EyePoint, Inc. (EYPT) Earnings Call Transcript & Summary

[Audio Gap] started. So I want to welcome everybody here. So if you could take your seats. We're going to try to make sure we stay on time today. So thank you, first and foremost, for coming today. We really appreciate it. We're very excited about where we are with EyePoint Pharmaceuticals. And I appreciate those of you calling in and those of you who took the time to come, particularly on this rainy day in New York City. We do have forward-looking statements we will be making. So I'm going to encourage you, just go to our website where our SEC statements are. I do want to just open up first and foremost and say, just remind everybody, this is a very capital-intensive and a risky business. And more important than anything is that we're here for our patients and to ensure that we are providing treatments to them, and in our case, for very serious retinal eye diseases. I try to stress at EyePoint to all of our employees, at the end of end of the day, that's what this is all about. But because it is a risky investment, I don't have to tell the investors here, you have to have a stomach for this business because of the failure rates that occur and it's very capital-intensive. I do want to mention, for those of you who are paying attention and encourage you, others who maybe have not paid attention to the drug pricing legislation going through right now, that can have a material impact on our ability, in many cases, to move products forward. We do need drug price legislation. I'm not at all against that. There are certain fixes we need to make, but it's got to be the right -- the right legislation. So please take a look, get yourself educated about what's going on. All right. With that as an introduction, let me introduce who our speakers are going to be today. Now I'm going to ask you to just go to our website if you want to see the individual bios of the management team here. I am Nancy Lurker, the Chief Executive Officer of the company. We have Dr. Jay Duker, who is our Chief Operating Officer. Unfortunately, Jay was hoping to be here today, but he has COVID. So he is going to be videoing in. And then George Elston, who is our Chief Financial Officer. Next slide. And then Dr. Dario Paggiarino, who is our Chief Medical Officer; and Dr. Said Saim, who is our Chief Technical Officer. I'm also pleased to say we have 2 very distinguished guests who are here with us today and I very much appreciate it, Dr. Carl Regillo, who will be videoing in, who is the Professor of Ophthalmology at the Jefferson University and Chief of the Retina Service Wills Eye Hospital. He's also a founder of the Wills Eye Clinic Retinal Research unit in Philadelphia. So thank you, Dr. Regillo for taking the time to video in. And then Dr. Charles Wykoff, who is also joining us here today in person. And Dr. Wykoff is the Chair of Ophthalmology at the Blanton Eye Institute in Houston Methodist Hospital. So thank you both for taking time to come. Really appreciate it. All right. Today, we are going to be covering an EyePoint overview. I will give just a very brief overview of the company. Dr. Duker will then present Durasert and an overview of EYP-1901. Dr. Saim will present the development in formulation. Said is involved in all the preclinical and formulation and discovery work that has gone on with EYP-1901. He's got some interesting data he's going to be presenting. And then Dr. Regillo will present our recently just announced 12-month DAVIO data at the American Society of Retinal Associates that just happened this week here in New York City. And then Dr. Jay Duker and Dr. Charles Wykoff will go through this new treatment paradigm that we believe potentially could happen with EYP-1901 which is treat to maintain, and we'll be talking about that here today. And then Dr. Dario Paggiarino will cover the Phase II plans for 1901, give a YUTIQ clinical update, YUTIQ is our very important in-line product for the prevention of posterior segment uveitis. And then George Elston will give a financial update. We're then going to open it up for question and answers. And I'd ask that you start thinking about any questions you may want to ask us. And then I'll give some brief closing remarks. So for a company overview, again, most of you know the company, but I think it always bears repeating, particularly for those who are -- who are may be relatively new to the story, we have a very compelling pipeline and, most importantly, it leverages our proven Durasert technology. We like this Durasert technology because it's difficult to deliver drugs to the back of the eye. This is not for the faint of heart. And you'll hear more about Durasert today. EYP-1901 is our lead key pipeline program. It's a combination of our Durasert technology bioerodible, coupled with our tyrosine kinase inhibitor, which is an anti-VEGF small molecule, and that is Vorolanib. We in-licensed Vorolanib from our Chinese partner, Betta. And we like the mechanism of action, which is different that vorolanib provides. And we do think there is a potential advantage to having a new mechanism of action available for patients in addition to the anti-VEGF large molecules available today. We have seen very positive safety and efficacy data from our Phase I DAVIO clinical trial, and you'll hear about that today. And then we'll talk as well about our Phase II clinical trials in wet AMD and in nonproliferative diabetic retinopathy, which we expect to have our first patient dosed this quarter of 2022. I mentioned briefly about Durasert. Let me just remind everybody, there's 2 main benefits to this drug delivery technology. Number one, it provides sustained 0-order kinetics. So you don't get what we call first order kinetics which is these large peaks and valleys that occur in drug PK levels in the eye. It's a very stable, consistent release. In EYP-1901's case, it actually lasts right up to 8 months before you start to see a drop occur and Dr. Said will go through that. Secondly, and probably most importantly, so far, Durasert has proven to be a very safe drug delivery for the eye. So we've got over 80,000 patients that have used Durasert in the 4 FDA-approved products that use this technology. And now with our DAVIO data, through 12 months, it continues to show a very nice safety profile and in this area, that's most critically important. And then lastly, we've got a very strong balance sheet, which we're pleased [indiscernible] this capital environment that we're in today, $171 million in cash and investments as of June 30. George is going to give an update on this. We continue to have cash runway into the second half of 2024, well past our potential readout of our Phase II data. And our commercial franchises are positioned for breakeven in 2022. So I'm now going to turn it over to Dr. Jay Duker who will be on video. Jay?

Let's see. Good morning, everybody. And I sincerely apologize for not being there in person. Nancy gave you the reason, but I had -- my joke was that I couldn't find a tie and therefore couldn't get into the University Club that's why it couldn't show up. Next slide, please. So could you show me the slides as well on the Zoom. So Nancy introduced Durasert. And again, there are 4 FDA-approved products that include Durasert. Of the 6 FDA-approved intravitreal sustained delivery products, our technology is in 4 of them. It is delivered in the office by a typical intravitreal injection, the type of injection that Carl or Charlie does probably 20 or 30 times a day, it's very standard. And as Nancy pointed out, the big advantage of Durasert is continued stable release of drug over weeks, months or even years, depending on how we design it. Our product is YUTIQ. We also have licensed the ILUVIEN [ product ] to Alimera. And previously, we developed Retisert and Vitrasert, both of which were licensed to B and L. EYP-1901 is slightly different than those other products in that there is the polyimide shell that covers the drug matrix those other products has been removed. That leads to bioerodibility of 1901, along with a burst of drug of the surface which is probably beneficial. Following this burst, you get constant 0 order of kinetic release over many months. Next slide, please. And then on to the next slide, EYP-1901 vorolanib. So just a little bit more about EYP-1901, again, this is a single intravitreal injection. Of note is that we can deliver up to 3 inserts with a single injection in the office. This gives us quite a lot of flexibility in dosing and also in the future brings up the possibility of delivering multiple drugs via a single injection. It's bioerodible, as we said, 0-order kinetics. And the drug we're using is called vorolanib. Vorolanib is tyrosine kinase inhibitor with great activity against all the VEGF receptors. It binds, as I said, all isoforms of VEGF. And interestingly, vorolanib was previously studied as an oral drug for wet age-related macular degeneration. It actually went through both Phase I and Phase II trials. Those trials have been published. And if you're interested in getting the reprints, we can supply them to you. But the drug as an oral delivery showed quite good efficacy in wet AMD but unfortunately, there were serious systemic toxicity which limited its usage and the drug never finished Phase II. I do want to point out there was no ocular toxicity noted. Next slide. This slide shows comparison of the nonerodible form of Durasert. So nonerodible has this polyimide shell. There is pores at either side, with either a polymer cap or silicon seal, and those allow for simple diffusion from the drug matrix. And depending on whether both ends are open or one end is open, you can determine the drug release. Next slide. The bioerodible form does not have the polyimide shell. It's almost entirely drug matrix and the drug matrix consists of almost all vorolanib. This leads to a high drug load per insert. And also the inserts, each one of them represents only about 1/5000 on the volume of the vitreous cavity. Next slide. This slide covers our IP. And as you can see, we have IP protection with patent applications out into 2042 on both the formulation and the injector that's being used to inject EYP-1901. Next slide. I'm going to now introduce Said Saim, who is our Chief Technology Officer, and Said is going to go into some of the science behind vorolanib and bioerodible Durasert. Said?

First why vorolanib one can ask, why are you selecting vorolanib amongst 40-some TKIs that have been approved by the FDA for most people in oncology? Well, vorolanib is pretty special molecule. It's probably the only one as far as I know that was studied actually for wet AMD as an oral therapy. And it's also because it's an anti-VEGF. It's a validated pathway for treating the retinal diseases that we're trying to address. So we're not going too far away from actually the main mechanism, but it also adds additional benefits. It doesn't work the same way as the current anti-VEGFs in the sense that it binds to the intracellular receptors of these VEGF receptors, thereby it blocks all VEGF familial growth factors with especially strong affinity for the VEGF receptor tool, the one that's involved in permeability and leakage from blood vessels. In addition, the molecule was designed to have reduced off-target binding to receptors associated with systemic side effects. So the molecule is designed specifically to be optimal for these retinal diseases. In addition, as Jay mentioned, the molecule was used in a Phase I and Phase II trial orally in wet AMD patients and quite interesting results were found. Not only the product, the oral product, was quite efficacious, but also it showed no ocular toxicity. And there is another effect that was observed perhaps unexpectedly and that Jay will go into detail with -- is that the fellow eye, because it was given orally, the drug was going to both eyes, the fellow eye had nearly no conversion from dry AMD to wet AMD. So this is one of the advantages of using TKIs because TKIs do not address just the anti-VEGF side of the pathways for developing this disease, it also addresses all the receptors that may be beneficial. And in the case of vorolanib, we find that it has quite a few additional benefits that we'll go into more detail of as we go through this presentation. Next. So what is vorolanib? The vorolanib was specifically designed to reduce off-target binding of a molecule sunitinib which is [ SUTENT ] used in oncology. There's one group in the molecule that was changed, and this change in the group proved to reduce systemic toxicity and to have a quite interesting differences in receptor binding which enhances the value of vorolanib. So next. So this is the VEGF signaling pathway of vorolanib as it grid binds the intracellular domain of tyrosine kinases. It targets both all 3 receptors, receptor VEGF receptor 1, 2 and 3, thereby inhibiting inflammation, blood vessel leakage and permeability and as well as blood vessel growth. This is unlike the current anti-VEGFs which basically bind the ligand. So now we're going to go into some of the proof-of-concept studies that belie the value -- the anti-VEGF value. So we're going to go through some of the standard studies that are run to demonstrate the anti-VEGF properties of this molecule. Because the anti-VEGF is what really has been validated in Eylea, Lucentis and other products, that they have value in treating the retinal diseases that we're trying to address. In this case, this is a cell model that shows that vorolanib significantly reduces new blood vessel formation. So when you look at the picture on the left versus the right, the number of blood vessel tubes are considerably lower after treating with VEGF and then vorolanib versus just treating with the VEGF. So -- and this effect happens at very low concentrations. You can see at 50 [ nanomolars ] as well as 100 nanomolars, both of them are highly inhibitive of blood vessel formation. 50 nanomolar happens to be the IC50, the [ half ] maximal inhibition concentration against the VEGF receptor 2. So one does not need very high concentrations in order to have an effect on blood vessel formation. The next model we'll talk about is also a cell-based model where we see here that you don't even need a level of IC50 to effect reduction in phosphorylation. Phosphorylation is the mechanism by which basically the pathways that leads to leakage and permeability take place. And in this case, you could see that levels as low as 10 nanomolars are sufficient to inhibit phosphorylation. This is important because as Jay was talking before, this technology that we're using in either YUTIQ or EYP-1901 is designed to release micro doses, low levels of the drug over an extended period of time. So the idea here is that you do not need very high level to have a therapeutic effect. Now for EYP-1901, we'll show you that the levels that are released are considerably higher than IC50, but they're constant and they do not go so high that you may actually create potentially toxicity. Next. So this is another validated model that can suggest activity in wet AMD. This is a laser CNV model in mouse. And you can see that vorolanib demonstrated significantly lower vascular leakage than the vehicle. You could see between either day 7 -- well, day 7 is when the laser injury was affected, so there's not much difference versus vehicle, but at day 14 and day 21, considerable reduction in leakage. Next. The other model is the oxygen-induced retinopathy model, this is in rat. And here again, you could see a significant decrease in the area of neovascularization in the group treated with vorolanib. This suggests basically that the drug could potentially have activity in diabetic retinopathy. So these are all the models. These are the basic known models that are used to demonstrate anti-VEGF characteristics for a molecule, just like Eylea and other products have. But next. Now this is not the regular anti-VEGF. This has properties that go beyond anti-VEGFs. And in this case, we just finished the study, a retinal detachment study. So this is in a mouse model where you basically take sodium hyaluronate viscous solution and inject it between the RPE and the photoreceptor. So you detach the RPA from the photoreceptors and it stays there for quite a while. And then you give either vehicle or vorolanib suspended in vehicle by [indiscernible] over a period of time and around day 16, 17, 18, you start looking at function and structure of the retina as well as visual function. So in this case, we're looking at visual acuity as measured by optokinetics as well as contrast vision. The contrast vision is whether the mouse can follow stripes moving around stripes that are of faint color. So on the visual side, you could see that there's a higher visual acuity function of vorolanib-treated mice versus vehicle. And on the contrast vision, now you see a significantly higher contrast vision in the vorolanib-treated mice versus vehicle. This is quite interesting findings and very much suggested potentially of neuroprotective properties. Obviously, this is just a function. We also went into looking at the structure of the retina. And here again, we find the preservation of structure. We see a significant loss in ONL, outer nuclear layer of the photoreceptors, thickness in vehicle-treated eyes, but not in the vorolanib-treated eyes. Here, again, there is a correlation basically between structure and function. And as we said, we just got some of these data. We're still in the process of further analyzing them, but this is quite interesting property of this molecule that is obviously not present in other anti-VEGFs. Next. So what are the key takeaways from the data we just presented? So this is different from your regular anti-VEGF. It binds the intracellular domain of receptors and not the ligand. We have compelling efficacy data in oral therapy in 2 clinical trials with no ocular toxicity. And we have data, obviously, that shows that even levels as low as 20% of IC50 for the VEGF receptor 2 can inhibit phosphorylation. So that's an important finding because we will use this vorolanib together with the Durasert technology to provide microgram per day levels, consistent microgram per day levels, and we have data from both YUTIQ as well as EYP-1901 that's sufficient to provide strong efficacy. And then beyond this, we perhaps just scratched the surface of what this molecule can do. The retinal detachment model indicates that the molecule potentially has neuroprotective properties. And as I said before, Jay is going to go into more details about how this molecule also prevents conversion from dry AMD to wet AMD. So this is kind of special finding, special characteristic [ our ] molecule and Jay is going to go into the actual data. So quite exciting findings for this molecule. Now we're going to go now into EYP-1901. Everything that I presented before was for the molecule itself. What are the characteristics of the molecule? Now a molecule is a molecule and stays basically just as a molecule unless it is put into a formulation with -- in a dosage form that provides you the right release mechanism over the correct extended period to actually achieve its intent. So the formulation technology used in EYP-1901 is based on the same technology as YUTIQ. YUTIQ is our product. It is for noninfectious posterior uveitis. It's been on the market for quite -- about 3, 4 years. And it's doing really well and we show some of the results from the Phase III trial. And basically, it provides the benchmark for zero-order kinetics and for how micro doses per day of a drug can actually achieve a very high degree of efficacy. This YUTIQ product [ releases ] over a period of 3 years, it's got 180 micrograms, it releases in a zero-order over 3 years. Here, we show the assay of explants from rabbit over a period of just 1 year and it shows how the assay changes over time. And you can see over a period of 1 year, it released about 60 micrograms which is equivalent to about 0.2 microgram per day over this period. And the release is zero-order, meaning the release rate is constant. You provide the tissues with constant zero-order release, thereby basically ensuring that the levels in the tissues such as retinal or choroid are constant throughout that period of time. And we'll show some of this data. So this is Meier Kaplan plot that shows the probability of recurrence of uveitis in YUTIQ-treated patients versus sham-injected patients. And you could see that at 1 year, 75% had no recurrence with this micro dosing. And it went through 3 years with only 50% requiring -- it's only past the 3-year time point when the drug -- when there's no more drug that actually the recurrence went to 100%. So a consistent performance and validated mechanism by which microdoses can actually be highly efficacious. Now this Durasert technology is not bioerodible. The EYP-1901 formulation is bioerodible, but we designed it to have the same similar qualitatively release profile as YUTIQ. And you can see here, similar to YUTIQ, these are also explants from rabbit that were assayed, 3 different doses, and you could see that the near zero-order release between 8 and 10 months. We don't want 3 years for wet AMD, we want 6 months. So this formulation was designed to release over 8 and 9 months to ensure that we consistently cover the 6-month time point. Basically -- can you go back, please? Yes. The inserts are essentially depleted past 8 months, which confirms, as we will see in the next slide, the pharmacokinetics [ and ocular ] tissues. And as you can see, the 3 doses, the percent release versus time is the same. So we have true dose proportionality at these microgram levels per day. So what does that mean when you get consistent zero-order release of a drug? How does it translate into the tissues where the mechanism for reducing blood leakage take place? If you go to the -- here is the profile, pharmacokinetic profile of drug in the vitreous, the retina, the choroid, the aqueous humor as well as the plasma. You could see aqueous humor and plasma, very low, below therapeutic levels. But in the vitreous, where the insert is injected as well as the retina and choroid, the levels are very constant, pretty much constant within the variability of the small number of rabbits per sample time throughout the 8-month period. After the 8-month period, when the drug is starting to get depleted, the levels in these tissues go down and below therapeutic levels. So exactly as you would expect it based on the zero-order release profile that we see. We have a little bit of a burst initially, which is good because it allows steady-state levels to be reached rapidly in the ocular tissues and effect rapidly an efficacious effect. Next. So we said this drug is bioerodible. And with this -- on the right side here, you see an enlarged illustration of the inserts at times [ zero ] before being dissolved and this is at 12 months. You could see the difference in size between T0 and after 12 months of dissolving in vitro. Slowly, the insert goes away. And we have similar data from in vivo studies being conducted in rabbit with accumulating similar data. And we also see it clearly going down over time. Now obviously, you don't want the insert to go away too fast because then you get particles of drug floating around. So we don't have that. We want to make sure the drug is fully dissolved and then the insert goes away with it. Next. So what are the key takeaways from this preclinical and safety data we just -- clearly consistent zero-order of micrograms per day through 9 months. This micro dosing mechanism has been shown to work both with YUTIQ and ILUVIEN and other products that Jay mentioned but also with the EYP-1901 as you will see some of the data from the Phase I trial that we conducted. We see steady state levels in ocular tissues for 8 to 9 months at levels by an order of magnitude higher than IC50. And the release is dose [ propor ]. This is important. So if you want to put a higher dose, you will get from this technology, you will get those proportionality. And the important thing also is that inserts are bioerodible over time. Next. So next, I'll introduce Jay Duker to talk about the formulation for clinical trials.

Thank you, Said. Could you go to the next slide, please? So we've mentioned these studies of oral vorolanib, and this slide summarizes the Phase I trial. Phase I trial was open-label, 6-month study dose escalation. There was no control. And of course, it was delivered orally. 25 patients were initially enrolled. The results showed best corrective visual acuities were maintained within 4 letters or improved in all but one participant. Interestingly, of the 25 patients, 60% never required a supplemental anti-VEGF injection while on oral vorolanib. The lowest dose that was studied in this Phase I trial was 50 milligrams every other day, which was clearly subtherapeutic. And if you take those patients out that were on those -- that low dose, 72% of the patients required no supplemental anti-VEGF injection during the 6 months. The OCT thicknesses were reduced, and in the several treatment-naive patients that were enrolled, they were reduced by about 80 microns. Next slide. So the company that was developing vorolanib [ orally ] were quite encouraged by those findings. And remember, vorolanib was felt to have fewer off-target systemic side effects, that's why it was elected to try this in wet AMD. Unfortunately, in the Phase II trial, the systemic side effects really became apparent. But what you're seeing here is the results of the patients who completed the trial. There was approximately 150 patients enrolled. And in this trial, there was really strict supplemental anti-VEGF criteria. I'm sure you've heard in various criteria of 50 microns of new fluids, 75 microns, 100 microns of new fluid, in this trial, it was any new fluid. And OCT, as you're probably aware, is highly sensitive to fluid. And so the investigators were instructed to give a supplemental injection if they saw any new fluid. And part of the rationale here was that some of these patients were getting placebo. And so the company investigators didn't want a placebo patient to go very long without an anti-VEGF on board. So in the placebo group, over a year, the median number of anti-VEGF injections was 9 -- now in the real world, we give about 6 anti-VEGF injections per year. So you can see this is a pretty highly treated group. But you can also see with the progressive dosing that there was a dose response, with about 4.5 supplemental injections in the highest dose. And actually, 20%, 1 out of 5, went the entire year without supplement in the highest dose even with that really strict criteria. So there was no ocular toxicity. There were certainly evidence here of a dose response with pretty good efficacy. But unfortunately, the systemic side effects limited the ability to complete the study. Next slide. There's another interesting finding which had to do with the fellow eye. So patients who entered the study with wet AMD in one eye, but not in the fellow eye, in the Phase I trial, none of those patients converted to wet AMD in the fellow eye. You might say not particularly surprising, it was a short trial, small numbers, and that's true. But then if you look at the Phase II trial, which had obviously bigger numbers and a placebo group. In the placebo group, 12.5% of those that did not have bilateral wet AMD converted to wet AMD in the fellow eye, which is pretty standard. If you read the literature, that's pretty standard for conversion rate. But only 1% of the eyes that were treated with systemic vorolanib converted. Again, this study was not designed to look at this, but it's pretty compelling data that systemic vorolanib was able to stop conversion to the fellow eye. Next slide. So we are very excited about the results of our Phase I trial from both a safety and efficacy perspective. And I'd now like to introduce Carl Regillo, one of the world's prominent retina specialists and clinical retinal researchers and Director of the Retina Service at [indiscernible] Wills Eye Hospital. Carl, why don't you go ahead and give us the Phase I DAVIO results?

Great. Thank you, Jay, and good morning, everyone. I'm sorry, I couldn't be there in person. Had some commitments back here in Philadelphia, but I was in New York and it was a good meeting at the ASCRS meeting. In fact, this is -- this study was one of the highlights of the program because we now have the full 12-month study results in all patients in the Phase I DAVIO study. Anyone hear me okay? Great. Thank you. You can go to the next slide, please. So what is DAVIO? Of course, we've been talking about vorolanib in the Durasert sustained delivery platform. This is a Phase I clinical trial in patients with wet AMD. And what we did is enrolled patients that were previously treated, active neovasc or AMD, similar to other studies of this type. There was no specific exclusion for the presence of fluid, so patients could come in having variable amounts of prior treatment and varying amounts of wet AMD under good control or not so good control. The criteria for supplemental anti-VEGF therapy is shown here. This is very typical of a study designed in this way to look at durability. You treat or rescue upon signs of recurrent -- significant recurrent [indiscernible] defined here as greater than 75-micron increase in OCT or a loss of 2 or more lines, which is 10 or more letters that's corrected acuity BCVA from neovasc or AMD. And any new macular hemorrhage is also indicative of significant new wet AMD activity so that would trigger a rescue. So this is a Phase I study, 12-month duration multicenter, open label, so it has no control, but it is dose escalation, as you would expect from a Phase I safety data. And we're looking at patients that received a treatment, an anti-VEGF treatment, so-called standard of care, at screening. And then shortly thereafter, within 7 days or so, received a single dose of EYP-1901, that's the baseline day 0 visit, and at a dose range from 440 to 390 micrograms delivered as the bioerodible insert. There's no redosing with 1901 here, just rescue, looking at the durability, of course, putting that to the test. Clinical assessments and evaluations for safety and for the potential need for supplemental anti-VEGF therapy was every 4 weeks. So patients were followed monthly over the course of 12 months. Next slide, please. You can go to the next slide. Thank you. So originally, it's a 3-arm, 3-dose study. There was an extra dose in there with that one patient, low mid-dose. But you have 3 patients on low, getting low dose, the one patient getting the low mid-dose inadvertently from 1 insert rather than 3, supposed to be high. The mid-dose and these and high-dose number there is 5 patients. And so this is how the study was designed. Primary endpoint, of course, Phase I being safety, looking at ocular and nonocular treatment emergent adverse events through 12 months with secondary endpoints, of course, looking for a biologic signal and activity here, including durability, supplemental anti-VEGF therapy through 6 months and even now through 12 months and then change in BCVA from baseline and also change in mean CST central set thickness as measured by OCT from baseline. And so 17 patients were enrolled. Thank you. And here are the baseline characteristics. It's very typical of a neovascular way and be patient population enrolled in our clinical trials, whether it be new onset or previously treated, as shown here. Mean BCVA, again, very typical, 69 letters. Mean CST, and these are previously treated, so we expect to see a central subfield thickness in the near normal range, and that's exactly what we have, which meant that most patients were responsive, most, and had good control of exudation, but not necessarily everybody at baseline at 299 microns normal being on the machine [ 3, 310 ] microns. Mean number of treatments anti-VEGF the year prior to enrollment was very high and that sort of self-selects the patients in this type of study. They were getting frequent treatments on the order of every about 6 weeks or so, 8 injections in that year on average, and the median time from wet AMD diagnosis was 17 months. Next slide. And so here are the results. And so for the first time actually we're seeing 12-month results, and that's what was new at the ASCRS meeting this past weekend. And 1901 had an excellent overall safety profile. Ocular AEs, ones that you would attribute to the implant or the procedure and the drug itself, was really very, very good. You see no vitreous floaters, no endophthalmitis, no retinal attachment, no implant migration into the anterior chamber which could sometimes happen with these types of implants, no posterior significant inflammation or any direct effects on the retina such as vasculitis or retinal vascular occlusion, something that we've seen with anti-VEGF therapy from time to time. With the ocular AEs that were observed, actually, there are only 2, both very mild, self-limiting and did not result in any visual problems. One mild case of major segment inflammation treated with topical steroid eye drops and that resolved very quickly without recurrence. And one asymptomatic vitreous hemorrhage which can occur from any intravitreal injection. There were no ocular serious adverse events, no drug-related systemic adverse events and no evidence of anything ocular or systemic from a toxicity standpoint related to vorolanib or the Durasert itself. And we did not see dose limiting toxicity. Next slide, please. So here's the 6-month results. This is the swimmers lane plot, which gives a nice patient level data both before enrollment, before the injection of 1901, and then, of course, over the 6 months of close observation at monthly intervals looking at both safety and the ability to control exudation. So we see here a significant reduction in the treatment burden at around 79% at 6 months. So to the left, of course, before time 0 is the year before enrollment in the study. Most patients are getting very frequent injections, many of them monthly or every 6 weeks or so, and all doses showed a reduction. Now the numbers are small, especially for the low dose and the high dose, but you can see the bigger number of patients in the mid-dose range, all of them showed some degree of decrease and very significant, north of 50%, in all groups in terms of the reduction in treatments needed to control disease. And we'll have evidence of proof that disease is under control by looking at new BCVA and OCT every time, which is coming up with the next slide. And here is now the new data through 12 months, and you can see very, very similar with durability impact a number of patients when the entire 12 months without needing a rescue. These are patients known to have active disease. We have information how these patients look before and they were getting frequent treatment. So that in and of itself is very impressive. And most patients went considerable times from day 0 after 1901 injected without the need for a supplement. There were some exceptions to that. You can see 3 notable exceptions getting a rescue the very first month. And those patients, of course, had an anti-VEGF injection shortly before, about a week before, 1901. So they represent poor responders or aggressive disease. And it's no surprise that they -- all those patients also needed quite a bit of supplements over time But virtually, all other patients had a reduction in their need for anti-VEGF therapy going forward out through 12 months. Next slide, please. So here, of course, durability doesn't mean anything if you're not controlling the disease and optimizing vision outcomes. And optimal vision outcome in a previously treated patient population means maintaining that vision. They came in with good vision and good central subfield thickness at baseline and we hope to hold that. That's the goal here. This is maintenance phase therapy, and that's indeed what you're seeing here, almost no significant -- there is no significant change in vision. You're talking within 2.5 letters over 6 months from baseline, and that's what you're seeing here. No significant loss of vision is what I'll say. Next slide. And this is the anatomic results. This tells you, of course, how good the treatment is doing with regards to exudative control. You can't get good vision outcomes if you don't have good exudative control and you're seeing excellent maintenance of the OCT, central subfield thickness, only 3 microns, that's negligible, change from baseline at 6 months. Next slide. And now the data visual here, changing mean BCVA from baseline. Within 4 letters of the baseline, we can see a nice flat curve. That's what you're hoping to see. If you're familiar with the port delivery system, which also showed excellent results in maintaining good vision, it looks just like this. And this is now over 12 months with the 1 1901 injection and much less anti-VEGF therapy. And next Slide. And anatomically by OCT the central subfield thickness is also holding up really nicely, very mild degrees of fluctuation here. And that probably reflects some patients that had some worsening and needed to be rescued. But overall, you can see excellent control of exudation anatomically out to 12 months. Next slide. And so how durable is 1901? Well, it showed, of course, across the board at all doses a significant reduction in the need or frequency of injections as the treatment further. And how long it lasts? And to give you a feel for that, you can see 53% of patients, slightly over half of the patients, did not require a supplemental anti-VEGF injection after one administration of 1901 up to the 6-month point. There were some exceptions. But of course, those that did need it beforehand needed it around on average months 4 or 5. And then, of course, you see patients going out and even up to 35%, 1/3 of the patients, not requiring any rescue up to a year. Next slide. There's a couple of cases and really nice to look at patient level data, especially the OCT and the corresponding vision. You can see at screening, which is about a week, 7 to 10 days before the 1901, you see the OCT up and left. And what you're seeing is good control of exudation. There are no signs of exudation in that eye, and that's good. That means they've had some previous anti-VEGF therapy and it's working well. And this patient received 1901 at day 0. [indiscernible] OCT starts to see a little bit of [ fluid ], start to merge at month 3 and then would triggered a rescue at month 4, of course, was the change in CST, which became significantly triggered based on the criteria. And then looked really good thereafter for a good long time frame all the way out to month 12. So for another 8 months, you see [ excellent exudative ] control, and this is just after the 1901 and one rescue at month 4. Next slide. Go back. Yes, this is the other case. This is a high-dose arm case. Again, at baseline, this patient is showing a good response to anti-VEGF therapy. Negligible signs of exudation are present. And in both of these cases, that screening, that most patients received an anti-VEGF as a standard of care in practice within 1 to 6 -- or 1 month to 6 weeks. So that's what we're seeing there. And then we see excellent control of vision -- of disease with good vision, excellent vision actually, and near-normal central subfield thickness throughout the entire 12 months, no rescue was necessary. And next slide. So the Phase I DAVIO study really did look very good. Clinical trial met all the objectives. Certainly an excellent safety profile with no ocular serious adverse events and 2 ocular adverse events, 1 mild inflammation and 1 mild vitreous hemorrhage both of which were asymptomatic and resolved, did not pose any problems at all. No drug-related systemic adverse events were seen either. From an efficacy standpoint, we saw good stabilization of best corrected visual acuity and OCT throughout normally 6 months, but now 12 months. And so we're really seeing the effect we hope to see with a good reduction in the need for anti-VEGF, with 53% of patients going injection-free up to month 6 and a 79% reduction in treating [indiscernible] at month 6. Next slide. So I'll pass the rein back to Jay, and I'm going to sign off, see some patients. And I guess I'll be back later for some questions and happy to discuss all of this at that point.

Thanks so much, Carl. That was great. Yes. Carl will be back in about 30 minutes. He will probably have done about 30 injections in the meantime.

That's [indiscernible].

Exactly. Charlie, could you come up to the podium. I'd like to introduce Charlie Wykoff. If I had introduced Charlie a couple of years ago, I would say he's up and coming superstar to retina. But Charlie has arrived and he is a superstar in retinal surgery and diagnoses and especially in design and executing clinical trials. I think the highest compliment I can give you, Charlie, is you're the Carl Regillo of your generation. So I'm going to start out this section by showing you the [ swim lane ] chart that you've seen already. This is the swim lane chart for 6 months. And if you look at this and say, well, let's suppose that EYP-1901 is safe and it's effective, it's tolerable and we get ability to inject it every 6 months, what would it might look like in the real world? Well, if our pivotal trial repeats what we saw in DAVIO, it looks as if about half of wet AMD eyes will be able to go 6 months or longer on EYP-1901 alone. Another 30% or 35% approximately would receive EYP-1901 and may require a supplemental anti-VEGF during that 6-month time period but only receive one. Therefore, significantly reducing the treatment burden. And finally, you'll have this group, illustrated by patient 2, patient 3 and patient 15, who may really not do that well with EYP-1901. Those 3 patients both required supplemental injection at month 1, but they are clearly eyes that we're failing standard of care as well. Next. So this brings up this concept that we're introducing as -- what we're calling treat to maintain. Treat initially with any current anti-VEGF standard of care, faricimab, Eylea, Lucentis, high-dose Eylea, it doesn't matter. Get your vision stable, maximal effect, get your retinas dry as possible, and we call that the induction phase, and then maintain those gains with EYP-1901 every 6 months or so, supplementing occasionally with the current anti-VEGF biologic. And so as I indicated on the previous slide, we believe over half of all wet AMD eyes may be maintained visually and anatomically with EYP-1901 alone and another large segment could require an occasional supplemental anti-VEGF but at a much reduced interval. Next slide. So Charlie, first, before we go into these questions, how many patients with wet AMD in your practice would get an anti-VEGF and then 5 weeks later have 75 microns or more of new fluid? What would you say that percentage is?

Thanks. Thanks, Jay. Great to be here with you. I wish you were in person. Unfortunately, I remembered my tie. So we look forward to seeing you next time. No, I'll just back up a second. I think you summarized the data really well. And I think the 2 take-homes I would think about before even talking about the efficacy is we got to keep remembering who these patients are that the team has enrolled into this trial, because this is not sort of your treatment-naive, typical wet AMD eye that we're seeing as a new patient in clinic. We got to remember that. These are eyes that your investigators, your high-quality investigators across the country, identified as frequent flyers or patients requiring repeated injections over the previous 3, 6, 12 months, on average, many months, 17 months coming into the trial. So these are your frequent flyers coming in, a very different population than many wet AMD patients. And secondly, and probably most importantly for all of us as clinicians given how much adverse event data we've seen from so many programs, is the remarkable safety that we're seeing. So I think once we cross those 2 bridges in my mind, I can then begin to think about what am I seeing from an efficacy perspective because those first 2 things are really critical. And then to get back to your first question, Jay, I think if you take this population of patients and you're dosing them every 4, 6, 8 weeks because they need it, which is how retina physicians practice, right, we don't treat patients consistently with every 6- or 8-week dosing unless they need it, that's something called treat-and-extend, where you find a patient's longest interval that they can tolerate and then you repeat it over time. And so we trust that these patients coming into this needed those treatments, which is standard of care across this country. And so what percentage of patients would need a treatment within 5 months? I would argue it would be almost 100% of this baseline population of patients. Again, that's different from a treatment-naive population, you got to be very careful what baseline population of patients you're looking at. And so within that context of seeing a greater than 50% portion of patients at 6 months not needing any treatment to me appears quite meaningful as a clinician, as someone that sees these patients every day. And to be able to tell patients that are needing frequent injections, you've got a 50% chance of not needing a treatment in the next 6 months, if I give you this drug is a big step forward, I would say.

So if we have this drug and we can't necessarily via OCT or other characteristics tell the clinicians which of the eyes are the ones that are going to go 6 months, how would you introduce it into your wet AMD population?

Yes, sure. And there's a lot to dig into there that I think is quite relevant and some of this gets pretty nuanced. But when you have -- I think we've learned a lot through the port delivery system program that I think is actually applicable here, and Carl mentioned that before, which is, right, when you have a chronic VEGF suppression state in the eye, which is what we're trying to achieve with bolus injections of biologics with Eylea, Avastin, Lucentis, right, you're trying to get chronic suppression of VEGF. But the challenge with the bolus injections is you get these massive peaks and troughs. And so as we learned with the PDS over the last 5 to 10 years is that when you have chronic VEGF suppression, fluid is different. It's -- we need to reconsider the way we think about OCT analyses here. Maybe a fully dry retina isn't actually the endpoint that we're trying to achieve. We're trying to achieve steady state and optimal visual outcomes. We've learned a lot about fluid status and we need to think about that differently. So in this case, with EYP-1901, we need to remember that we have a chronic now VEGF suppression state. And so we need to think about the OCT patterns a little bit differently. Maybe completely dry is not the absolute goal. So in my clinic, the way I would use this based on the data we've seen, assuming this plays out in Phase II and then the pivotal trials, would be to sort of have a, I'm hesitant to use this word, which is the way I'm thinking about it, which is foundational, right? So you have a foundational treatment where you know that you have chronic VEGF suppression and suppression of many of these tyrosine kinase pathways, but I think there's a lot of interest there as well beyond what VEGF A is doing with these receptors. But once you have that, then looking for fluctuations. And if you see fluctuations beyond their steady state with this drug on board, that's when you might add a supplement.

Would you have any problem with that approach of -- if you've got a 6- to 9-month maintenance therapy but every 3 to 4 months you might need to add a supplemental standard of care?

I think that makes a lot of sense for the current treatment paradigm. Again, the current anti-VEGFs are fantastic. They're excellent, they're here to stay, but it is a tremendous burden, particularly for the patients, if you really focus on the greatest burden, it's the patient challenge. And we see that in real-world data. Talk to the patients and that's an obvious burden. But holistically, when you look on these -- at these patients, on average, they're not receiving the injections that they need to get optimal outcomes. And so to bring a product to the space that has a great safety profile, again just doubling down on that, that has this foundational treatment that you can add additional anti-VEGF [indiscernible] therapies on top of, I think, is quite meaningful. And another point I would bring up, Jay, is sort of the data that Said went into, which I think is fascinating. It brings out the molecular biologist in me, which is, right, we're so used to thinking about anti-VEGF treatments, and we've got to be very specific about which pathways we're manipulating here. But the data that Said showed about this potential neuroprotective role with this particular tyrosine kinase inhibitor to me as a clinician is exciting. Because it suggests at a high level that there may be additional benefits of tyrosine kinase inhibition, at least with vorolanib here, beyond simple VEGF inhibition and improvement in exudation status. So I look forward to more data on that, but that is a very encouraging sign. And again, sort of again drives me to think about this more broadly than just a fluid-based analysis. I think there's going to be benefit to this drug beyond just stabilizing exudation, which we're also seeing.

I agree, Charlie. What do you think about pan-VEGF blockage? In other words, blocking all isoforms? Do you think there's any advantage to that?

I think there's no doubt in that. And I love the fact that we have the oral data with vorolanib, I had a couple of patients in that study. And so I know that data very well. I think you presented it beautifully. And that certainly demonstrated proof of concept for this pathway. I think it's also reassuring that there's so many different companies pursuing tyrosine kinase inhibition. This makes a lot of sense, right? We know that VEGF A inhibition of the protein of the ligand directly has a dramatic and quite meaningful clinical benefit. And again, they're here to stay. But can we get better outcomes by moving intracellular to inhibit not only receptor 2, but also the other receptors and then have a broad anti-angiogenic anti-exudation and possibly anti-inflammatory, possibly pro neuroprotective effect, I think, is quite exciting. I think there's a lot to learn in the space still. But to me, this mechanism has clearly been validated, both in your program here, in the oral program, and other TKI programs. And so it's just a matter of finding the best tyrosine kinase inhibitor, the best delivery mechanism for that and then proving that this is truly effective in comparative trials.

Could you just say a few words about the possibility of home OCT and how that might change the paradigm with a sustained release drug like EYP-1901 as well?

Yes, it's fascinating how COVID has affected this as well, right? Before COVID, they were starting this move to home monitoring within retina, but it was sort of a trivial or peripheral move. With COVID, you're seeing really acceleration of that. And it's for a good reason and it fits nicely with the paradigm shift as well as we -- as we have now more durable therapeutics for [indiscernible], for example, some data that may last longer than some of our current therapeutics. You have the port delivery system. But as we develop more durable agents, it makes a lot of sense from a patient care perspective to be able to do a substantial amount of monitoring remotely. And what's nice about EYP-1901 is it's not a device from a clinician's perspective. You don't need to think about sort of external monitoring over time. You're really looking for the biological effect. And so it lends itself really nicely to home OCT monitoring because you can follow those fluid fluctuations, and that's what you would expect to see as sort of the first biomarker when EYP-1901 is beginning to trail off and the patient might need another injection or to have a supplemental anti-VEGF bolus injection in between the 6-month intervals that I would imagine these patients receiving injections once it's approved.

Great. Any other comments about wet AMD in 1901 before we move on to some of the other indications?

Wet AMD, I think it's just important to remember for the whole audience out there that this is a variable disease. It's very heterogeneous, right? Some patients come in, and we've learned this from our PRN trials, CAT, HARBOR, many of them and need a few anti-VEGF injections and then may be stable over time. And then you have patients that have get monthly injections and still can have progressive exudation. And you're seeing that population in particular in the DAVIO program, those 3 patients that Carl highlighted I think are quite meaningful, right? If you get an anti-VEGF injection, standard of care and 1 month later you have more fluid, those patients are not under good control. And that really would not be a good candidate for any of the sort of long-acting treatments that are potentially currently available or in development, in my opinion. You want to bring eyes into a program like this and the other ones out there being pursued that are under good control, because the goal of EYP-1901 here is to provide a treatment that's going to be durable for eyes that are already under control. And the sweet spot that I see here is for the majority of patients that have already have optimized anatomy, and that's the treatment period and then the maintained period, is for the eyes, once they're stable atomically we try to really dramatically decrease that treatment burden and improve compliance over time.

Great. So you are one of the world's experts on anti-VEGF and NPDR. Tell us a little bit about how 1901 might fit into that paradigm?

Yes. I know we'll go through that potential trial design later here this morning. And I'm excited for that. I think that this is a huge unmet need in the community. We have -- we need to remember what's causing blindness here. And sort of in the older patients and population at large, it's wet AMD first and foremost. But then in the working age adult population in the United States, we've got to remember the diabetic retinopathy is the most common cause of irreversible blindness. And we see this every day as clinicians and it's tragic to see it because it's not necessary. We don't have to go blind from diabetic retinopathy. And the key place to treat these patients, I firmly believe is at the NPDR level before they had DME, when they're still asymptomatic. And we have really good data that our current anti-VEGF agents are highly effective at that stage. But they're not being used in the vast majority of patients, both in my clinic and every retina specialist clinic because it's a tremendous burden to have to give monthly and then every other month and even every once every 3- or 4-month injections long-term to these patients that are asymptomatic. It's just not sustainable on a population basis, and that's why we're not doing it. But I think biologically, it makes a lot of sense. So to be able to have a drug that can last 6, 12 months to dramatically change the natural history of the disease would be powerful and has the real potential to change the epidemiology of blindness for people in this country.

What do you think the sweet spot is for NPDR? 6 months? 9 months? A year? What would you like to see?

I think any of those would be clinically useful. But I think the time line here, probably a little bit longer than wet AMD for the sweet spot. I'd love to see a 9-month, even potentially a 12-month [ treatment ].

Great. Before we move on to the Phase II programs, any other thoughts about how 1901 might be used in DME or other VEGF-dependent conditions? Do you think should get straight read through to those other conditions if we show the efficacy in wet AMD in a pivotal trial?

Yes. I think the data that I'm seeing so far on the DAVIO trial in these high need anti-VEGF dependent eyes and wet AMD, I think that there's a lot of potential fertilization in these other exudative diseases. So diabetic neuropathy makes a lot of sense to me. DME also makes a lot of sense to me. Again, this may not be the agent to achieve the rapid drying that our current anti-VEGF agents can achieve, but again we don't need another agent in that space. We have a lot of great bolus proteins that we can inject in the eye and achieve rapid drying. What we do need is an agent that's more durable and allows an eye to maintain its current status over time. And I think the data there that I would think about is the open-label extension following ride and rise, the endurance data following vista. These are years 4 and 5 follow-up among eyes that were initially treated with center-involved DME with visual acuity loss. And what we've learned from these really long-term follow-ups is that once you get the DME under control, the problem becomes not so much DME recurrence, that is still quite relevant in a minority of patients, but it's actually a worsening of diabetic retinopathy. So it's hard to talk about DME in a vacuum without thinking about DR and vice versa, so we need to always think about both of these. But the long-term DME patients, what I worry about is actually worsening of their diabetic retinopathy. And so to be able to get an eye under really good control with bolus injections and then transition to a more durable agent where they need fewer injections I think would be a paradigm shift in the way we think about DME. It's something that makes a lot of sense from what we see clinically.

That's great insight. Charlie, stay close because I'm sure audience is going to have a lot of questions for you at the Q&A. But we're going to move on. Next slide, please. So we're going to talk about our Phase II clinical trial plans. Next slide. And I'd like to introduce Dario Paggiarino, our Chief Medical Officer, who's going to walk you through our wet AMD and NPDR trial design. Dario?

Thank you, Jay. Good morning. So we heard about the DAVIO results and, obviously, very encouraging in supporting the -- moving this product into the next phase of clinical development, Phase II. And so we plan to initiate 2 studies this quarter. And so I'll cover the design of these 2 studies. And while I start with the wet AMD study Phase II study. This is going to be a prospective, randomized, masked positive controlled study compared to aflibercept. And the objective of this study following the wet AMD study, the Phase I study that just we covered, the DAVIO study, the objective of this Phase II study will be to confirm the effect of the product in a larger population, to compare -- very importantly, compare now on a double-mass study the effect of the product against our standard of care today, Eylea. And third, also to have the possibility of understanding better the dose relationship. And that's very important because we need to really have a good feel of what those doses were going to move forward into the next phase of development. So as you can see here, all patients are randomized to -- once randomized receiving 3 monthly aflibercept injections. The difference is that the patients assigned to the -- 1 of the 2 doses, EYP-1901 doses, will also receive at week 8 the insert 30 minutes after the injection, the aflibercept injection we gave. And then from that point on, this patient will be seen monthly. And we plan to unmask the study at week 32, which is essentially 6 months after the placement of the insert. And we'll continue then the study through week 56. So week 32 will have -- again, hopefully, we'll have a good feel about the efficacy, dose relationships and the other endpoints that I'm going to cover in the next slide. So primary objectives, of course, BCVA at week 32, as I mentioned. We also look at other key secondary endpoint in these studies that you can imagine, central subfield of thickness and, of course, time to rescue medication. Very importantly, burden, as we have seen from the DAVIO study, that's an important parameter, whether or not you're actually -- a patient is actually rescued or supplemented with anti-VEGF therapy. It's also important to see over the course of the study, how many injections anti-VEGF injection is actually requiring. These are patients who are pretreated. They have a relatively recent diagnosis, 9 months, of wet AMD. And they have to have received at least 2 injections in the previous 6 months. And you can see here the OCT criteria baseline are really adjusted to reflect our experience that we acquired in the DAVIO study. And so we're trying to address and possibly exclude the patients who actually needed a supplemental injection at month 1. And we have some ideas of how we could do that. And so the OCT criteria here are reflective of that strategy. And of course, these were a minority, as you can see, a minority of patients in the DAVIO 1 study. Next slide. So we will -- like in DAVIO, we will also apply rescue of supplemental injection criteria. And these are very typical. They vary somewhat from program to program, but this is, again, the ones you see here are fairly typical and cover, of course, include a combined criterion that includes both changes in central subfield thickness and BCVA letter, the first one. And then, of course, we also have a couple of other criteria related to changes specifically in BCVA only or in CST. And of course, presence of new or worsening vision-threatening hemorrhage is also a typical criteria in these studies, okay? Next slide. So the second study that we plan to initiate in the third quarter is a non-proliferative diabetic retinopathy study. We mentioned earlier that there is -- although there are products, anti-VEGF therapies approved today to treat NPDR, we also heard that it's very limited usage. And so what that means is that we -- in a Phase II study like this one, we can still do a controlled study, but we can control, again, sham. And so this is, again, prospective randomized study using the same 2 doses that we're using in wet AMD in the Phase II wet AMD study. And patients are randomized and they receive either 1901 or sham. And then they will be followed every 3 months. We plan to unmask at week 36, about 9 months after the placement of the insert randomization. And the rationale is, as you -- as Dr. Wykoff mentioned earlier, 9 months seems to be a really a good target for potential redosing. And this is a single EYP-1901 injection study. But what we want to understand is really the duration of the product. So as we unmask in 9 months, we'll have a sense of how many patients actually will -- how well these patients will do specifically and primarily in terms of their diabetic retinopathy severity, which brings me to the next slide. Primary endpoint, very typical in these studies. We use a diabetic retinopathy severity scale. It's essentially scoring parameters, ocular parameters, that are captured through fundus photography. And so it's a clear picture of how the diabetic retinopathy is progressing. And this is a validated scale and, again, used very typical -- it's being used definitely in previous anti-VEGF therapy studies for NPDR. It's also important to -- as was mentioned earlier, it's also important to understand is the treatment not only potentially improving the diabetic retinopathy scale, but it is also addressing the risk of potential complications that may occur at this stage of the disease and namely the occurrence of diabetic macular edema center involving diabetic macular edema and possibly the development of proliferative disease. So now these patients who had no proliferative disease at baseline were also evaluated for the potential of developing neovascular changes. The -- these are patients who have the either moderately severe or severe diabetic retinopathy. And they could have received anti-VEGF injection as long as it's not occurred -- it did not occur in the previous 12 months. And as I mentioned earlier, they might have some macular edema but not center involving. Next slide. So now moving to YUTIQ. YUTIQ was launched in 2019 for noninfectious uveitis affecting the posterior segment. Since then, we have run quite a number of post-marketing studies. Now I'm going to cover a couple of them that are particularly important for us. And so the first one is the CALM study. The CALM study is a registry study, you can call it that way. It's a real world study. In other words, we supply the product and we really want to understand in the real world how -- outside the clinical trial, how is the product used? Why is it important for posterior segment uveitis? Because this condition is a -- from an ideology standpoint, is caused by a number of diseases that it could be either primary, but often is associated with systemic diseases. So it's -- it's a very complex disease that it's important to understand. Because what we want to capture in the real world is how the patient is used in this variety of conditions that have a commonality posterior segment inflammation. So the registry, the CALM study is well has -- start getting 500 patients will -- we have about 150 patients enrolled to date and we will present in upcoming retina conferences this year. So second -- next slide. The second study, post-marketing study, is what we call the synchronicity study. Why is the synchronicity study important? It's important specifically because we're going to look at macular edema in these patients. About 50% of the patients in the Phase III trial of YUTIQ had macular edema. This is an opportunity for us to really expand on the impact of addressing macular edema in patients with posterior inflammation. This is strictly not necessarily including a uveitis inflammation that uveitis patients that I was referring to with systemic conditions, but also there are situations, and these are patients seen primarily by retina specialists. There are patients who are seen because they have postoperative inflammation. And -- but the most important thing is despite the use of short-term steroids they, at some point, would benefit from a long duration, a steroid releasing product like YUTIQ, and this is exactly where we're looking in this study. We're looking at patients with edema for a variety of reasons, including post-operative, and we plan to enroll -- we actually enrolled the first patients already. We plan to enroll about 125 patients and with data in the second half of 2023. And I think that concludes my presentation, and I'm introducing George Elston, our Chief Financial Officer. Thank you.

So again, thank you, everyone, for joining us here today. I think there's a lot going on here at EyePoint and the biggest question for this room and those online is how we're going to pay for it. And I think most importantly, we're sitting here today with a great balance sheet. We've done a very good job as a company to keep our balance sheet in order. We had successful financings last year. I've got some preliminary Q2 information I'm sharing with you this morning, and we released that on a press release earlier today. We did end June 30 with $171 million of cash. And our short- and long-term debt remains unchanged at $40 million. Recall, we refinanced that earlier this year at a much lower interest rate and our balance sheet is in good shape. From a P&L perspective, we had a very strong Q2 from our commercial business, a record $11.3 million of net product revenues from our both YUTIQ and DEXYCU franchises. We've talked about in the past that we have positioned those franchises to be breakeven this year, and we're on a great track for that. YUTIQ, in particular and really going on to what Dario and others talked about today, we had a record demand in Q2, 900 units of customer demand in Q2, a 43% increase over the prior year. And that goes to the expanded use of YUTIQ in some of these inflammatory conditions and additional efforts ongoing with retinal specialists. So that team has done a spectacular job and we look forward to continued performance by the commercial business this year. We are reaffirming our cash guidance into the second half of 2024. As we heard earlier, we have a data readout end of 2023 for the wet AMD trial, and our goal has been to maintain about a year of cash on hand on the other side of that data. I will touch on some news we learned on Friday related to our DEXYCU's franchise on the pass-through rule from CMS, and they announced in their preliminary rules last Friday that those drugs that are expiring will not get extended pass-through. However, they have kept the door open for any non-opioid pain indication. And so we are evaluating next steps for a potential pain indication for DEXYCU. If this rule is final, which we'll learn about later this year, then DEXYCU's pass-through will expire. Reimbursement through pass-through will expire at the end of this year. Recall that we entered into a collaboration last year with ImprimisRx. We actually handed over our commercial organization to them. And so our role in DEXYCU is really shipping and then paying a commission to our partner. And we will continue to update you as we work through the plans for DEXYCU pain indication. With that, I'm going to ask Nancy to come back up and we will start our Q&A.

Yes. I think what we'll do is we'll have -- let's have all the speakers come up and sit. And then what -- what we'll do is if you've got a question, just raise your hand, we've got some runners who can come around and give you the mic to ask your question. We also have various analysts, I believe, that are calling in so who've got a question, feel free to hit the message board to the operator and she'll tee up your questions. So, okay. Go ahead. Yes, go ahead. Why don't we stand up, if you don't mind, just real quickly. And just real quickly, just to introduce who you are.

This is Georgi Yordanov from Cowen. So maybe starting with Dr. Wykoff, specifically now that we have multiple different options that offer some of that extended duration on the market with faricimab and the PDS, how do you -- if eventually approved, an implant like 1901, how do you see it like fit into the treatment paradigm kind of like in relation to those other options that we have out there? And then I'll have a couple of follow-ups.

Great question. And I think from a clinician's and a patient's perspective, truly the more tools we have in the toolbox, the better. So I'm a big believer in development having new options. So I support what's out there and I'll support many other developments from the Board and some space. Specifically, of the 3 that you mentioned, right, we have Phase III data for a couple of them and then very early Phase I data here, so it's hard to make comparisons. But when I go back to go to talk about before which is who are the patients that we're looking at in the studies that we have. So for example, with faricimab, Vabysmo, we have treatment-naive eyes with wet AMD being treated in the Phase III program, very different baseline population than what you're seeing in the DAVIO program. You got to always remember, the patient population we're talking about, because durability is going to be very different when you measure on average among patients that are treating naive at baseline at 1 and 2 years compared to a population like DAVIO, they're heavily pretreated because they need their [ sharpness ]. So you got to be careful about comparing durability here among this baseline population. And the PDS, I put sort of in a category of its own because it really is such a unique approach. They have phenomenal efficacy data there among those patients that have been treated now with PDS. The main challenge I think you're seeing in the commercial landscape for clinicians is the safety profile, is the adverse event profile. And we've gotten better at the space as learning about what those adverse events are and how to minimize them. I think the whole space is still trying to learn what is that incidence of safety event? How do we minimize that to get to more patients.

I'm going to actually ask your thoughts, Jay, if you're still on, if you want to comment on that any further.

I am still on, and Charlie covered it very well. The only thing I would add is that a drug like faricimab may not be able to extend many or any patients out longer than 6 months. And so that while they may have a role in the 3- to 4-month interval if clinicians are looking for even longer duration that 1901 may be able to offer it. And the second issue we brought up here, which is the differential mechanism of action. And so the idea of using a TKI with occasional supplement of a ligand and a blocker may be advantageous also.

Great. And just a couple of follow-ups. So maybe the next one for Dr. Duker and Dr. Paggiarino. Can you talk to us about how you selected the rescue criteria for the Phase II trial? It seems a little different from the Phase I. But maybe kind of like how are you thinking about balancing, evaluating the durability of 1901 with maintaining that vision which is required for regulatory submission?

So Georgi, you hit the nail on the head. Visual acuity is the primary endpoint. And so we tightened up the visual acuity criteria to only allow 5 letters loss as long as it's associated with new subretinal fluid or intraretinal fluid. So we'd like to keep the visual acuity as tight as possible. And it's not that supplemental injection percentage or actual number is not important, but it's not as important as visual acuity. So if you think of it in these terms, in DAVIO, in the 6 months after the implant went in, we had an average of 1.2 supplemental injections in the 17 eyes. In the DAVIO 2 in those 6 months, in the control group, everybody is going to get a mandated injection of Eylea every 2 months. So they're going to have 3.0 injections. So if we have the same or stable visual acuity, same or stable OCT but we've reduced the treatment burden from 3 injections to 1 injection, I think that would be looked on very favorably by the FDA.

And then final question for Dr. Saim. How -- in terms of the implant and the duration that it stays in the eye, how are you thinking about redosing? And kind of like what are some of the considerations in terms of redosing? And then again, also how are you thinking about it from a regulatory standpoint?

Georgi, who did you want that -- you're talking about in the Phase II data? I'm a little unclear on the question still.

Just in terms of like the actual implant, so maybe either Dr. Duker or...

I could take that and then Said can pipe in. In the laboratory, the drug drops below therapeutic levels about 8 to 9 months after it's inserted. We think that every 6-month label will be advantageous, but it's pretty clear from DAVIO 1 that 40% of the eyes could go up to 9 months with just one injection. So the flexibility to go longer would be advantageous and the flexibility to dose it in patients who need it every 6 months, I think, would be appreciated. We do know that a small bit of the matrix hangs around longer than the drug. We showed you the picture that illustrated that. But it's a small fraction of the total. And that residual material should eventually completely biodegrade.

Said, do you want to add anything?

I think that's good.

Okay. Next, it looks like we got a number of questions, so I'm going to ask. There we go. And please introduce yourself.

All right. This is [indiscernible] from B. Riley Securities. So first question -- first couple of questions directed to Dr. Saim. So can you comment on the Durasert technology if it can be conjugated to a bigger molecular. For example, TKI is probably 500, 1000 for a molecular weight, it's about 500 if it can be up to like 10,000 or 20,000 for a bigger molecular?

Okay. So the question, just so people can hear is, can we deliver larger molecules in our Durasert technology?

Yes. So the technology is obviously validated for the steroids as well as for this TKI which are small molecules. We've done some work on large molecules. There's a need to obviously change a little bit the approach to the formulation. But we believe that molecular weights of about 2,000, 3,000 can readily be accommodated with the technology as is. Modifications are needed when we go to biologics, peptides and proteins. But until we validate it, we can't really say for sure.

Yes. Let me also add, and we didn't really talk about this, but we are also actively looking at other types of molecules we can bring in. We actually think Durasert would work quite well with a complement inhibitor. So that's something that we're working quite hard on. And we do believe it could work in the Durasert technology.

Got it. That's very helpful. The second question is, can you maybe comment on -- tell us some challenge when you are trying to translate what you saw from preclinical model like the one in mouse or rabbit? And how about -- when you do the translation into nonhuman primate or in human in terms of PK/PD or volume and dose levels and eventually the max tolerable dose?

Okay. So I think the question was, if I heard correctly, was translating from the preclinical data into the nonhuman primates, which, by the way, we are not required nor do we plan to do any nonhuman primate studies. Let's take it into humans.

Yes. So the way -- all of our PK studies were done in rabbit, the rabbit being the species that is most sensitive to intravitreal injection of product. So the FDA requires us to do rabbit. And the way we are metrically scaled to human is as the FDA requires it, you just multiply by 3.5, it's a difference in vitreous volume between the rabbit and -- so this is how we scaled up. We didn't see any [ novel ], the [ novel ] was 6 inserts in the rabbit. And we saw no toxicity in humans, which means probably it will translate just as well in NHP.

And one last question. So when you do have the Phase II trial, do you have different dose levels from low to high levels? Just want -- I'm curious what's the TKI concentration at the 6 months for different dose levels? For example, for the low dose level, is the dose level above, say, IC50 or is it lower than IC50 at 6-month time point?

So at the levels we're dosing in human allometrically skilled from rabbits. We see levels in the retina and -- in the retina and the choroid, let's just say like 5 to 10x the levels -- IC50 levels for VEGF receptor 2. So about an order of magnitude higher than IC50 for the doses we're using in the clinical trials.

Can you comment on whether it's the low dose level or it's high end, the most?

So I would say it's medium and high dose -- medium and high dose.

Yes, we're not going forward with a low dose into our Phase II, just the medium and high dose.

Yatin Suneja from Guggenheim. A couple of questions for me. So the first one, actually, I wanted to clarify what Dr. Wykoff said. So you said you would like to see somewhere around 9 to 12 months in duration. What do you actually mean? Like what percentage of patients getting to that 9- to 10-month, 12-month threshold with it? And I think in the Phase II, we have seen about 40% getting to that 40% mark -- 9-month mark. So just comment there, and I do have a couple more.

Yes, sure. It's very important to think about this, as I talked about before, knowing your baseline population. Every disease state is also important to consider separately. So for example, in diabetic retinopathy and we've learned from multiple data sets over the last 15 years that the level of VEGF suppression that you need to achieve a clinically relevant endpoint is probably different than the level of the VEGF suppression you need [ indeed ] or wet AMD, all very different disease states. And so I think for the same implant, if it works and let's say 50% of eye is 6 months durability in wet AMD, a hard-to-treat population like in DAVIO, my expectation is that, that percentage would go up substantially over a 6-month time point. And the other issue for the end point for an NPDR trial of diabetic retinopathy severity improvements, quite relevant, important endpoint, particularly for regulatory approval and understanding the biology of the drug. But clinically, clinicians are going to be using it to slow the progression of disease, which is a different endpoint than DRSS improvement, right? We're using it clinically to decrease the incidence of DME and PDR development. They're stated secondary endpoints. But for us, clinically, that's the most important endpoint that we're using. And that may be a different time period than [indiscernible] improving. So for example, the primary end point is at 9 months, it's showing [indiscernible] improvements, maybe clinically that same implant could be used with a longer duration of action.

If I could -- if I could chip in to say Dr. Regillo is back on and I'd like to ask Carl his opinion on what is the sweet spot for longevity for nonproliferative diabetic retinopathy in your mind, intervals of 6 months, 9 months, 1 year. And at those sweet spots, what percentage reduction in DRSS would you like to be seeing?

Yes. I do think this reflects what's been already and I think it's a 6- to 9-month time frame or more. Charlie said that could range quite a bit. And I'd like to see at least a 30% [indiscernible]. So by improving the DRSS level that, of course, decreases the risk of impending complications [indiscernible]. So for me, to be able to counsel patients, say, hey, look, we do an injection in order to achieve lower the likelihood of having a problem, lower the likelihood of needing a lot of injections. I think once every 6 or 9 months would be good. Longer, even better, of course. If you can go 9 to 12, that'd be more of a home -- big home run.

Thank you, Carl.

Then in terms of the patient population for DAVIO 2, this is not a naive patient population, a little bit different population, right? Can you just talk about how often would you expect to use Eylea in this population? Because if you look at the trial design in the 6-month period, all patients, at least on the Eylea arm, have option to get 3 Eylea doses. So how is this patient population -- how aggressive do you use Eylea in this patient population? And what sort of a treatment reduction we should be looking at? Because I think the study from the non-inferiority standpoint is a pretty good setup should work because everybody can be rescued. Is the treatment burden I think that becomes a key here in the data readout?

Let me just repeat these questions. I want to make sure that our guests who are calling in can hear them. So if I heard correctly, you're saying the patient -- sorry, the patients -- you want to know on our Phase II trial with the current patients we're enrolling what would they typically be treated and what would you typically expect in a real-world practice? In the trial, they're going to be injected every month -- or excuse me, every other month. So just to be clear, that's mandated in the trial. I think you want to know from Dr. Wykoff, Dr. Duker or Dr. Regillo, how they would normally be treated in real world?

Well, I'll start out by answering, we have really good real-world data now for the IRIS Registry. And on average, in The United States, maintenance therapy is 6 injections a year. So the Eylea control group at 3 injections over 6 months represents what we would expect. It's hard to predict what we're going to see in the 1901 arms. I said already in DAVIO 1, it was 1.2 injections over 6 months. However, 60% of those injections were in 3 patients, the 3 patients who required rescue at 1 month. So we hope to eliminate those bad eyes in which case we hope to see even lower supplemental rate. But we don't know until we do the study.

I can also comment...

Go ahead, Carl.

I was going to say, Charlie, you've published on this, I've published on this with first-generation anti-VEGFs, the median durability in the maintenance phase, about 8 weeks with ranibizumab and about 9 weeks with [ anti-VEGF ]. So that does translate into about every other month in the maintenance space that is actually important thing in order to get optimal disease control and vision outcomes. Now when you say real world, of course, there's often relative undertreatment reported, and therefore vision is not well maintained beyond the induction phase. But in an optimal, ideal, real-world setting, as Jay just mentioned, 6 per year, which [indiscernible] in the maintenance phase, is actually what you need, either ranibizumab or aflibercept to maintain [indiscernible] and get a good outcome over the course of 1 to 2...

Yes. One additional point I would make is, right, if you look back at the original [ DAVIO 1, DAVIO 2 ] data sets, treatment-naive population and you treat them with Eylea, we have good data, published data, that 25% or so of those patients really need monthly Eylea to achieve their optimal outcomes both anatomically and visually. I think the Phase II trial that we're looking at with 1901 is a nice design because it's really leading out probably, in my perspective, those patients that are needing monthly Eylea by putting the fluid criteria, for example, [indiscernible] for enrollment. You're bringing patients into a controlled study that are going to do very well with every other month Eylea because you've gotten rid of the patients that are on monthly Eylea. So you're going to see a very robust control on it. And I think compared to that [indiscernible].

Maybe a final question for the company, can you just talk from a commercial perspective how big is this patient pool? I think you mentioned maybe we are weeding out the 25%, but just maybe company, if you want to elaborate, based on the DAVIO 2, what are the commercial implications?

Well, we expect that this is a potential billion dollar-plus market for this opportunity for this product for EYP-1901. The market itself is, I think worldwide, you're looking at close to, what, $15 billion, if you look at all the drugs that are currently being used. So it's a very, very large market. And I might also add, it's continuing to grow because it's unfortunately demographic-related and it's -- these are diseases as people get older and the demographics are all getting older. So coupled also with in fact diabetes is increasing in incidence. So you put all that together, we certainly think this can be a $1 billion plus drug given its opportunities, the amount of patients that can from the DAVIO-1 trial, again, Phase I data, that certainly speaks to that could potentially be controlled and where this maintenance therapy is used. I'm going to see, Jay, if you want to comment on that at all.

I think you've hit the big picture well. I actually don't think that we are reducing our patient population by much with the criteria that we're using. I would just ask my colleagues, Carl, Charlie, to say, do you feel like this inclusion, exclusion criteria is going to limit the label here?

Yes, I'll take that. It's a great example here is, and we've already talked about it as Vabysmo or faricimab. So the trial in wet AMD, right, the program was treatment-naive wet AMD eyes. But if you look clinically, clinicians are actually using it first and foremost and they're hard to treat previously treated patients. And so the development program and the patients you enroll in a trial like this are really important to understand the biology and the comparison to the non-label drug, currently Eylea but it's not meant to determine exactly who's going to be given this drug in the real world. There may be label implications once you get to pivotal trials. But I think what you've seen previously and what I would expect with this drug is that this would be used widely for wet AMD patients potentially at baseline in combination with anti-VEGF agent, but then also in previously treated eyes. So I don't foresee this being sort of the population necessarily that would be limited to in the real world.

Okay. Other questions?

Jennifer Kim from Cantor. I have a few questions for Dr. Regillo and Dr. Wykoff at first. My first question is, with the design of DAVIO 2 with the injection being given 30 minutes after aflibercept, I'm just wondering how easily do you think that would be integrated into practice in the real world? The second question is, with there being 2 components of something like EYP-1901 with it being the TKI and the delivery technology, what -- and Dr. Wykoff, you pointed out the promise of the neuroprotective benefits, what are your thoughts on the differentiation of those 2 components of vorolanib and Durasert?

Yes, I'm happy to jump in there first and Carl, I certainly want to hear your opinions also. It is a burden for patients to get an injection in the eye. And the patients never heard of that and they hear I'm going to put a needle in your eye, it's a big deal, that's a big discussion with patients. And so when you overall trivialize because we do it so frequently and it's highly effective and extremely safe overall, but it's a big deal from a patient perspective. And so I think there is some incremental challenge to doing additional injection. I don't think that is a meaningful or significant increased challenge. But it's something, it's a workflow issue. I think it's very achievable in clinical practice. And you're seeing many other development programs look at that currently with ongoing, for example, Phase III program that are dual injections routinely. So this is doable and I think something that is clinically implementable. And then you bring up 2 good differentiators here for 1901. I think the slow-release mechanism here with the Durasert technology is quite meaningful, giving you that foundational or baseline sort of VEGF suppression. I think the VEGF suppression is key, and that's what we're measuring here. But I am a big believer in the additional mechanism of actions of tyrosine kinase inhibitors in general and now what we're seeing here with vorolanib. I think there's a lot of untapped and incompletely understood possible benefits of additional tyrosine kinase inhibitors across multiple receptor pathways. And I think what we're seeing is potentially the tip of the iceberg here with the neuroprotective data that Said presented.

Jay or Dr. Duker or Dr. Regillo, do you care to comment on that?

No, I can definitely agree with Charlie. With regards to tolerating a second injection, in the course of a clinical trial, 30 minutes, [indiscernible] now quite a bit in other program and it works just fine. In practice, it doesn't necessarily have to be 30 minutes. So that could help with [indiscernible] practice, doesn't even need to be the same day. We'll be treating our patients with anti-VEGFs and say, all of a sudden, we're going to introduce something that's going to give you much more very [indiscernible] of these infections. I'll do it with you at this [indiscernible] then see how it goes. So I think in practice, may not even be necessary. Here in the context of the trial, we have to keep it all the same.

Okay. And then one more question for the company. Just wondering about the NPDR study. First of all, I noticed that you sort of narrowed down the time line window of initiating this quarter. So congrats on that. And then second, could you just remind us on the expectations around enrollment and timing of data for that trial and how many clinical sites you anticipate for that trial.

I'm going to have Dr. Paggiarino answer that. So question was the timing of both. Why don't you speak to the wet AMD trial, Dario, as well as the NPDR trial and number of sites, et cetera.

Sure. So the wet AMD trial.

Please speak up.

Yes. Okay. Sorry. So the wet AMD trial will include 50 sites and we plan to enroll in approximately 6 months. The NPDR is going to take a little longer. So we anticipate again to start in this quarter, but we anticipate an enrollment over approximately 9 months. And that would be conducted in about 30 sites.

It's a great presentation, and this is I-Eh Jen from Laidlaw & Company. Just got three questions here. The first one is dealing with DAVIO 1. From months of 4 to 5 and 2 to 6, I think that's from 70-some percent drop to 50%. My question is that even the patient size is small, did you guys figure out what kind of a share characteristic of the patient which dropped from 70% to 50%?

Jay, maybe you can answer that. That's from Yale regarding drop. Yes. So if you heard the question, great, drop off.

And I'm going to repeat what you said, yes, the N is so small, it's really hard to make a conclusion. What I would say though is if you look at the time to first rescue but eliminate the 3 eyes that got rescued at month 1. There is a trend in the high dose to be rescued later than in the medium dose. So we do think there's a bit of a dose response. But as for the characteristics, the N is too small. I would also like to point out though is some got their supplement at month 4 and they never got another one for the whole year. We had 1 who get supplemented at month 5, I believe, and never got another one. And so that need for supplementation. We don't believe is an indication that the implant has actually gone subtherapeutic.

Okay. Great. That's helpful. And in terms of DAVIO 2, the first 2 weeks period, there is the treatment of the conventional therapy before you started the 1901. What was the rationale behind that? And could that help to alleviate or reduce the patient which is not better controlled from the initial therapies?

Okay. You want -- I'll have Dario and then, Jay, you take it.

So we had discussions with the agency, with the FDA, about what a study would look like, especially we try to anticipate what a pivotal trial would look like because we -- as much as we can, we want to test a design in Phase II that hopefully will replicate with high level of certainty in a larger population in Phase III. So the rationale for the 3 injections is really something that the FDA indicated specifically for the control arm. In other words, they -- despite the fact that these patients have been pretreated to some extent, the FDA specifically asked that the patients randomized to the aflibercept arm to be actually dosed monthly. And then, of course, within label. So I think the intent there is to be able to maximize the efficacy of the control arm despite the fact that this is not our initial -- essentially a non-naive population. So that's the rationale for the 3 injections of aflibercept. And of course, we also plan to do that in the dose arms, the 1901 dose arms, because we want to make sure that everybody is really at the end of the induction in the same place when it comes to evaluating the effect of the insert. So the -- and that's the decision for the insert to be placed right after the third intravitreal injections of aflibercept. I don't know, Jay, do you want to add anything?

No, you covered it perfectly, Dario. It was really the agency's insistence in the pivotal that we reinduce the control arm, but they had no objection to us reinducing the 1901 arms because the rationale was by the time you read out in the pivotal 9 months later, the effect of the Eylea in the 1901 arms would have washed out.

Okay. That's very helpful. And the last question I have, either for Dr. Regillo or for Dr. Wykoff, which is that how would you assess a patient become stable from the initial therapy to introduce -- potentially to introduce 1901? And flip side on that question later on is that we have seen patients in 40% or so in 9 -- or 10-month period. And when you think that the patient should take the second redosing of 1901 and what might be the criteria for your decision?

So it's got to be Charlie because Carl signed off. So Charlie, go ahead.

Yes. Thanks for that question. I think I'll take the second part of it first, right? The pharmacokinetics now of 1901 are very clearly described, right? By the end of 6 months, there were decreased significantly the active drug. And then by 9 months, it's probably not clinically active anymore. And so I think especially if you're focusing on the DAVIO-1-type patient, these frequent need injections, I would want to consistently treat them over time. So I wouldn't want to wait until the fluid recurred to retreat them in the real world. I would want to treat them every probably 6 months consistently long term. And then asking -- addressing the first part of your question, which is sort of the question as I've heard it was how would you incorporate EYP-1901 during sort of the induction phase when you have [indiscernible] stabilizing these eyes with monthly Eylea injections on label for Eylea even though it's a previously treated population and then trying to keep them stable long term without this need for repeated bolus injections. In the real world, it could be certainly used in that way. It could also be used in combination with anti-VEGF injection at baseline. So for example, my own practice, I can imagine not waiting for a few months to use EYP-1901 and I would use it probably at baseline in conjunction with anti-VEGF agent, if I had my choice. And again, the reason for that is I'm going to get a full anti-VEGF effect with the bolus injection of EYLEA or Vabysmo or Lucentis, whichever drug we want to use. But I'm really hopeful that this TKI has additional benefits beyond the exudative events that we're seeing. And I want to get that additional benefit as early as possible for my patients.

Other questions?

This is [ Jake ] from H.C. Wainwright. I have a quick question to the company. From a competitive advantage standpoint, what are your expectations from the Phase II study with 1901? Obviously, there are a lot of assets, a lot of anti-VEGFs being developed in Phase IIs and Phase Is, either suprachoroidally administered or intravitreally administered. So what are your ideal expectations from the Phase II study?

Yes. So the question was what our expectations for Phase II given the competitive landscape and how do we see this stack up to some of the other products that are in development or even on the market? So I'm going to actually have, Jay, if you want to take that?

Sure. What we hope to see is continued safety in this population. We hope to see a visual acuity change that is numerically noninferior to Eylea. I stress numerically because the study isn't powered enough to show necessarily an absolute noninferiority margin. And we hope to see a significant reduction in treatment burden that would be a benefit to the patients, practitioners and payers and also noticed by the FDA as an advantage to the patients. So we have a different patient population in DAVIO-2. And we would hope that this different patient population will respond to 1901 even better than what we saw in DAVIO-1.

Jay, maybe you can comment some on the delivery intravitreal of EYP-1901 versus what we see with some others, which is -- the large molecules clearly are intravitreal as well, but we've got a port delivery system, we've got suprachoroidal out there, just potentially how would you see that as a former practicing retinal surgeon?

So I think, again, we've got the experience of 80,000 patients getting Durasert around the world. So we really pretty much know how it behaves. I was one of the first to put the Durasert form of anti-CMV retinitis [indiscernible] almost 30 years ago. And I still have patients in my practice that have their old [ ganciclovir ] implants in their eye and it's inert, it caused no problem, no inflammation. So I think from a safety perspective, we've got a true proven track record. Charlie touched on the safety aspects of the port and I really would rather have him perhaps comment on our competitors if you really want that.

Charlie, do you want to take that?

Yes, sure, happy to take that. I agree with the comments that Jay, you made. I think safety here is critical. In so many development programs over the last 5 years, we've seen challenging adverse event profiles and to have such a clean profile of the stage with all this historical experience with on-label products already is quite reassuring from a clinician's and a patient's perspective. And then where this will exactly fit from a durability perspective? I think we still need to wait and see additional data, right? We have a limited number of patients here. We're seeing a meaningful reduction in treatment burden and that is quite promising, especially to be able to do it without a device in or on the eye, I think, is quite meaningful and quite differentiated.

Daniil Gataulin from Chardan. A question for Dr. Wykoff. So in real-life setting, how do you see balancing the monitoring regimen with the extended treatment regimen to make sure that you don't miss patients whose disease is progressing?

Yes, it's a great question. And just to summarize, it was sort of how do you think about using this drug and then potentially related to retreatment so you don't let the disease get out of control. This is where I think the pharmacokinetic descriptions that you saw before from Said and Dario are quite meaningful because we know the pharmacokinetics of this EYP-1901 very well. So by 9 months, you're probably at a place where you have minimal active drug left in the eye. And so for eyes of wet AMD that we know to be a chronic disease with the large majority of patients needing ongoing therapy long term to optimize their visual anatomic outcomes, I think I would certainly use this in a repetitive fashion and not wait for patients to have recurrence of their disease process before getting retreated. And maybe the first time you used it, you would sort of look at the interval so that if they were dry at 6 months, you might wait until 7 months, you might wait until 8 months and then see when they start to have a little bit of recurrence of fluid. But then once you found that interval, I would be a believer in the consistent pharmacokinetics of this drug and continuously retreat them at that same interval. So Carl briefly mentioned it before, but he and I and many others have been involved with prospective trial looking at the treat-and-extend paradigm with our current bolus therapeutics, and it seems like the majority of patients, although not all, have a consistent retreatment interval. And I would expect this drug to be the same, whereas some eyes would recur possibly at 6 months, some recur at 8 months and define that sweet spot and then use that repeatedly over time.

Got it. And a question for the company. Is the implant for NPDR exactly the same as the one for wet AMD in terms of release kinetics?

Jay, could you just repeat that question? I want to make sure that everyone heard it properly.

Sure. Are we using the same implant in the NPDR study as we are in wet AMD? The answer is yes, same dose, same implant, same injector.

Jay, maybe you could comment though, I think given the fact that we -- NPDR, you've heard Dr. Wykoff and I think Dr. Regillo mentioned, it would be great if it could go out 9 months. Why do we think it potentially could go out longer in NPDR versus wet AMD with the same implant?

So first, there may be a disease altering aspect to this when you suppress VEGF and perhaps have some neuroprotection constantly for 9 months, you may get some disease-altering changes. The second thing is that diabetic retinopathy tends to progress slowly so that if your drug is out of the eye at 9 months, it might be 12 months or 14 months or longer before you might start to see the effect clinically wear off. And this isn't a situation like wet AMD where a recurrence is known immediately to the patient, it's known immediately to the doctor and can cause severe visual loss. NPDR just doesn't work that way. So even though the drug may be technically out of the eye in 9 months or at least subtherapeutic, we may end up seeing a longer effect.

Thank you.

One follow up here.

Yes. Go ahead, one other -- another question.

Yes. This is [indiscernible] from B. Riley, one follow-up here. So just curious when you house these 2 trial design on the...

Can you put the mic closer? Thank you. So it's -- we're have a hard time hearing.

Yes, sorry about that. So when you have the Phase II trials and at the third dose, you will -- at the same day, you'll have 2 injections, both anti-VEGF and the TKI inhibitors. And just curious what's the total injection volume there? And you need to keep those patients at the clinic for a while to monitor the ocular pressure. And it will be great if you can put into the context of your past experience with Durasert where you may have some coadministrations at the same day, just want to hear some comments there.

Okay. Jay, why don't you take the co-administration with DAVIO-1, do we see any IOP elevation? And then actually, Dr. Wykoff, you can answer the clinical practical issues that you might see.

So we didn't see either short-term or long-term IOP elevations with the inserts. Charlie, you'll comment on this, too, after an Eylea injection for a minute or 2 or up to 5 minutes, you can see a spike in IOP. But by 30 minutes, it should be back to baseline. And that's why other studies that have involved 2 injections, that 30-minute separation is what the FDA has recommended. So we'll be monitoring it, but we don't expect it to be a problem.

Yes. I agree completely. Clinically, we do this all the time. We're going to get volumes into a fixed space so you expect the pressure to go up. If you don't, that would be highly unusual. And we monitor patients routinely in the real world to make sure that their vision is stable, that they can see after the injection. And some patients do have a challenge with persisting IOP elevation, that's been well published, with repeated injections over time. I mean with a device that bioerodes like this, I would probably expect actually less of an IOP response to a fluid injection.

I want to just ask, do we have any questions coming in from our call-in audience? I'm asking Stern. I think we're taking questions from analysts on the phone at this point.

Look, we have a longer [indiscernible]...

Okay. Other questions? I'm sorry.

Yes. This is George Elston. There is an online question from Yi Chen from Wainwright and it's -- first question is why only was 1 patient enrolled in the low to mid-dose in DAVIO trial? And Jay, maybe you can answer that.

Yes, I can. So as you've heard, we can insert up to 3 inserts in a single injection. And as we enrolled, the low dose in the medium dose arms in DAVIO-1, there were no issues. When some of the investigators went to insert all 3 inserts in the high dose, they didn't always get all 3 inserts in. In one case, they got only one insert in, that became the low medium arm. And in 3 cases, they got 2 inserts in, that became 3 extra eyes in the medium dose. Dario Paggiarino very rapidly identified what the issue was and it was really just technique. This injector system is a modified YUTIQ injector and there's a plunger and Dario noted that as you got to the third insert, the resistance was greater in the plunger. And what we think happened is some of the investigators just abandoned the injection too soon. So we educated them and we did a little work in redesigning the plunger system for the next trial and we think we've solved it.

Okay. His follow-up question is probably for both Jay and Dr. Wykoff. Can we talk -- can you talk about 1901 over gene therapies being developed for wet AMD?

Go ahead, Charlie.

Yes. Great question, important question. Many ongoing gene therapy programs given by intravitreal injection and via subretinal injection during vitrectomy and also suprachoroidally, the early data there is positive, that you can get production of an anti-VEGF protein intraocularly over many months to years. There are -- there's a unique adverse event profile that we're seeing be better defined over time for each of these routes of administration. And you have one sponsor in pivotal programs with the subretinal delivery during vitrectomy. So I think that there is definite potential value there for the space. The value that I think 1901 brings in that sort of environment is that this is a drug with a limited duration of activity, which is a plus and a minus. But related to gene therapy, one thing that you need to remember is it can't be turned off as far as we understand gene therapy currently, which could be a plus but it could also be a minus. And the value here is that we know the pharmacokinetics very well and the drug has a finite duration of activity and then needs to be reused. From a safety perspective, I think that's valuable. If there is some effect of a drug, it's nice to be able to turn it off and it's nice to be able to reuse it on a patient-specific basis.

Okay. We do have some questions from online. I'm not sure for -- if Stern, if you can tee those up because we do -- I do want to give -- the people who have asked questions online that we answer those. So maybe you could either bring them up now or you could -- on your mic, Christina, if you could just read some of those?

Yes, sure. So there's one question from Anupam Dalal. Can you contextualize the retreatment criteria for the wet AMD randomized study? For example, how would you compare versus PDS versus other contemporary wet AMD randomized studies not using PDS?

Okay. Jay, I think you heard that. Could you maybe answer that? How do we compare our DAVIO-1 retreatment criteria versus some of the other clinical studies that were done?

Well, Charlie can step in here, too. But to my knowledge, PDS is the only Phase III trial that had retreatment criteria. I don't know if Progenix Bio's Phase III does. Charlie, you may know better than I. But what we try to do with our criteria was acknowledge that you can have increased fluid, including subretinal fluid, but not affect the vision. And you may recall that in the refillable port Phase III, they allowed up to 150 microns of new fluid before rescue. We also were much more interested in keeping visual acuity near stability and that's why we altered the visual acuity supplemental criteria to be 5 letters. So other than refillable port, I'm not aware of any other program that has had retreatment criteria to Phase III. Charlie, are you?

Yes. Thanks, Jay. I agree with all your comments. If you broaden it to look at other development programs that aren't in Phase III, it is remarkable how these retreatment criteria can be variable. I think, overall, the retreatment criteria you're seeing here are quite conservative. I think that's important from an investigator and a patient perspective. Patient safety, patient visual outcomes are paramount. And we -- what we don't want to do is to try to gain the system such that you allow patients to lose vision and then be able to claim durability. And the goal here of this is to optimize outcomes, optimize anatomy and vision long-term for patients. Other point I would make, based on Dario's line, the bullet point at the bottom of the retreatment criteria which I think maybe the most important one, which was, there is some level of investigator discretionary. If the investigator feels that the patient needs to be retreated, they can be rescued and retreated in this program, and that's quite meaningful. I think that speaks to the confidence in the biological activity of 1901 over time. Is there other programs that don't allow that? We don't allow an investigator to say "hey, for a safety reason, I want to retreat here to make sure we optimize outcomes. But here, you're really seeing that.

Okay. Do we have any other questions coming in? I think we might be having a little bit of a problem getting some of these questions in. Other questions from the audience while they tee up others, Christina?

Yes, I have one more question from online. So the FDA has typically and explicitly ignored treatment burden as a metric of benefit historically. Have your more recent conversations indicated something different?

No. It's very clear, the FDA still looks at BCVA as the primary end point. And we do not expect that to change it. Look, at the end of the day, it's all about vision. So -- but in the real-world practice, I'll ask Dr. Wykoff, if you want to comment, even though the FDA won't accept that as an endpoint, how that impacts in real-world practice.

Yes, it's quite relevant. You can't hear me tell me I think [indiscernible] because I think diabetic retinopathy is a great [indiscernible] here and we briefly talked about it before where the approval endpoint, diabetic retinopathy severity improvement, very relevant to many different things, but it's not really a clinical endpoint that we use. What we use is progression to PDR and development of DME quite different than the approval endpoint. And so, right, what's approvable is obviously extremely relevant to development programs. But then clinically, clinicians will look at a drug like this, potentially slightly differently. So reduction of treatment burden in the real world is a paramount importance. It's a paramount importance from a patient perspective, just ask them. You'd rather get fewer injections and they would 100% say yes. But then even more important on a population basis is if we get more durable therapeutics, the hope and the promise is that we'll see better visual outcomes long term because we'll be able to retreat patients more consistently with their biological needs and not see this visual decline that we're seeing in every real-world study to date.

I just have one more comment. I don't think it's fair to say the FDA ignores reduction in treatment burden. It's just not a primary endpoint. I've said this earlier, if we have noninferiority visual acuity and we're safe and we're tolerated and we have a significant reduction in treatment burden, even if some eyes still require supplemental injection, I think the FDA would look favorably at that since each injection carries risk and get a patient's lifetime, the risk of endophthalmitis, even though it may only be 1 in 5,000 with each injection, it's a cumulative risk.

Yes, if I may add. I've been working with FDA for many years, absolutely, the primary objective is noninferiority here. But at the end of the day, they really do an assessment based on benefit to risk. And granted that this is a safe product and its non-inferior in terms of BCVA, reducing the burden for the reason we said, can only improve that ratio in favor of the product.

So this is regarding the endpoint. What about the duration of the endpoint? I think most AMD studies have a 12-month endpoint. I think the company has talked about maybe a possibility of the [indiscernible], can you just talk about that?

Yes. So let me just repeat the question. The question is what about the primary endpoint time frame. Most studies had a 12-month endpoint. We've been talking about a 9 -- 8- to 9-month endpoint. Dario, why don't you answer that?

Yes. And absolutely. I mean we want to learn from the single injection study, the duration, but -- and we unmask, as I mentioned, 6 months after the insert, 8 months essentially, but absolutely, we anticipate that as we move into a pivotal trial, that the time point would be very typical, around 12 months as the FDA has actually previously indicated for other programs. And so to be more specific, they -- given the 3 induction injections, they specifically say you have to wait 1 month after the last Eylea injection, it takes you to 3 months. At the 9 months, that makes it 12. So we anticipate that 12 months will be probably, yes.

Let me just clarify because this can get a little confusing. So right now, remember, our Phase II is not aimed for pivotal. So -- but once we get to Phase III, we expect that you will have it read out 9 months after the last injection. Because we plan to do 3 induction doses, that takes you to 12 months. Does that make sense? Yes.

One more. For the DAVIO 2 study, are you using a blended efficacy measure at [indiscernible]?

So for the DAVIO-2, we unmask at 8 months, right? So we plan actually to unmask at 8 months, so we blend the 7 of 8 months. Yes. So the blending, as you all know, has advantages from a statistical standpoint, so we plan to do so.

Not to mention, given that the control arm will be receiving Eylea every other month, the blending of the 2 readouts for vision balances that fact.

Okay. Other questions? Christina, do we have some coming from online?

Yes. One moment.

Any more from the audience? Yes, [ Yale ].

Maybe just a quick question to follow up on the previous one, which is if pivotal study is 12 months as the endpoint, we anticipate a big 6-month subsequent [indiscernible]?

Jay, why don't you answer that? This is on for the Phase II study, should we anticipate a retreatment at 6 months or not? And then we can -- Phase III. Thank you. Thank you for clarifying. Phase III.

That's the plan at present.

So the answer is yes. For Phase III, we plan on doing a reinjection at 6 months.

I would add though that I say it's the plan, we really have to get a little more dosing and longevity information before we make that definitive.

Okay. I don't want to keep people long. If we don't have any more, Christina, I think we need to...

There's just one more question that we'll take from the online. So would management be willing to discuss the potential applicability of tech to other targets such as complement inhibitors and thinking about geographic atrophy?

Yes. I'm going to have Dr. Duker answer that.

Yes, we've been thinking about it for a while. I think the value we can add to a molecule is longevity of action. And I personally believe that both C3 and C5 are validated targets in geographic atrophy. So a trick or a hard part right now is finding the optimal C3 or C5 blocker or perhaps another blocker from the complement system that would benefit from being in Durasert. And the company has been extraordinarily active in the last 9 months looking for such a partner.

Okay. Any other last questions? All right. I want to just take a moment, first and foremost, to thank Dr. Wykoff and Dr. Regillo who took time out of their busy practice. We greatly value your wisdom and insights and can't thank you enough for taking this time. I thank you. And then I also want to thank a lot of the support staff, the Stern team, our PR firm, Green Room. The technical staff here, who has done a magnificent job. The food staff here, the University Club has been phenomenal helping us get this set up. And then many of the EyePoint employees. You don't see what goes on in the background to make this work, but there's many, many employees involved. Joy, in particular, thank you. She does a lot of the logistics here. And then George, who really helps spear all of this, thank you. And the entire executive team who is very involved. It's a lot of hours that get put into this. We hope you found it useful. And I appreciate your questions, very insightful. And we look forward to continuing to bring 1901 through the clinic and hopefully providing some real benefit to patients. Thank you very much.