and-extend when we actually get the drug approved.
Our competitors will have that struggle that if you're doing every six months, and then how do you find who need rescue? And I think that is really a key fundamental. And indeed, our competitors show, even in their study, that the patient who needs rescue and those who don't seem to be the same type of patient. So confirming what we have said all along, that you couldn't really quite tell that from the beginning who you need rescue, who doesn't. And finding them will be very tricky. And again, as a physician myself, I don't want to change the practice when a company comes in with a different molecule. I want to actually use my current practice and then adjusting when a new drug comes along. And I think that the flexibility dosing that we have, allowing that easily implemented.
I think that is fundamentally, in a very crowded market, how we can be commercially successful.
Okay. So I want to go to that flexible dosing because you're trying to get on the label. Maybe I don't know if you're going to specifically put three to six months on the label, but you obviously want that flexible dosing. But when you see every three to six months, or when a physician sees every three to six months, do they assume that it just doesn't work as long as some of the others that might have six months on it? So how do you think that that's going to be viewed in the market?
Yeah, I think that is a very good question. A physician looking at that wouldn't see what the Street might look at it slightly differently. The flexibility is important. And again, to be fair, if our competitors show no rescue needed 100%, that might be different. But that doesn't seem to be the case in their trial and even in gene therapy trial. And even in the recent approval, a lot of patients do need quite a lot of treatment. So I think that we think that this is actually wet AMD is. We have patients need treatment every four weeks. We have patients, yep, can even with the current drug get to four months. However, the difference is that we don't think that using our drug, that we need to use it more than every 12 weeks or three months.
And so I think we set the three months at that. Just like that, people don't set less than four weeks in our current drug. And so I think the three months that we don't expect a lot of patients will need every three months with our drug, but we keep that flexibility. In fact, that in Vabysmo, that they have a one to four months label. And actually, that really helped them. I think that was something very subtle, but it's important that the flexibility of the physician. And then the six months is like, well, no matter what label you have, you can always do more than six months. And I think what the six months come along is actually really quite practical that most physicians that we spoke to doesn't want to see, they still want to see the patient at least every six months.
So, I think that, again, a couple of years ago, people talk about nine months, talk about a year as if it's really important. However, that every company now moved back to six months. So, I think in reality, that everyone that we spoke to, our competitors spoke to, the six months is really where it needed to be. So, we get that flexibility of three to six months. In fact, that three to six months means that you can do 3.5 months. You can actually even potentially that can even do 2.5 months, which agency quite often allow you to do one or two weeks beyond the label. So, I think the flexibility is the key. Physicians don't like that the restriction that to be only given every six months, and they need to count up the six months.
Then to find the patient, and the patient suddenly get worse, will call into the office. Again, unscheduled visit is something that physicians hate.
Just to be clear, your competitors right now, the way their phase III trials are designed, is going to be, they're going to be stuck at six months?
Yeah, my understanding is that both competitors are reducing at every six months. But then they will try to have rescue if the patient needs rescue. And so they rescue with a biologic with an Eylea as well. So again, that is also adding to the concern. I think some payer might be concerned about that too because you added to the cost.
Annabel, I just want to emphasize again, we made this point earlier. But if you look at our six-month data, it's extraordinarily comparable to their six-month data. And in some cases, we believe it's slightly better because of the things that we've mentioned in terms of patient population. But you highlight something where you have this risk because we're going for flexible dosing, people say, "We don't think you can make six months." Our six-month data is every bit as good as their six-month data. We're just giving physicians the ability to redose with our product earlier if needed in that patient population that you can't identify until you start treating them. So it's really important. So we kind of say around the shop, we're looking for the flexibility of a biologic with the duration of a tyrosine kinase inhibitor. That's our goal.
Great. So I mean, I think it would be remiss to not mention that it's a suprachoroidal delivery. And you've had a very clean safety profile. So maybe you can talk about the benefits of delivering in a suprachoroidal space as opposed to intravitreally.
Yeah, I think there's some nuance about suprachoroidal delivery. However, we do clearly see that it becomes adopted by multiple companies. Our partners are going into that. We already have one approved product. We have one that one of our partners is already on phase III. Our partner, REGENXBIO, we're also moving forward to the phase III. And we are moving to our phase III. I think the reality is that, at the moment, because our current products are relatively small, not many physicians have used it. But again, when we come to AMD, diabetic retinopathy, oncology, and everyone that are moving to that, then it'll be a routine practice. I still remember the days that intravitreal injection is a very scary procedure. But now that people can do 40 to 100 in a day. So I think it's just that transition.
Compare intravitreal, it's just virtually no different other than that instead of injecting it all in one go very quickly in half a second, you take about five to 10 seconds to do it. So it's not really different other than that you just need to injecting slower because you're not injecting to a more open space. Like the intravitreal is in the middle of the eye, almost an empty space. And the suprachoroidal is on the coat of the eye that you need to sort of spread that space. So that's why that you need a little bit longer. But when we talk about a little bit longer, it's only five to 10 seconds. And actually, with our new CPT code, that the physician actually gets paid 10% more than intravitreal. That compensates for that 10 seconds.
So I always joke about the fact that you get around $10-$15 more for 10 seconds extra of your time. And I think that the physicians are happy with that.
That's 20 times longer.
Well, I think that.
Shame on you for doing that.
If the patients are all lying down in the room and you jump around them, yes. I think the longest time is actually not the actual injection, but lying the patient down, prepping the patient. We did a calculation that if you actually consider all the prepping the patient and so on, that 10 seconds are barely 1% of the overall time.
Yeah, maybe talk about the suprachoroidal space as far as the safety profile that you're seeing right now.
Yeah, so I think that's an excellent point. I think injecting inside the eye intravitreal, the highest concern, the major concern is endophthalmitis, which is infection, a severe infection in the eye. Luckily, that happened only one in 2000, one in 3000 injection. However, that, if you had a 100 injection, it becomes one in 30. So I think it's something that per patient and per injection. Sometimes people not thinking about it that way. But by injecting in the coat of the eye in suprachoroidal, theoretically speaking, you have no risk of endophthalmitis. Just like if you're putting eye drops in, you don't have endophthalmitis because when the drug is outside the eye. And in the suprachoroidal space, there is the choroidal immune surveillance. So any bacteria accidentally get into that space will be cleared out by the immune system. So I think that's really a key difference.
And we have more than 10,000 injections now that we have not a single case of endophthalmitis. I appreciate 10,000 is not yet proved the point, but we have the biology to support that. But in fact, that if you have intravitreal injection, 10,000, you're expecting two or three cases already, but we have none.
What about the other two companies?
So.
With endophthalmitis.
Oh, yeah. I mean, but again, when you're looking at all clinical trials, including our competitors in TKI, they have reported endophthalmitis. They claim it's nothing to do with their drug, but with the intravitreal injection procedure. And similar with Eylea high dose and Vabysmo, and every single individual have endophthalmitis reported.
Okay. Want to get to one aspect of the phase III design you're looking now in the treatment-naive population. That's a switch from what you've been looking at, which has been very treatment-experienced or very hard to treat patients, so why the shift there?
Yeah, I think there's another reason for the commercial reason. I think that maybe some years ago that people thought about using TKI as just a segment of the patient. And in fact, our competitor might be still going after a particular segment of patient. I think that because of our understanding that looking at a particular segment is more difficult. And however, that we do believe that from a commercial point of view, that our drug can be used on every single patient. And that's why that treatment naive would help us to understand that. I think we believe that also we see in other studies that if it worked well in the hard to treat patient and treating them and overall the treatment naive will be easier. And we would expect that even a higher percentage of patients will get to six months.
I think it's almost the opposite, that when you move from phase III to phase II to a naïve population, it will be an advantage. Also, commercially, we think that we would be able to share that. That's similar to what we see with Eylea high dose and Vabysmo when they're using treatment-naïve patients. By adjusting the dosing, allowing us to adjust to the patient's need. Actually, that's what's important.
Okay. One last question that we have no time for, but I'm going to ask it anyway. How large do you expect the phase III to be? And do you think of partnership to deal with the late-stage development and commercial?
Yeah, so we're currently expecting to enter phase II at the beginning of 2025. And we're expecting to start the study in the second half of 2025. And we were looking at a design, as you mentioned, that treatment-naive or very early, including a non-inferiority study design and are competing with what the agency requested, an Eylea 2 milligram as a comparator. I think there's a misunderstanding out there that sham injection was not recommended, but it's allowed. I think that is something that is very confusing in the community. The agency had talked about that, something they don't recommend for a long time. But I think it's how that you mask and how to use the sham injection. So we would discuss that with the agency in more detail. And we'll share that exact design later on next year.
Okay. Did you want to?
I was just going to say we're looking at a wide variety of financing options, including partnering for phase III.
Okay. Great.
I knew you wanted that in, so I'll do that.
That's what I wanted in there. All right. A close.