Great. Oops, sorry. All right, good morning, everyone, and welcome to the Clearside presentation. I'm happy to have George Lasezkay here, CEO, and Charlie Deignan, right there, hiding in the corner. As you know, Clearside has a microinjector platform for delivering ophthalmic drugs into the suprachoroidal space. I guess that makes it more efficient and safer. And now you've developed a 2-prong strategy of proprietary and partnered products. W hy don't I let you give a 5-minute overview, and then we can-
Okay. Slide into questions.
I think you just did it. No, you'd do it better.
Great to be here. Thanks for inviting us. Always glad to participate in this Stifel conference. As you mentioned, we've pioneered a new route of administration into for the treatment of retinal diseases, and that is injecting therapeutic agents into the suprachoroidal space. We do that with our patented SCS Microinjector.
We've done it both with insoluble small molecules and with gene therapy. We've been able to administer both of those types of therapeutic agents into the suprachoroidal space s o why is that important? Well, there's a couple reasons we think that this really can make a difference. One is that we're putting the therapeutic agent in close proximity to the disease and the affected tissues of the retina.
W e think that's an advantage a nd two, it's compartmentalized in the suprachoroidal space, so everything that we're administering goes in and stays right there. It's very localized, very compartmentalized. Two benefits of that. One- or potential benefits of that. One is safety benefit. There's no distribution of the drug to the front of the eye, so there's no chance of any anterior chamber toxicity.
There's no systemic distribution either, so it stays in the suprachoroidal space. And we've seen with gene therapy in particular, that while it's not as immunoprivileged as the subretinal space, there's far less inflammation putting in gene therapy in the suprachoroidal space than there is in the intravitreal space. So it has that safety advantage as well.
Number two, the other benefit of the compartmentalization is the product stays there, and so it stays there for a long time, so it has the potential for a very extended duration of activity. T hat's, you know, that's what we believe is the importance of the potential utility of putting things into the suprachoroidal space.
Now, you mentioned a two-pronged strategy, and we do have a two-pronged strategy. Number one is to do strategic external collaborations, and we have collaborations with REGENXBIO, who's now partnered with AbbVie for their gene therapy product. We have a collaboration with Aura Biosciences, where their viral-like drug conjugate is being used for the treatment of choroidal melanoma. We've partnered commercially with Bausch + Lomb and with Arctic Vision for our XIPERE product, which was the first product ever approved by the FDA for suprachoroidal administration.
Just two weeks ago, on November first, we announced a new partnership with BioCryst Pharmaceuticals for their plasma kallikrein inhibitor in the treatment, potentially for the treatment of diabetic macular edema. So that's one prong of our strategy t he other prong is to develop our own internal drug device combination products a s I mentioned, XIPERE was the first drug device combination approved for suprachoroidal administration t hat was in late 2021, currently being commercialized by Bausch + Lomb in the United States.
T hen secondly is our lead clinical development product, CLS-AX, axitinib, a tyrosine kinase inhibitor for the potential treatment of wet AMD that's in a phase 2b trial that we call ODYSSEY. T hose are the two prongs of our strategy w e continue to execute on those strategies, and we're very confident that the suprachoroidal route of administration has something to offer to physicians and to patients.
O ne other thing I'd say about that is you see now, compared to a couple of years ago, we were the only ones talking about this. Now, when you go to medical conferences and ophthalmology conferences, there's lots of presentations, not just by us, but by other people, talking about the potential utility of the suprachoroidal approach. W e're really very proud of the fact that we pioneered this and that others have started to see the utility or the potential utility of suprachoroidal space.
Yeah. Before we go into your proprietary products, I did want to ask you about XIPERE and how, not necessarily how it's selling, but how it's being received by the physician community, whether they're getting used to it right now, whether y ou feel it's priming the market for some of the, you know, seemingly, more novel uses of a suprachoroidal injector platform. So how is, how is that, that going with XIPERE?
Well, it's a new route of administration, and I think there's been some, there's some growing, some growing pains with that. Bausch has done a good job in training a lot of physicians to use this. The follow-through has to be the actual use of it with XIPERE. And so they're doing a good job now, following up with physicians, making sure they're comfortable, making sure they remember their training.
There's a lot of clinical trials w e've got, like, six clinical trials going, so if you, if you talk to the retinal community, there's a lot of awareness and a lot of actual experience with the suprachoroidal approach. I think as everybody gets more comfortable with this new form of administration, I think XIPERE is gonna do well. We hear anecdotally that it's working very well when it's used, especially in terms of duration.
Doctors are using it and are very happy using it. But there, you know, there is some learning curve for the commercialization team about how to best get this into the hands and, and have doctors use it right and correctly and feel comfortable with it i think it probably takes them a couple of couple of administrations.
Mm-hmm.
-to feel very comfortable with it. T he training is very straightforward and very simple s o it's just a matter of experience and practice.
Mm-hmm.
I can remember back in the days when nobody thought people would do an intravitreal injection...
Right.
There had to be a lot of training on that. W e're comfortable that the uptake is happening in a good process, and as we give them more options and more reasons to think about suprachoroidal, I'm very comfortable that XIPERE will do well, and the follow-on products will do well.
Okay. All right, so in that vein, I just wanted to talk about your proprietary platform first- which is primarily CLS-AX. That is a next generation TKI. I think people are kind of excited about something, an option outside the anti-VEGFs, which are-
Mm-hmm
... pretty ubiquitous, and everyone's kind of doing tweaks to the Anti-VEGF for extended duration.
Mm-hmm.
But you're coming in with TKIs-
Mm-hmm
... which will not only give you extended duration, but hits other receptors, you know, beyond just the VEGF-A and VEGF-B-
Mm-hmm I believe.
You know, tell us how you see this fitting into the landscape. You're the first of three right now n ot the first of three. You're one of three-
One of three.
... that are developing this space. Do you think this is gonna be a full evolution of, you know, anti-VEGF to TKI, or is it gonna be just another option in the toolbox that people have to choose from?
I think it's more likely to be the latter. I think it's more likely to be an additional tool for physicians to use in their practice. I don't see this, at least at this time, I don't see it supplanting anti-VEGF, the Eylea or the Lucentis of the world. I don't see that. And if you look at our ODYSSEY trial, we're using it in combination with loading doses of Eylea.
F irst and foremost, we see it as the potential is there for extended maintenance therapy. It's a different mechanism of action, as you pointed out. We've got a different route of administration. So we think that there's... I like to explain it sometimes in thinking about, like, cancer chemotherapy, where there's multiple different compounds that can be used in different combinations.
And it gives the oncologist a lot of options and different protocols to treat diseases. I think that's going to be more likely what happens in the wet AMD space, is there's going to be people that respond very well to anti-VEGF, at least initially. But we do know that there's a significant number of people that don't respond very well to anti-VEGF w e do know that over time, they tend to become, I'll call it, refractory, and they're less effective and requiring more injections.
I think that, while I don't see the VEGFs going away at all, I think it's gonna be combination approach, and tailored to each specific patient is whether they need this extended maintenance, whether they're not responding very well to anti-VEGFs. There is a potential eventually that maybe a TKI could be the sole, you know, product used to treat wet AMD, but right now we look at it as maintenance, and we look at it in combination with anti-VEGFs.
But isn't the bulk of sales for Anti-VEGF? I mean, everyone gets the loading dose- but, like, isn't the bulk of sales right now, essentially maintenance?
Yes.
Y ou kind of will be potentially replacing a good chunk of anti-VEGF use-
Well, I would say-
With maintenance
... Yeah, I guess over time, we would look to replace-
You're right
... a fair amount of it. But I was trying to get to the point. I don't see VEGFs going away.
Okay, they won't go away.
Okay.
That's-
They're not gonna go away.
That's fair enough.
But I think we'll be able to take some, some significant market share from there.
Okay. So maybe you can just go through the OASIS trial, what you saw. You know, obviously, we had stable BCVA. We had stable CST, I think- actually, you tried it out.
Mm-hmm.
You know, as we all saw the pictures, right?
Yeah.
You had anywhere between 77% and 85% reduction in injection burden over six months m ind you, it was in a small population, but outside of those, you know, key headlines, like, what are some of the other features that-
Well, the thing that was-
... stood out?
Yeah, well, the one fact that you didn't cover and I'll cover now is that-
Safety?
... Well, yes. Well, thank you for giving me that. Sure. It was very clean.
Yeah.
There were no safety issues whatsoever w e saw no inflammation, no signs of inflammation, no problems with the procedure, nothing s o it was very, very clean safety issue. N umber two, and it's related to the treatment burden reduction that you mentioned, is that in the extension study, when we went out six months, we saw that more than 2/3 of the patients in that extension study did not require any supplemental treatment until at least six months.
If you break that down, then 50%, or a little, slightly more than 50% actually, of the patients in the extended study did not require supplemental therapy at six months s o they were gonna go at least seven months and maybe longer. T hat was the end of the trial w e couldn't follow them any farther. That was what really was encouraging to us to do ODYSSEY in phase 2b-
Mm-hmm
... is that we saw this extended period of time, this extended duration of activity with stable BCVAs and stable CSTs s o it was very encouraging for us to go on and develop Odyssey and launch into our phase 2b trial.
Was this a different patient population than what we've seen in other TKI trials?
Yeah, you're talking about OASIS?
Oh, yes.
In OASIS, we specifically were looking at very difficult-to-treat patients. Some of our investigators called them anti-VEGF addicts. You know, Eylea, for example, is on label every two months, you know, after loading dose. These were people that were taking it every month, every six weeks on a regular basis t hey were getting results, but they were incomplete results and required a lot of additional therapy. So we took on a very difficult patient population in OASIS.
Now, true, it was an open-label study, but that was very encouraging to us to say, "These most difficult-to-treat patients, we produced those numbers." And I think that patient population was a little bit more difficult to treat than some of our competitors in their early-stage clinical trials t hey weren't as particular going after that very difficult-to-treat patient population.
In ODYSSEY, we're treating. I wouldn't say a treatment-resistant or sub-responder group. We are treating patients who have treatment experience, but they're not as difficult as the patients that we looked at in OASIS. And so we actually think, well, we should do just as well, if not better-
Mm-hmm.
'Cause it's a slightly easier patient population.
Right. And your target for duration is six months? You said five to six months.
We're hopeful that we're 5-6 months.
Why you think only 5-6 months?
I don't know the data yet.
Okay.
I would love it-
I mean-
I would love it if I had 100% in six months.
I mean, everyone's kind of like, some of your competitors are trying to aim for longer.
Oh, well-
I know that, I know that physicians like to at least have their patients in every six months to monitor them, but.
Physicians in our discussions with our clinical advisors, some of the top KOLs, they say, "Look, I'm still gonna see my patients every three months at least.
Mm-hmm.
Okay? They have advised us over and over again that they think that 5- 6 month for treatment, if you can get the vast majority of your patients, almost certainly to get to that amount, that we have a very good product that will be very, very competitive. And they don't see it as being disadvantaged at all with someone who might say, "Well, I can give you 9- 12 months."
They're still gonna see their patients every 3- 4 months. I think they feel like every six months, every 5- 6 months, gives them a little bit more control over the situation, gives them something that they can give to their patients that's safe. And then it doesn't leave them in this kind of middle ground between six and 12 months. I don't know where I'm gonna drop off, so I'm gonna see these patients anyhow. W e've polled all of our KOLs over and over again, and they keep encouraging us that 5-6 months is gonna be a really great-
They have a business driven also.
Well, yeah.
Yeah.
You said that, I didn't.
It's reality. Okay. All right. So ODYSSEY, Phase 2 enrolled pretty rapidly.
Mm-hmm.
What, what do you think drove that? Is it the comfort? Obviously, the data were strong, but is this a sign that they're gaining more comfort with the Microinjector platform?
Yeah, I believe that's the case. I think both the things you mentioned are the case. I think they saw the OASIS data w e presented it at multiple meetings. People were very interested in it t hey, they thought it was very compelling. It's a very competitive environment out there-
Mm-hmm
... you know, to recruit people, patients, especially for wet AMD. So we were very pleased on the response we got. And I think that between XIPERE being launched in the U.S., the other multiple clinical trials, using our SCS Microinjector from REGENXBIO and Aura- and our OASIS trial, and the conversations at the medical conventions that talk about suprachoroidal, in particular, and just in general.
I think people were eager to sign up. We targeted 30 sites. We had 32 sites. 30 of the sites were actively enrolling. So we had a very good. We had 95%+ of the sites were actually enrolling patients, which was really great. And I think people were really excited to get the injector in their hands w e had about probably 10 or 11 sites that were holdovers from OASIS.
Mm-hmm.
T hey were anxious to get back into the study, and other people were just saying- "I want to be in, I want to be in." So it was exciting, and it really took off. It was slow lead, and then it got exponential.
And then, yeah.
It just went like that, so.
Pretty rapidly.
We were very pleased with the recruitment.
Yeah, I want to talk about the trial design. All of these TKI trials look just a little bit different.
Mm-hmm.
Y ou all have a loading dose-
Mm-hmm
... I believe. I wasn't sure about Ocular Therapeutix, but definitely, yours has a loading dose, and, 1901 from EyePoint is loading dose. You have an injection of CLS-AX at the second loading dose.
Correct.
EyePoint's at the third. What is the difference there? And, you know, does that affect the final endpoint of, you know, the time of the final endpoint, 32 or 36 weeks? Like, what are the little nuances there that ... Why are there nuances? Why are there differences, and doesn't FDA just have a standardized way of looking at everything?
Well, they don't. These are all, these aren't registration trials. T he FDA gives you a lot more latitude in phase II to do it the way you want to do it. I'll just point out, like, when Ocular did one of their phase I trials, they actually gave an additional dose of aflibercept a month after they put their insert in. A ll of us are trying to figure out, these are early trials on safety and efficacy with a new molecule.
W e're trying to figure out whether there takes some time for the mechanism to work. W e don't want inappropriate or early rescues, okay? And one of the things that drove us to do it this way was we wanted to make sure that we tamp down on off-protocol rescues early. When we looked at the OASIS data, we saw that the vast majority of the rescues and off-protocol rescues.
Because remember, it was an open-label trial, were done in the first month or two, because people weren't, they didn't know what to expect from CLS-AX. I think they know now, they don't need to go and be that, let's say, nervous about it. But in our trial, in Odyssey, what we've done is the evaluating physician is totally blinded.
T he evaluating physician is going to look at the patient data and line it up with the supplemental treatment criteria, and there won't be a bias of saying, "Well, it's my patient, and it's a new drug, and I don't know," which we thought drove a lot of the early rescues that were m ost of the early rescues were off protocol.
W e think the design limits, if not eliminates, those early off-protocol rescues a nd that's what we were very concerned about. W hen you look at the 36-month time point, where the primary analysis will be, we don't think that extra one loading dose, the third loading dose, is really gonna influence what we see six months later or nine months later.
B ecause it should only have a month or so of activity covering. Y ou could make a case that we're going into phase III, maybe we'll do it on the third loading dose instead of the second loading dose. But again, we're trying to get a feel for the duration that would be the most appropriate duration to line up in a phase III trial, and I think we can figure that out, whether the loading dose was on the second or the third.
Okay.
We're comfortable with it.
T he way you're preventing the off-protocol rescue early was that it's administer CLS-AX no less than 12 weeks, and-
Yeah, I mean-
At least every 24 weeks. Definitely you don't want it earlier than three months.
Right.
T hen you absolutely want it every six months just to see?
Right. We're assuming m y dream would be that nobody in the treatment arm requires any supplemental treatment until we get to that six-month time point. Then everybody, if they've never gotten it before, will get a second dose.
You'll have a retreatment.
We will have a re-
Administration in that trial?
Yes. So it, it'll be a multiple dose trial in the CLS-AX arm. T heir first dose on baseline, and then if they don't require any supplemental therapy, which I hope it'll be the case u ntil you get to week 24, they will get a second dose there, just to give it a multiple dose, six months apart.
Right. At what point do we see the primary endpoint, is it 36 weeks? So you will-
36 weeks.
- report it out at 36 weeks-
Yeah
... regardless. Okay. All right. T hen you are t he primary endpoint is gonna be non-inferiority, BCVA, CST first more than anything and then analyze the injection.
The trial is not set up as a non-inferiority trial.
No, it's not.
It's not, it's not powered for non-inferiority, it's not powered for superiority w hat we're doing is statistical estimations. We're looking and seeing how many patients went how long. This is all trying to gather data to set up the best Phase III possible, which in Phase III, would obviously have to be either non-super non-inferiority or superiority powered.
But this is not powered to show non-inferiority. We're gonna do a comparison of the BCVAs between the two groups. Hopefully, we will only be a couple of letters apart, enough that's clinically not meaningful, and then we'll have a really good idea of what we want to do in phase III in our dose.
Is there a threshold that you're looking for, a certain percentage of patients, you know, going out six months? Or like, what, what is the determinant for you to know how to design that phase III trial?
I think that we would be looking at 75+% go 5-6 months.
Okay.
That's what we would be hopeful... I mean, actually, in my dreams, 100% would make six months, but we have to be a little more-
Realistic.
If that happens, I'll buy everybody a beer in the company.
Okay.
But I think that's what we would like to see. That's what we're very hopeful of w e think that CLS-AX could be a twice-a-year maintenance.
Okay, great. And then last thing, I know that the FDA had... They're still working with guidelines, given the new drugs that are in the market. Everyone's using Eylea as the sham-
Pretty much.
- arm pretty much at this point i don't know if that's gonna change going forward, but, like, there has been some talk about sham arms in the use of sham, sham Eylea, I guess, sham anti-VEGF injections-
Mm-hmm
... and how that might unblind the trial.
Right.
Is there, you know, concern about that? Has that been baked into your trial in any way?
Yeah, we understand that, and we've had that conversation to understand that there is some concern i don't know what's gonna happen when the draft guidelines become final. There's been a lot of people who submitted comments on that point, so we'll see what the FDA finally says b ut from our perspective, we do not see a problem with sham suprachoroidal injections.
Mm-hmm.
I think, Dr. Chambers' point of view is people might see things from a sham intravitreal. They'll see stuff being injected versus they don't see anything being injected, and somehow that might unblind them from a suprachoroidal, since we're behind the visual field, since we're behind the retina, they don't see anything, whether they get a sham or they get the actual product.
I think he's kind of admitted that shams for suprachoroidal may be acceptable because it doesn't have the same potential issue that sham IVT, they have because you could maybe see the product going in, in front of the retina.
Okay. And then finally, just wanted to ask a final question on CLS-AX. Just wanted to ask how you see the TKI landscape playing out. I mean, obviously, anti-VEGF—the wet AMD market absorbed three, four different players already and they're all doing pretty well between Vabysmo and Lucentis and Eylea and Vabysmo. Do you see the same ability to absorb multiple TKIs, or is it getting to the point that the market is getting too saturated?
I think you've answered the question by just the way you've looked at the anti-VEGF. I think there's room for more than one TKI. Unless there's some unusual safety issue with any one of them, either related. I don't think it'd be related to the drug itself, but it may be related to the injection or the administration form of administration. Like the, how many Durasert can you have in your eye, and do they fully, you know, erode?
Dissolve, yeah.
Dissolve away. Same thing for the hydrogel. But I think from a safety point of view, I think they're all gonna be—the drugs are all gonna be fine. I actually am hopeful that EyePoint reports pretty good news. Hope it's pretty good.
Yeah.
I hope it's not great-
Not, not that good.
... but I hope it's pretty good. No, but I
Good enough?
... I honestly do.
Yeah, I know.
I think, I think it'd be very encouraging for the three TKI companies that as data comes out from each one of them, that it's encouraging, it's reinforcing the fact that tyrosine kinase inhibitors, by their different mechanism of action, by blocking all the VEGF receptors versus just soaking up the excess VEGF that's, that's floating in the eye. I think, I think that's good for all of us, and I think there's room for all of us. I do.
Okay, good. So let's... Is there a question back there?
[inaudible] how you see the market developing? Is it gonna be like an oncology market where one month better, how many times you got a choice? Because it's all about maximizing first. How do you think about the development of the eye market?
Listen, I think that they're all trying for different durations of activity i think probably Ocular is going for the longest. They're really pursuing right now more diabetic retinopathy early on, and I think I understand why that is t hat's a lower VEGF burden t hey can probably put their hydrogel in there and get some pretty good data on a lower VEGF set of circumstances.
From EyePoint and from us, I think we're looking more at the six month time frame. I think, listen, I think it's gonna be a number of different products. Doctors are gonna pick and choose. As I was saying earlier to one of Annabel questions, doctors are still gonna see their patients every 2-3 months.
P utting in an insert that gives you 9-12 months may not have the same benefit to physicians and patients as you might think. I think it's a great, interesting technology going forward, but it, practically, I think doctors want a little bit more control about that. If there's a problem, it's harder to resolve that problem if it's in there for a long period of time.
I think, listen, I think that all of us are, we have a lot of similarities. We have some interesting differences, and going back to Annabelle's question, I think you're gonna see it like a cancer chemotherapy. I think it's because they're gonna use multiple different approaches.
They may not use one TKI in all of their patients, but I think all three of us think that the mechanism makes sense. We're all excited about adding to the physician's, you know, toolkit to treat patients, and we'll let the market sort it out once we have more data. You know, which one is the preferred one? Time will tell. But we're confident in our approach, we're confident in the safety of our product.
W e think we have a really good chance. We are a little bit behind in terms of timing, but kinda depends how you look at it. I 'm not sure Ocular is that far ahead of us in wet AMD. They're trying to get ahead of us by doing this phase I, going to a phase III under an SPA. But, I think if we have really good data that we report out next year, and our ODYSSEY data is due out Q3 of next year, I think if we have really strong data there, we'll be in a great situation. Very comfortable with that.
Yeah.
Yes.
We don't have time to get into gene therapy. I was gonna ask you-
Well-
how that might change the market.
Okay.
But if you want to give me a minute on that one. Do you think that gene therapy is gonna disrupt it?
You mean what REGENXBIO is doing?
Yeah, more on the suprachoroidal side because-
Well, I think, I think from a suprachoroidal side, I think from gene therapy, I think it's been pretty clear that putting gene therapy in suprachoroidal space has less adverse effects than putting it in the vitreous. I think there's no doubt about that, and I think there's a great future in gene therapy of a wide variety w e haven't even started talking about inherited retinal disease and gene replacement and stuff like that.
I think anytime you're putting a gene, especially if it's accompanied by a viral vector, you're going to get a response t he body's set up to reject viruses. All of the work that we've done, and we've seen other people do, indicate that it's gonna be much more acceptable to put it in suprachoroidal space than in the vitreous.
Okay. Unfortunately, we're out of time.
Oh.
So many more questions, but.
Sorry. I know.
Anyway.
As always, it was fun.
Always.
Thank you.