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. Thank you first and foremost for coming today. We really appreciate it. We're very excited about where we are with EyePoint Pharmaceuticals, and 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 to just go to our website where our SEC statements are. I do wanna just open up first and foremost and say, and just remind everybody, you know, this is a very capital intensive and a risky business.
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 the day, that's what this is all about. Because it is a risky investment, I don't have to tell the investors here, you know, you have to have a stomach for this business because of the failure rates that occur, and it's very capital intensive. I do wanna mention, for those of you who are paying attention, and encourage you, others who maybe have not, pay attention to 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 gotta be the right legislation. 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. George Elston, who is our Chief Financial Officer. Next slide. Dr. Dario Paggiarino, who is our Chief Medical Officer, and Dr. Said Saim, who is our Chief Technology Officer.
I'm also pleased to say we have two very distinguished guests who are here with us today, and I very much appreciate it. Dr. Carl Regillo, who will be videoing in, who's the Professor of Ophthalmology at Thomas Jefferson University and chief of the Retina Service, Wills Eye Hospital. He's also a founder of the Wills Eye Hospital Retina Research Unit in Philadelphia. Thank you, Dr. Regillo, for taking the time to video in. Then Dr. Charles Wykoff, who is also joining us here today in person. Dr. Wykoff is the Chair of Ophthalmology at the Blanton Eye Institute in Houston Methodist Hospital. 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 and 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. Dr. Carl Regillo will present our recently just announced 12-month DAVIO data at the American Society of Retina Specialists that just happened this week here in New York City. 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.
We'll be talking about that here today. Dr. Dario Paggiarino will cover the phase 2 plans for EYP-1901, give a YUTIQ clinical update. YUTIQ is our very important in-line product for the prevention of posterior segment uveitis. 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. For a company overview, again, most of you know the company, but I think it always bears repeating, particularly for those who are maybe 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 Pharmaceuticals. We like the mechanism of action, which is different, that vorolanib provides. 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 1 DAVIO clinical trial, and you'll hear about that today.
We'll talk as well about our phase 2 clinical trials in wet AMD and in non-proliferative diabetic retinopathy, which we expect to have our first patient dose this quarter of 2022. I mentioned briefly about Durasert. Let me just remind everybody, there's two main benefits to this drug delivery technology. Number one, it provides sustained zero-order kinetics, so you don't get what we call first-order kinetics, which is this 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 eight months before you start to see a drop occur, and Dr. Said Saim will go through that. Secondly, and probably most importantly, so far, Durasert has proven to be a very safe drug delivery for the eye.
We've got over 80,000 patients that have used Durasert in the four FDA-approved products that use this technology. Now with our DAVIO data through 12 months, it continues to show a very nice safety profile. In this area, that's most critically important. Then lastly, we've got a very strong balance sheet, which we're pleased with particularly in this capital environment that we're in today. $171 million in cash and investments as of June 30th. 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 2 data, and our commercial franchises are positioned for break-even in 2022. I'm now going to turn it over to Dr. Jay Duker, who will be on video. Jay.
Let's see. Good morning, everybody. I sincerely apologize for not being there in person. Nancy gave you the reason. My joke was that I couldn't find a tie and therefore couldn't get into the university club. That's why I couldn't show up. Next slide, please. Could you show me the slides as well on the Zoom? Nancy introduced Durasert, and again, there are four FDA-approved products that include Durasert. Of the six FDA-approved intravitreal sustained delivery products, our technology is in four 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.
As Nancy pointed out, the big advantage of Durasert is continued stable release of drug over four weeks, months or even years, depending on how we decide it. Our product is unique. We also have licensed the ILUVIEN product to Alimera. Previously, we developed Retisert/ Vitrasert, both of which were licensed to B&L. EYP-1901 is slightly different than those other products in that the polyimide shell that covers the drug matrix has been removed. That leads to bioerodibility of EYP-1901, along with a burst of drug on the surface, which is probably beneficial. Following this burst, you get constant zero-order kinetic release over many months. Next slide, please. On to the next slide, EYP-1901 vorolanib.
Just a little bit more about EYP-1901. Again, this is a single intravitreal injection. Of note is that we can deliver up to three 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, zero-order kinetics. The drug we're using is called vorolanib. Vorolanib is a tyrosine kinase inhibitor with great activity against all the VEGF receptors. It binds, as I said, all isoforms of VEGF. Interestingly, vorolanib was previously studied as an oral drug for wet age-related macular degeneration. It actually went through both phase one and phase 2 trials. Those trials have been published, and if you're interested in getting the reprints, we can supply them to you.
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 2. I do wanna point out there was no ocular toxicity noted. Next slide. This slide shows a 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 a silicone 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 1/5,000th of the volume of the vitreous cavity. Next slide. This slide covers our IP. 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 gonna now introduce Said Saim, who is our Chief Technology Officer, and Said's gonna go into some of the science behind vorolanib and bioerodible Durasert insert. Said?
First, why vorolanib? One can ask, why are you selecting vorolanib amongst the 40-something TKIs that have been approved by the FDA for mostly 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. 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 family or growth factors, with especially strong affinity for the VEGF Receptor- 2, 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. The molecule is designed specifically to be optimal for these retinal diseases. In addition, as Jay mentioned, the molecule was used in a phase 1 and phase 2 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.
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. 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 other receptors that may be beneficial. 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. What is vorolanib? Vorolanib was specifically designed to reduce off-target binding of a molecule, sunitinib, which is in 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 quite interesting differences in receptor binding, which enhances the value of vorolanib. Next. This is the VEGF signaling pathway of vorolanib. Basically, it binds the intracellular domain of tyrosine kinases. It targets all three receptors, 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. Now we're gonna go into some of the proof of concept studies that belie the value, the anti-VEGF value.
We're gonna 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. 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 VEGF. This effect happens at very low concentrations.
You can see at 50 nM as well as 100 nM, both of them are highly inhibitive of blood vessel formation. 50 nM 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 affect a reduction in phosphorylation. Phosphorylation is the mechanism by which basically the pathways that lead to leakage and permeability take place. In this case, you could see that levels as low as 10 nM are sufficient to inhibit phosphorylation.
This is important because Jay was talking before, this technology that we're using in either YUTIQ or EYP-1901 is designed to release microdoses, low levels of the drug over an extended period of time. 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 full high that you may actually create potential toxicity. Next. 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 at 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. 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. Next. Now, this is not the regular anti-VEGF. This has properties that go beyond anti-VEGFs. In this case, we just finished a study, a retinal detachment study.
This is in a mouse model where you basically take sodium hyaluronate and viscous solution and inject it between the RPE and the photoreceptor. You detach the RPE from the photoreceptors, and it stays there for quite a while. You give either vehicle or vorolanib suspended in vehicle by gavage 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. 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 faint or faint color.
On the visual side, you could see that there's a higher visual acuity function of vorolanib-treated mice versus vehicle. 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 suggestive potentially of neuroprotective properties. Obviously, this is just a function. We also went into looking at the structure of the retina. Here again, we find 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. With which, 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. What are the key takeaways from the data we just presented? This is different from your regular anti-VEGF. It binds the intracellular domain of receptors and not the ligand. We have compelling efficacy data as an oral therapy in two clinical trials with no ocular toxicity. We have data, obviously, that shows that even levels as low as 20% of IC50 for the VEGF Receptor- 2 can inhibit phosphorylation. That's an important finding because we will use this vorolanib together with the Durasert technology to provide microgram per day levels, consistent microgram-to-day levels.
We have data from both YUTIQ as well as EYP-1901 that's sufficient to provide strong efficacy. 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. As I said before, Jay is gonna go into more details about how this molecule also prevents conversion from dry AMD to wet AMD. This is kind of special finding, special characteristic of our molecule, and Jay is gonna go into the actual data. Quite exciting findings for this molecule. Now, we're gonna go into EYP-1901. Everything 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 in a dosage form that provides you the right release mechanism over the correct extended period to actually achieve its intent. The formulation technology used in EYP-1901 is based on the same technology as YUTIQ. YUTIQ is our product. It is for non-infectious posterior uveitis. It's been on the market for quite about three, four years, and it's doing really well, and we show some of the results from the phase 3 trial. It provides the benchmark for zero-order kinetics and for how microdoses per day of a drug can actually achieve very high degree of efficacy. This YUTIQ product releases over a period of three years.
It's got 180 mcg. It releases in a zero-order over three years. Here, we show the assay of explants from rabbits over a period of just one year, and it shows how the assay changes over time. You can see over a period of one year, it releases about 60 mcg, which is equivalent to about 0.2 mcg per day over this period. The release is zero-order, meaning the release rate is constant. You provide the tissues with constant zero-order release, thereby ensuring that the levels in the tissues, such as retina or choroid, are constant throughout that period of time, and we'll show some of these data. This is Kaplan-Meier plot that shows the probability of recurrence of uveitis in YUTIQ-treated patients versus sham-injected patients.
You could see that at one year, 75% had no recurrence with this microdosing. It went through three years with only 50% requiring. It's only past the three-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. You can see here, similar to YUTIQ, these are also explants from rabbit that were assayed. Three different doses, and you could see that the near zero-order release between 8 and 10 months.
We don't want three years for wet AMD. We want six months. This formulation was designed to release over eight to nine months to ensure that we consistently cover the six-month time point. Yeah, basically. Can you go back, please? Yeah. The inserts are essentially depleted past eight months, which confirms, as we'll see in the next slide, the pharmacokinetics in ocular tissues. As you can see, the three doses, the percent release versus time is the same, so we have true dose proportionality and, at these, microgram levels per day. 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 are very low, below therapeutic levels. 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 eight-month periods. After the eight-month period, when the drug is starting to get depleted, the levels in these tissues go down and below therapeutic levels. 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 we see this on the right side here. You see an enlarged illustration of the inserts at time zero before the being dissolved, and this is at 12 months. You can see the difference in size between T zero and after 12 months of dissolving in vitro. Slowly, the insert goes away. We have similar data from in vivo studies being conducted in rabbit. We're 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. We don't have that. We wanna make sure that drug is fully dissolved, and then the insert goes away with it. Next. What are the key takeaways from this preclinical and safety data we just. Clearly consistent zero order of mcg per day through nine months. This microdosing 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 1 trial that we conducted. We see steady-state levels in ocular tissues for eight to nine months at levels about an order of magnitude higher than IC50. The release is dose proportional.
This is important. If you wanna put a higher dose, you will get from this technology, you will get dose proportionality. The important thing also is that inserts are bioerodible over time. Next. 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? We mentioned these studies of oral vorolanib, and this slide summarizes the phase 1 trial. Phase 1 trial was open label, six-month study, dose escalation. There was no control, and of course, it was delivered orally. Twenty-five patients were initially enrolled. The results showed best-corrected visual acuities were maintained within four 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 1 trial was 50 mcg every other day, which was clearly subtherapeutic. If you take those patients out that were on that low dose, 72% of the patients required no supplemental anti-VEGF injection during the six months.
The OCT thicknesses were reduced, and in the several treatment-naïve patients that were enrolled, they were reduced by about 80 microns. Next slide. The company that was developing vorolanib orally was quite encouraged by those findings. Remember, vorolanib was felt to have fewer off-target systemic side effects. That's why it was selected to try this in wet AMD. Unfortunately, in the phase two trial, the systemic side effects really became apparent. What you're seeing here is the results of the patients who completed the trial. It was approximately 150 patients enrolled. In this trial, there was really strict supplemental anti-VEGF criteria. I'm sure you've heard of various criteria of, you know, 50 microns of new fluid, 75 microns, 100 microns of new fluid. In this trial, it was any new fluid.
OCT, as you're probably aware, is highly sensitive to fluid. The investigators were instructed to give a supplemental injection if they saw any new fluid. Part of the rationale here was that some of these patients were getting placebo. The company investigators didn't want a placebo patient to go very long without an anti-VEGF on board. In the placebo group, over a year, the median number of anti-VEGF injections was 9. Now, in the real world, we give about six anti-VEGF injections per year. You can see this is a pretty highly treated group. You can also see with the progressive dosing that there was a dose response with about 4.5 supplemental injections in the highest dose.
Actually, 20%, one out of five, went the entire year without supplement in the highest dose, even with that really strict criteria. There was no ocular toxicity. There was 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. Patients who entered the study with wet AMD in one eye but not in the fellow eye, in the phase 1 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. If you look at the phase 2 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. We are very excited about the results of our phase one trial from both a safety and efficacy perspective.
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 my alma mater, Wills Eye Hospital. Carl, why don't you go ahead and give us the phase 1 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 ASRS meeting. In fact, this study was one of the highlights of the program, because we now have the full 12-month study results on all patients in the phase 1 DAVIO study. Can everyone 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 1 clinical trial in patients with wet AMD.
What we did is enrolled patients that were previously treated, active neovascular 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 exudation, defined here as greater than 75 micron increase in OCT or a loss of two or more lines, which is 10 or more letters, best corrected visual acuity BCVA from neovascular AMD.
Any new macular hemorrhage is also indicative of significant new wet AMD activity, so that would trigger a rescue. This is a phase 1 study, 12-month duration, multicenter, open label, so it has no control, but it is dose escalation, as you would expect from a phase 1 safety data. We're looking at patients that received a treatment, an anti-VEGF treatment, the so-called standard of care, at screening, and then shortly thereafter, within seven days or so, received a single dose of EYP-1901. That's the baseline day zero visit, and at a dose range from 440 mcg- 390 mcg, 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 eight- week, every four weeks, so patients were followed monthly over the course of 12 months. Next, slide, please. You can go to the next slide. Thank you. Originally, it's a three-arm, three-dose study. There was an extra dose in there with that one patient, the low mid dose. You have three patients on low, getting low dose. The one patient getting the low mid dose inadvertently from one insert rather than three, supposed to be high. The mid dose, n is eight, and high dose, number there is five patients. This is how the study was designed.
Primary endpoint, of course, phase 1 being safety, looking at ocular, non-ocular treatment, emergent adverse events through 12 months. Secondary endpoints, of course, looking for a biologic signal and activity here, including durability, supplemental anti-VEGF therapy through six months and even now through 12 months, and then change in mean BCVA from baseline and also change in mean CST, central subfield thickness, as measured by OCT from baseline. Seventeen patients were enrolled. Thank you. Here are the baseline characteristics, very typical of a neovascular or wet AMD 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 had. Which meant that most patients were responsive and had good control of exudation, but not necessarily everybody at baseline at 299 microns. Normal being, depending on the machine, 300 microns-310 microns. Mean number of treatments, anti-VEGFs 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 six weeks or so, eight injections in that year on average, and the median time from wet AMD diagnosis was 17 months. Next slide. Here are the results.
For the first time, actually, we're seeing 12-month results, and that's what was new at the ASRS meeting this past weekend, 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 detachment, no implant migration to the anterior chamber, which can 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 were only two, both very mild, self-limiting, and did not result in any visual problems.
One mild case of anterior 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 intra-retinal 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. We did not see dose-limiting toxicity. Next slide, please. Here's the six-month results. This is the swimmer's lane plot, which gives nice patient-level data both before enrollment, before the injection of 1901, and then, of course, over the six months of close observation at monthly intervals, looking at both safety and the ability to control exudation.
We see here a significant reduction in the treatment burden at around 79% at six months. To the left, of course, before time zero is the year before enrollment in the study. Most patients are getting very frequent injections, many of them monthly or every six weeks or so. 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.
We'll have evidence or proof that disease is under control by looking at mean BCVA and OCT over time, which is coming up with the next slide. Here's now the new data through 12 months, and you can see very, very similar with durability. In fact, a number of patients went the entire 12 months without needing a rescue. These are patients known to have active disease. We have information how these patients looked beforehand. They were getting frequent treatment. So that, in and of itself, is very impressive. Most patients went considerable times from day zero after 1901 injected without the need for a supplement. There were some exceptions to that. You could see three notable exceptions getting a rescue the very first month.
Those patients, of course, had an anti-VEGF injection shortly before, about a week before, EYP-1901. They represent poor responders or aggressive disease. It's no surprise that they, all those patients also needed quite a bit of supplements over time. Virtually all other patients had a reduction in their need for anti-VEGF therapy going forward out through 12 months. Next slide, please. Here, of course, durability doesn't mean anything if you're not controlling the disease and optimizing vision outcomes. Optimal vision outcome in a previously treated patient population means maintaining that vision. They came in with good vision and a 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 six months from baseline, and that's what you're seeing here. No significant loss of vision is what I'll say. Next slide. 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. You're seeing excellent maintenance of the OCT central subfield thickness. Only three microns, that's negligible change from baseline at six months. Next slide. Now the data visual here, change in mean BCVA from baseline. Within four letters of the baseline, you 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. This is now over 12 months with the EYP-1901 injection and much less anti-VEGF therapy. Next slide. Anatomically by OCT, the central subfield thickness is also holding up really nicely. Very mild degrees of fluctuation here. 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. How durable is EYP-1901? Well, it did show, of course, across the board at all doses a significant reduction in the need or frequency of injections. That's the treatment burden and how long it lasts. This will give you a feel for that.
You can see 53% of patients, just slightly over half of the patients, did not require any supplemental anti-VEGF injection after one administration of EYP-1901, up to the six-month point. There were some exceptions, but, of course, those that did need it beforehand needed it around, on average, months four or five. 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. Here'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, 7-10 days before the EYP-1901, you see the OCT up and left.
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. This patient received EYP-1901 at day zero. Excellent OCT. You start to see a little bit of fluid start to emerge at month three, and then what triggered a rescue at month four, of course, was the change in CST, which became significant. It triggered based on the criteria. Then looked really good thereafter for a good long timeframe all the way out to month 12. For another eight months, you see excellent exudative control, and this is just after the EYP-1901 and one Eylea at month four. Next slide. Ooh, one back. Yep. Yeah, this is the other case.
This is a high-dose arm case. Again, at baseline, this patient was showing a good response to anti-VEGF therapy, negligible signs of exudation are present. In both of these cases at screening, those patients received an anti-VEGF as standard of care and practice, within one to six or one month to six weeks. That's what we're seeing there. We see excellent control of disease with good vision, excellent vision, actually. Near normal central subfield thickness throughout the entire 12 months. No rescue was necessary. Next slide. The phase 1 DAVIO study really did look very good. Clinical trial met all the objectives. Certainly an excellent safety profile with no ocular serious adverse events.
The two ocular adverse events, one mild inflammation and one 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, not only six months but now 12 months. 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 six and a 79% reduction in treatment burden at month six. Next slide. I'll pass the rein back to Jay, and I'm gonna sign off, see some patients, and I guess I'll be back later for some questions, and happy to discuss all this at that point.
Okay. Thanks so much, Carl. That was great. Yeah. Carl will be back in about 30 minutes, and he'll probably have done about 30 injections in the meantime.
That's why we need to treat, decrease the burden.
Exactly. Charlie, could you come up to the podium? I'd like to introduce Charles C. Wykoff. You know, if I had introduced Charles a couple years ago, I would say he's an up-and-coming superstar in retina. Charles has arrived, and he is a superstar in retinal surgery and diagnoses, and especially in designing and executing clinical trials. I think the highest compliment I could give you, Charles, is you're the Carl D. Regillo of your generation. I'm gonna start out this section by showing you the swimmer's lane plot that you've seen already. This is the swimmer's lane plot for six months. 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 an ability to inject it every six 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 six 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 six-month time period but only receive one, therefore significantly reducing the treatment burden. Finally, you'll have this group, as illustrated by patient 2, patient 13, and patient 15, who may really not do that well, with EYP-1901. They, those three patients both required supplemental injection at month one, but they are clearly eyes that were failing standard of care as well. Next.
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, a maximal effect, get your retinas dry as possible, and we call that the induction phase. Then maintain those gains with EYP-1901 every six months or so, supplementing occasionally with the current anti-VEGF biologic. 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. Another large segment could require occasional supplemental anti-VEGF, but at a much reduced interval. Next slide.
Charles, first, before we go into these questions, how many patients with wet AMD in your practice would get an anti-VEGF and then five 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. Fortunately, I remembered my time, so we'll look forward to seeing you next time. You know, no, I'll just back up a second. I think you summarized the data really well. I think the two 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. 'Cause 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. These are your frequent flyers coming in, a very different population than many wet AMD patients. Secondly, and probably truthfully 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. I think once we cross those two bridges in my mind, I can then begin to think about what am I seeing from an efficacy perspective, because those first two things are really critical.
To get back to your first question, Jay, I think if you take this population of patients, and you're dosing them every four, six, eight weeks because they need it, which is how retina physicians practice, right? We don't treat patients consistently with every six or eight-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. We trusted these patients coming into this needed those treatments, which is the standard of care across this country. What percentage of patients would need a treatment within five 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. Within that context of seeing a greater than 50% proportion of patients at six months not needing any treatment, to me appears quite meaningful as a clinician, as someone that sees these patients every day. 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 six months if I give you this drug," is a big step forward, I would say.
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 gonna go six months, how would you introduce it into your wet AMD population?
Yeah, sure. There's a lot to dig into there that I think it's 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. As we learn with the PDS of the last 5-10 years is that when you have chronic VEGF suppression, fluid is different.
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. In this case, with EYP-1901, we need to remember that we have a chronic now VEGF suppression state. We need to think about the OCT patterns a little bit differently. Maybe incompletely dry is not the absolute goal. In my clinic, the way I would use this based on the data we've seen, assuming this plays out in phase 2 and then the pivotal trials, would be to sort of have a, I'm hesitant to use this word, but it's the way I'm thinking about it, which is foundational, right?
You have a foundational treatment where you know that you have chronic VEGF suppression and suppression of many of these tyrosine kinase pathways. I think there's a lot of interest there as well beyond what VEGF-A is doing with these receptors. Once you have that, 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 six to nine-month maintenance therapy, but every three to four 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-VEGF are fantastic. They're excellent. They're here to stay. It is a tremendous burden, particularly for the patients. If you really focus on the greatest burden, it's the patient challenge. We see that in real-world data. Talk to the patients, and it's an obvious burden. Holistically, when you look at these patients on average, they're not receiving the injections that they need to get optimal outcomes. To bring a product to the space that has a great safety profile, again, just doubling down on that has this foundational treatment that you can add additional anti-VEGF-A monotherapies on top of, I think is quite meaningful.
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 gotta 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. 'Cause 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 sort of drives me to think about this more broadly than just a fluid-based analysis.
I think that there's gonna be benefit to this drug beyond just stabilizing exudation, which we're also seeing.
Oh, 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. I love the fact that we have the oral data with vorolanib. You know, I had a couple patients in that study, and so I know that data very well, and I think you presented it beautifully. 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. Again, they're here to stay. 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 this space still, but to me, this mechanism has clearly been validated, both in your program here, in the oral program and other TKI programs. 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 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?
Yeah. It's fascinating how COVID has affected this as well. Right before COVID, there was certainly this move to home monitoring within retina, but it was sort of a trivial, sort of peripheral move. With COVID, you're seeing really acceleration of that, and it's for good reason, and it fits, you know, nicely with the paradigm shift as well as we have now more durable therapeutics. With Vyzulta, 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. 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. 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 six-month intervals that I would imagine these patients receiving injections once it's approved.
Great. Any other comments about wet AMD in EYP-1901 before we move on to some of the other indications?
Yeah. You know, 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. All right? Some patients come in, and we've learned this from our PRN trials, CATT, HARBOR, many of them, and need a few anti-VEGF injections and then may be stable over time. Then you have patients that have q-monthly injections and still can have progressive exudation. You're seeing that population in particular in the DAVIO program. Those three patients that Carl highlighted, I think are quite meaningful. Right?
If you get an anti-VEGF injection standard of care, and one 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, you wanna bring eyes into a program like this and the other ones out there being pursued that are under good control. 'Cause the goal of EYP-1901 here is to provide a treatment that's going to be durable for eyes that are already under good control. The sweet spot that I see here is for the majority of patients that already have optimized anatomy, and that's the treatment period, and then the maintain period is for the eyes.
Once they're stable anatomically, we try to really dramatically decrease that treatment burden and improve compliance over time.
Great. 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.
Yeah. I know we'll go through that potential trial design later here this morning. I'm excited for that. I think that this is a huge unmet need in the community. We have, you know, we need to remember what's causing blindness here. Sort of in the older patients and population at large, it's wet AMD first and foremost. In the working age adult population in the United States, we've got to remember that diabetic retinopathy is the most common cause of irreversible blindness. 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.
The key place to treat these patients, I firmly believe, is at the NPDR level before they have DME, when they're still asymptomatic. We have really good data that our current anti-VEGF agents are highly effective at that stage. 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 three or four-month injections, long-term to these patients that are asymptomatic. It's just not sustainable at the population basis, and that's why we're not doing it. I think biologically it makes a lot of sense.
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? Six months, nine months, a year? What would you like to see?
I think any of those would be clinically useful, but I think the timeline here probably a little bit longer than wet AMD for the sweet spot. I'd love to see a nine-month, even potentially a 12-month retreatment.
Great. Before we move on to the phase 2 programs, any other thoughts about how EYP-1901 might be used in DME or other VEGF-dependent conditions? Do you think we should get straight read-through to those other conditions if we show the efficacy in wet AMD in a pivotal trial?
Yeah. I think the data that I'm seeing so far in the DAVIO trial in these high-need anti-VEGF dependent eyes and wet AMD. I think that there's a lot of potential utilization in these other states of diseases. Diabetic retinopathy 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. 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.
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 four and five follow-up among eyes that were initially treated with center-involved DME with visual acuity loss. 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 worsening of diabetic retinopathy.
It's hard to talk about DME in a vacuum without thinking about DR and vice versa. We need to always think about both of these. The long-term DME patients, what I worry about is actually worsening of their diabetic retinopathy. 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, but something that makes a lot of sense from what we see clinically.
Yeah, that's great insight. Charlie, stay close because I'm sure our audience is gonna have a lot of questions for you in the Q&A. We're gonna move on. Next slide, please.
Thank you.
We're gonna talk about our phase two clinical trial plans. Next slide. I'd like to introduce Dario Paggiarino, our Chief Medical Officer, who's gonna walk you through our wet AMD and NPDR trial designs. Dario.
Thank you, Jay. Good morning. We heard about the DAVIO results, and obviously very encouraging in supporting the moving this product into the next phase of clinical development, phase 2. We plan to initiate two studies this quarter. I'll cover the design of these two studies, and we'll start with the wet AMD study, phase 2 study. This is gonna be a prospective randomized, masked positive control study, compared to aflibercept. The objective of this study following the wet AMD study, phase 1 study that we just you know covered the DAVIO study.
The objective of this phase 2 study will be to confirm the effect of the product in a larger population, to compare, very importantly, now in a double-masked study the effect of the product against our standard of care today, Eylea. 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 dose or doses we're gonna move forward into the next phase of development. As you can see here, all patients are randomized, once randomized, are receiving three monthly aflibercept injections. The difference is that the patients assigned to one of the two doses, EYP-1901 doses, will also receive at week eight the insert 30 minutes after the injection, the aflibercept injection at week eight.
From that point on, these patients will be seen monthly, and we plan to unmask the study at week 32, which is essentially six months after the placement of the insert, and we'll continue the study through week 56. Week 32, we'll have again, hopefully, a good feel about the efficacy, dose relationship, and the other endpoints that I'm gonna cover in the next slide. Primary objectives, of course, BCVA at week 32, as I mentioned. We also look at other key secondary endpoint in these studies, as you can imagine, central subfield thickness and of course, you know, time to rescue medication and very importantly, burden. As we have seen from the DAVIO study, that's an important parameter.
Whether or not you are actually a patient is actually rescue or supplemented with an anti-VEGF therapy, it's also important to see over the course of the study how many injections, anti-VEGF injections actually requiring. These are patients who are pre-treated. They have a relatively recent diagnosis, nine months of wet AMD, and they have to have received at least two injections in the previous six months. You can see here the OCT criteria baseline are really adjusted to reflect our experience that, you know, we acquired in the DAVIO study. We're trying to address, you know, and possibly exclude the patients who actually, you know, needed a supplemental injection at month one.
We have some ideas of how we could do that, and so the OCT criteria here are reflective of that, strategy. Of course, this is what a minority of patients in the DAVIO 1 study. Next slide. We will, like in DAVIO, also apply rescue supplemental injection criteria. These are very typical. They vary somewhat from program to program, but this is again, the ones you see here are fairly typical and of course include a combined criterion that includes both changes in central subfield thickness and BCVA letter, the first one. Then, of course, we also have a couple of other criteria related to changes specifically in BCVA only or in CST.
Of course, presence of new or worsening vision-threatening hemorrhage is also a typical criterion in this, in these studies. Okay. Next slide. The second study that we plan to initiate in the third quarter is a non-proliferative diabetic retinopathy study. We mentioned earlier that although there are products, anti-VEGF therapies approved today to treat NPDR, we also heard that it's very limited usage. What that means is that we, in a phase 2 study like this one, can still do a control study, but we can control again, sham. This is again a prospective randomized study using the same two doses that we're using in wet AMD, in the phase 2 wet AMD study.
You know, patients are randomized and they receive either EYP-1901 or sham. They will be followed every three months. We plan to unmask at week 36, about nine months after the placement of the insert or randomization. The rationale is, as you know, as Dr. Wykoff mentioned earlier, nine months seems to be a really good target for potential redosing. Now, this is a single EYP-1901 injection study, but what we want to understand is really the duration of the product. As we unmask in nine months, we will have a sense how many patients actually will, you know, 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 ocular parameters that are captured through fundus photography. It's a clear picture of how the diabetic retinopathy is progressing. This is a validated scale, and again used very typical, it's been 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 is it 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, excuse me, diabetic macular edema. Possibly the development of proliferative disease.
These patients who had non-proliferative disease at baseline were also evaluated for the potential of developing, you know, neovascular, you know, changes. These are patients who have either moderately severe or severe diabetic retinopathy, and they could have received anti-VEGF injection as long as it did not occur in the previous 12 months. As I mentioned earlier, they might have some macular edema, but not center-involving. Next slide. Now moving to YUTIQ. YUTIQ was launched in 2019 for non-infectious uveitis affecting the posterior segment. Since then, we have run quite a number of post-marketing studies. Now I gonna cover a couple of them. They're particularly important for us. 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, you know, outside the clinical trial, how is the product used? Why is it important for posterior segment uveitis? Because this condition is a, from an etiology standpoint, is caused by a number of diseases that it could be either primary, but often is associated with systemic diseases. It's a very complex disease that you know it's important to understand, because what we wanna capture in the real world is how the implant is used in this variety of conditions that have a commonality, posterior segment inflammation.
The registry, the CALM study, you know, is targeting 500 patients. You know, we have about 150 patients enrolled to date, and we will present in upcoming retina conferences this year. 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 gonna look at macular edema in these patients. About 50% of the patients in the phase 3 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 a retina specialist. There are patients who are seen because they have postoperative inflammation. But the most important thing is they, despite the use of short-term steroids, they at some point would benefit from a long duration, you know, a steroid-releasing product like YUTIQ, and this is exactly what we're looking this, in this study. We're looking at patients with edema for a variety of reasons, including postoperative. We plan to enroll, we actually enrolled the first patient already.
We plan to enroll about 125 patients, and with data in the second half of 2023.
I think that concludes my presentation. I'm introducing George Elston, our Chief Financial Officer. Thank you.
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 gonna pay for it. 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 30th 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 both YUTIQ and DEXYCU franchises. We've talked about in the past that we have positioned those franchises to be break even 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. That goes to the expanded use of YUTIQ in some of these inflammatory conditions and additional efforts ongoing with retinal specialists.
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 franchise on the pass-through rule from CMS. 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. We will continue to update you as we work through the plans for a DEXYCU pain indication. With that, I'm going to ask Nancy to come back up, and we will start our Q&A.
Yeah. I think what we'll do is let's have all the speakers come up and sit and then 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. If you've got a question, feel free to hit the message board to the operator, and she'll tee up your questions.
Hi.
Okay, go ahead.
Hello. Can you hear me?
Is it on? Yeah.
Yeah.
Go ahead.
Uh, this is-
Why don't you stand up, if you don't mind, just real quickly. Just real quickly, just introduce who you are-
Uh, this is-
To the audience.
Georgi Yordanov from TD Cowen. Thank you so much for the great presentation. 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 fit into the treatment paradigm, kind of like in relation to those other options that we have out there? Then I'll have a couple follow-ups.
Great question. I think from a clinician and a patient's perspective, truly the more tools we have in the toolbox, the better. I'm a big believer.
Sure.
In development having new options. I support what's out there, and I look forward to many other developments coming forward in the space. Specifically, the three that you mentioned, right? We have phase three data for a couple of them and then very early phase one data here. It's hard to make comparisons. When I go back to what we talked about before, which is who are the patients that we're looking at in the studies that we have? For example, with faricimab and Vabysmo, we have treatment-naive eyes with wet AMD being treated in the phase three program. Very different baseline population than what you're seeing in the DAVIO Program.
You've got to always remember the patient population we're talking about, because, you know, durability is gonna be very different when you measure on average among patients that are treatment naive at baseline of one and two years compared to a population like DAVIO that are heavily pretreated because they need those shots. We gotta be careful about comparing durability here among different baseline population. The PDS, I put sort of in a category of its own 'cause 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.
I think we've gotten better at learning about what those adverse events are and how to minimize them, but I think the whole space is still trying to learn what is that incidence of safety event, how do we minimize that to get this to more patients.
Great.
I'm gonna actually ask if, Jay, if you're still on, if you wanna 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 six months. While they may have a role in a three-four month interval, if clinicians are looking for even longer duration, then 1901 may be able to offer it. 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 blocker may be advantageous also.
Okay.
Great. Just a couple follow-ups. 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 2 trial? It seems a little different from the phase 1, but maybe kind of like how you are thinking about balancing evaluating the durability of 1901 with maintaining that vision which is required for a regulatory submission?
Georgi, you hit the nail on the head. Visual acuity is the primary endpoint. We tightened up the visual acuity criteria to only allow five letters loss as long as it's associated with new subretinal fluid or intraretinal fluid. We'd like to keep the visual acuity as tight as possible. It's not that supplemental injection percentage or actual number is not important, but it's not as important as visual acuity. If you think of it in these terms, in DAVIO, in the first six 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 six months, in the control group, everybody's gonna get a mandated injection of Eylea every two months. They're gonna have 3.0 injections.
If we have the same or stable visual acuity, same or stable OCT, but we've reduced the treatment burden from three injections to one injection, I think that would be looked on very favorably by the FDA.
And then-
Okay, go Georgi.
Final question is for Dr. Saim. In terms of the implant and the duration that it stays in the eye, how are you thinking about redosing? Kind of like what are some of the considerations in terms of redosing? Again, also how, like how are you thinking about it from a regulatory standpoint?
Yuri, you're talking about in the phase 2 data? I'm a little unclear on the question still.
Just in terms of like the actual implant. So maybe either Dr. Duker or
Yeah. I could take that and then Said can pipe in.
Yeah.
In the laboratory, the drug drops below therapeutic levels about eight to nine months after it's inserted. We think an every six-month label will be advantageous, but it's pretty clear from DAVIO 1 that 40% of the eyes could go up to nine months with just one injection. The flexibility to go longer would be advantageous, and the flexibility to dose it in patients who need it every six 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 that picture that illustrated that. But it's a small fraction of the total, and that residual material should eventually completely biodegrade.
Said, do you wanna add anything?
I think that's good.
Okay.
Yeah.
Looks like we got a number of questions. I'm going to ask. There we go. Please introduce yourself.
All right. Good morning, everyone, and thank you for the helpful overview here. This is Yuan Zhi from B. Riley Securities. First couple of questions directed to Dr. Saim. Can you comment on the Durasert technology, if it can be conjugated to a bigger molecule? For example, TKI is probably 500 for molecular weight is about 500. If it can be up to like 10K or 20K for a bigger molecule.
Okay. The question, just so people can hear, is, can we deliver larger molecules in our Durasert technology?
Yes. The technology is obviously validated for the steroids as well as for the 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 two or three thousand can readily be accommodated with the technology as is. Modifications are needed when we go to biologics, peptides, and proteins. Until we validate it, we can't really say for sure.
Let me also add, 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. That's something that we're working quite hard on, and we do believe it could work in the Durasert technology.
Yeah. Got it. That's very helpful. The second question is, can you maybe comment or tell us some challenge when you are trying to translate what you saw from clinical model, like the one in mouse or rabbit? How about when you do the translation into non-human primate or even human, in terms of PK/PD or volume and dose levels and eventually the max tolerable dose?
Okay. I think the question was, if I heard correctly, was translating from the preclinical data into either non-human primates, which by the way, we are not required nor do we plan to do any non-human primate studies, but taken into humans.
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. The FDA requires us to do rabbit. The way we allometrically scale to human is as the FDA requires it, you just multiply it by 3.5. It's the difference in vitreous volume between the rabbit and human. This is how we scaled up. The NOAEL was six inserts in the rabbit, and we saw no toxicity in humans, which means probably it will translate just as well in NHP.
One last question. When you do have the phase 2 trial, you have different dose levels from low to high levels. I'm curious, what's the TKI concentration at six 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 the six months time point?
At the levels we're dosing in human, allometrically scaled from rabbits, we see levels in the retina and the choroid, let's just say like 5-10 times the levels or IC50 levels for VEGF Receptor- 2. 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?
I would say it's the medium and high dose, yeah.
Yeah. We're not going forward with the low dose into our phase 2, just the medium and high dose.
Yeah.
Yeah.
Got it. Thank you.
Thank you. Yatin Suneja from Guggenheim. A couple questions for me. The first one, actually, I wanted to clarify what Dr. Wykoff said. You said you would like to see somewhere around 9-12 months in duration. Like, what do you actually mean? Like, what percentage of patients get into that 9-10-month, 12-month threshold with it? I think in the phase 2, we have seen about 40% getting to that 40% mark, nine-month mark. Just comment there, and I do have a couple more.
Yeah, sure. It's very important to think about this. As we talked about before, knowing your baseline population, every disease state is also important to consider separately. For example, in diabetic retinopathy, I think 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 VEGF suppression you need in DME or wet AMD, all very different disease states. I think for the same implant that works in, let's say, 50% of eyes at six 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 six-month timeframe.
The other issue is for the endpoint for an NPDR trial of diabetic retinopathy severity improvements, quite relevant, important endpoint, particularly for regulatory approval and understanding the biology of the drug. 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. That may be a different time period than DRSS level improvements. For example, the primary endpoint is at nine months. It's showing DRSS level improvements. Maybe clinically, that same implant could be used with a longer duration of action.
Got it. Thank you for that clarification.
If I could jump in for a second.
Yeah, go ahead, Jay.
Dr. Regillo is back on, and I'd like to ask Carl his opinion on what is the sweet spot for longevity for non-proliferative diabetic retinopathy in your mind. Intervals of six months, nine months, on year. At those sweet spots, what percentage reduction in DRSS would you like to be seeing?
Yeah, I do think this may reflect what's been already mentioned by Gary. I think it's the nine-month timeframe or more. Charlie said that could range quite a bit and I'd like to see at least a 30% improvement in the two or more steps of DRSS in the population. By improving the DRSS level, that of course decreases the risk of treatment-threatening complications, which is the ultimate goal. For me to be able to counsel a patient and say, "Hey, look, we need to do an injection in order to achieve this and lower the likelihood of having a problem, lower the likelihood of needing a lot of injections," I think once every six or nine months would be good. Longer even better, of course. If you can go 9 to 12, it's
That'd be more of a big home run.
Got it. Thank you.
Thank you, Carl.
In terms of the patient population for DAVIO 2, this is not a naive patient population, a little bit different patient 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 six-month period, all patients, at least on the Eylea arm, have option to get three Eylea doses. 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. It's the treatment burden, I think, that becomes a key here in the data readout.
Let me just repeat these questions. I wanna make sure that our guests who are calling in can hear them. If I heard correctly, you're saying, Yatin, that the patients. You wanna know in our phase 2 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. Just to be clear, that's mandated in the trial. I think you wanna 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. On average in the United States, maintenance therapy is six injections a year. The Eylea control group at three injections over six months represents what we would expect. It's hard to predict what we're gonna see in the 1901 arms. I said already in DAVIO 1, it was 1.2 injections over six months. However, 60% of those injections were in three patients, the three patients who required rescue at one month. We hope to eliminate those bad eyes, in which case we hope to see even lower supplemental rate. We don't know until we do the study.
I can also comment. Go ahead, Charlie.
Go ahead, Carl.
I was gonna 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 eight weeks with bevacizumab and about nine weeks with lucentis. That does translate into about every other month in the maintenance phase, that is after the induction phase, in order to get optimal disease control and vision outcomes. Now, when we say real world, of course, there's often relative undertreatment reported, and therefore vision is not well-maintained beyond the induction phase. In an optimal, ideal real-world setting, as Jay just mentioned, six per year with every other month in the maintenance phase is actually what you need, either ranibizumab or Lucentis to maintain the visual gains and get a good outcome over the course of one to two years.
Yeah. One additional point I would make is, right, if you look back at the original VIEW 1, VIEW 2 datasets, 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 two trial here that we're looking at with 1901 is a nice design because it's really weeding out probably, in my perspective, those patients that are needing monthly Eylea by putting the fluid criteria, for example, in there for enrollment. You're bringing patients into a controlled study that are going to do very well with every other month Eylea 'cause you've gotten rid of the patients that are gonna need monthly Eylea. You're gonna see a very robust control arm here.
Got it.
I think compared to that, you know, the hope that there's a dramatic reduction in the burden, which I think there will be.
Maybe final question for the company. Can you just talk from commercial perspective, how big is this patient pool? I think you mentioned maybe we are reading out the 25%, but just maybe company, if you wanna elaborate. Based on the DAVIO 2, what are the commercial implications?
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 $15 billion, if you look at all the drugs that are currently being used. It's a very, very large market. I might also add, it's continuing to grow because it's unfortunately demographic related, and these are diseases as people get older, and the demographics are all getting older. Coupled also with the fact diabetes is increasing in incidence. You put all that together, we certainly think this can be a billion-plus drug, given its opportunities, the amount of patients that can from the DAVIO 1 trial, again, phase 1 data.
That certainly speaks to that could potentially be controlled and where this maintenance therapy is used. I'm gonna see, Jay, if you wanna 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 ask my colleagues, Carl, Charlie, to say, you know, "Do you feel like this inclusion/exclusion criteria is gonna limit the label here?
Yeah, I'll take that. You know, It's a great example here, and we've already talked about it, is Vabysmo or faricimab. The trial in wet AMD, right? The program was treatment-naive wet AMD eyes. If you look clinically, clinicians are actually using it first and foremost in their hard to treat previously treated patients. The development program and the patients you enroll in a trial like this are really important to understand the biology and the comparison to an on-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 the 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. I don't foresee this being sort of the population necessarily that would be limited to in the real world.
Okay. Other questions?
Hi, Jennifer Kim from Cantor Fitzgerald. Thank you so much for your very useful presentations. I have a few questions for Doctors Regillo and Wykoff 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 two components of something like EYP-1901, with it being TKI and the delivery technology, what are and Dr. Wykoff, you pointed out the promise of the neuroprotective benefits. What are your thoughts on the differentiation of those two components of vorolanib and Durasert?
Yeah, I'm happy to jump in there first, and Carl, certainly wanna hear your opinions also. You know, it is a burden for patients to get an injection in the eye, full stop. If a patient's never heard of that and they hear, "I'm gonna put a needle in your eye," it's a big deal. That's a big discussion with patients. I mean, overall trivialize it 'cause we do it so frequently, and it's highly effective and extremely safe overall, but it's a big deal from a patient perspective. 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, you know, 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 3 program that are dual injections routinely. This is doable, and I think something that is clinically implementable. Then you bring up two good differentiators here for EYP-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. I am a big believer in the additional mechanism of actions of tyrosine kinase inhibitors in general. 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. I think what we're seeing is potentially the tip of the iceberg here with the neuroprotective data that Said presented.
Jay Duker 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 later, we've had now quite a bit in other programs, and it works just fine. In practice, it doesn't necessarily have to be 30 minutes. So that could help with patient flow, make it easier. Plus, in practice, doesn't even need to be the same day. We'll be treating our patients with anti-VEGF, and say, "All of a sudden, you know, we're gonna introduce something that's gonna give you much more durability, decrease the burden of these injections. I'll do it for you at this visit. Then let's see how it goes." So I think in practice may not even be necessary.
Here in the context of the clinical trial, you know, we have to keep it both, the same.
Okay. One more question for the company. Just wondering about the NPDR study. First of all, I noticed that you sort of narrowed down the timeline window of initiating this quarter. Congrats on that. 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 gonna have Dr. Paggiarino answer that. The 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. The wet AMD trial
Please speak up.
The wet AMD trial will include 50 sites, and we plan to enroll in approximately six months. The NPDR is gonna take a little longer, so we anticipate again to start in this quarter, but we anticipate an enrollment over approximately nine months. That will be conducted in about 30 sites.
All right. Thank you so much.
It's a great presentation. This is Yale Jen from Laidlaw & Company. Just got three questions here. The first one is dealing with the DAVIO 1. From months four to five and to the 6th, there I think that's from 70-some% drop to 50%. My question is that even the patient size is small, did you guys figure out what kind of shared characteristic of the patient which dropped from 70%- 50%?
Jay, maybe you can answer that. That's from Yale regarding.
Yes.
The drop.
Yeah.
Yeah, the drop. If you heard the question, great. The drop-off.
I'm gonna repeat what you said, Yale. 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 three eyes that got rescued at month one, there is a trend in the high dose to be rescued later than in the medium dose. 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 eyes got their supplement at month four, and they never got another one for the whole year. We had one get supplemented at month five, I believe, and never got another one. That need for supplementation. We don't believe it's an indication that the implant has actually gone subtherapeutic.
Okay, great. That's helpful. In terms of DAVIO 2, in the first two weeks period, there is the treatment of the conventional therapy before you started the EYP-1901, what was the rationale behind that? Could that help to alleviate or reduce the patient, which is not better controlled from the initial therapies?
Dario.
So-
Okay. I'll have Dario and then Jay, you take it.
Jay.
Okay.
We had discussions with the agency, with the FDA, about what a study would look like. Especially, you know, we try to anticipate what a pivotal trial would look like because we, as much as we can, we wanna test a design in phase 2 that hopefully will replicate with high level of certainty in a larger population in phase 3. The rationale for the three injections is really something that the FDA indicated specifically for the control arm. In other words, despite the fact that these patients have been pretreated to some extent, the FDA specifically asked that the patients randomized to the aflibercept arm be actually dosed monthly. And then, of course, you know, within label.
I think the intent there is to be able to maximize the efficacy of the control arm, despite the fact that this is not an initial, essentially a non-naive population. That's the rationale for the three injections of aflibercept. Of course, we also plan to do that in the dose arms, the nineteen oh one dose arms, 'cause we wanna make sure that everybody is really, you know, at the end of the induction, in the same place when it comes to evaluating the effect of the insert. And that's the decision for the insert to be placed, you know, right after the third intravitreal injections of aflibercept. I don't know, Jay, you wanna add anything?
That's it. 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 nine months later, the effect of the Eylea in the 1901 arms would have washed out.
That's very helpful. 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, potentially to introduce 1901? A flip side on that question later on is that we have seen patients in 40% or so in 9 or 10-month period. When you think that the patient should take the second redosing of 1901, and what might be the criteria for your decision? Thanks.
It's gonna be Charlie, because Carl signed off. Charlie, go ahead.
Yeah. Thanks for that question. You know, I think I'd take the second part of it first, right? The pharmacokinetics of EYP-1901 are very clearly described, right? By the end of six months, you know, the active drug decreased significantly, and then by nine months, it's probably not clinically active anymore. I think especially if you're focusing on the DAVIO 1-type patient who needs frequent injections, I would want to consistently treat them over time. 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 six months consistently long term.
Addressing the first part of your question, which is sort of the question I, as I heard it was: how would you incorporate EYP-1901 during sort of the induction phase when you have been phase 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 certainly be used in that way. It could also be used in combination with an anti-VEGF injection at baseline. So for example, in my own practice, I could 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.
The reason for that is I'm gonna get a full anti-VEGF effect with the bolus injection of Eylea or Avastin or Lucentis, whichever drug you wanna use. I'm really hopeful that this TKI has additional benefits beyond the exudative events that we're seeing. I'd wanna get that additional benefit as early as possible for my patients.
Other questions?
Hey, this is Chen from H.C. Wainwright. I have a quick question to the company. From a competitive advantage standpoint, what are your expectations from the phase 2 study with EYP-1901? You know, obviously there are a lot of assets, a lot of anti-VEGFs being developed in phase 2s and phase 1s, either suprachoroidally administered or intravitreally administered. What are your ideal expectations from the phase 2 study? Thank you.
Yeah. The question was, what are our expectations for phase 2, 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? I'm gonna actually have Jay, if you wanna 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 non-inferior to Eylea. I stress numerically because the study isn't powered enough to show necessarily an absolute non-inferiority margin. 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. 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?
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 for CMV retinitis with ganciclovir almost 30 years ago. 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. 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 he really would.
Yeah. Charlie, do you wanna take that?
Yeah, 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 five years, we've seen, you know, challenging adverse event profiles. To have such a clean profile at this stage with all this historical experience with on-label products already is quite reassuring from a clinician's and a patient's perspective. Then where this will exactly fit from a durability perspective, I think we still need to wait and see additional data, right? We have 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.
Hi. Daniil Gataulin from Chardan. A question for Dr. Wykoff. 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?
Yeah, it's a great question. Just to summarize, it was sort of how do you think about using this drug and then potentially relate it 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 'cause we know the pharmacokinetics of this EYP-1901 very well. By nine months, you're probably at a place where you have minimal active drug left in the eye.
For eyes with 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. Maybe the first time you used it, you would sort of look at the interval so that if they were dry at six months, you might wait till seven months, you might wait till eight months, and then see when they start to a little bit of recurrence of fluid. But then once you've found that interval, I would be a believer in the consistent pharmacokinetics of this drug and continuously retreat them at that same interval.
Carl briefly mentioned it before, but he and I and many others have been involved in prospective trials 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. I would expect this drug to be the same, whereas some eyes would recur possibly at six months, some might recur at eight months, and to find that sweet spot and then use that repeatedly over time.
Got it. The question for the company is the implant for NPDR exactly the same as the one for wet AMD in terms of release kinetics?
Yes.
Jay, could you just repeat that question? I wanna 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've NPDR, you've heard Dr. Wykoff, and I think Dr. Regillo mentioned that it would be great if it could go out nine months. Why do we think it potentially could go out longer in NPDR versus wet AMD with the same implant?
First, there may be a disease altering aspect to this. When you suppress VEGF and perhaps have some neuroprotection constantly for nine 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 nine months, it might be 12 months or 14 months or longer before you might start to see the effect clinically wear off. 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. Even though the drug may be technically out of the eye in nine months or at least subtherapeutic, we may end up seeing a longer effect.
Thank you.
One follow-up here.
Yes, go ahead. Another question.
Yeah. This is Yuan from B. Riley. One follow-up here. Just curious, when you have the phase 2 trial design on the-
Can you put the mic closer? Thank you. We're having a hard time hearing.
Yes. Sorry about that. When you have the phase 2 trials and as the third dose, you will at the same day have two injections, both the anti-VEGF and the TKI inhibitors. Just curious, what's the total injection volume there? Do you need to keep those patients at clinic for a while to monitor the ocular pressure? It will be great if you can put into the context of your past experience with the Durasert, where you may have some co-administrations at the same thing. Just wanna hear some comments there.
Okay. Jay, why don't you take the co-administration with DAVIO 1. Do we see any IOP elevation? Actually, Dr. Wykoff, if you could answer the clinical practical issues that you might see.
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 two or up to five 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 two injections, that 30 minutes separation is what the FDA has recommended. We'll be monitoring it, but we don't expect it to be a problem.
Yeah, I agree completely. Clinically, we do this all the time. We're giving it volumes into a fixed space, so you expect the pressure to go up. If you don't, that would be highly unusual. We monitor patients routinely in the real world to make sure that their vision is stable, that they can see after the injection. Some patients do have a challenge with persistent 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 wanna 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.
Yep, we have.
Okay. Other questions? I'm sorry.
Yes. This is George Elston. There is an online question from Yi Chen from H.C. Wainwright, and it's, First question is why only was one patient enrolled in the low to mid-dose in DAVIO trial? And Jay, maybe you can answer that.
Yes, I can. As you've heard, we can insert up to three inserts in a single injection. As we enrolled the low dose and the medium dose arms in DAVIO 1, there were no issues. When some of the investigators went to insert all three inserts in the high dose, they didn't always get all three inserts in. In one case, they got only one insert in. That became the low, medium arm. In three cases, they got two inserts in. That became three 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. Dario noted that as you got to the third insert, the resistance was greater in the plunger.
What we think happened is some of the investigators just abandoned the injection too soon. 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.
Yi's follow-up question is probably for both Jay and Dr. Wykoff. Can you talk about EYP-1901 over gene therapies being developed for wet AMD?
Go ahead, Charlie.
Yeah, great question. Important question. Many ongoing gene therapy programs given by intravitreal injection and by 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 is a unique adverse event profile that we're seeing be better defined over time for each of these routes of administration. You have one sponsor in pivotal programs with the subretinal delivery during vitrectomy. I think that there is definite potential value there for the space. The value that I think EYP-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.
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 could also be a minus. The value here is that we know the pharmacokinetics very well, and the drug has a finite duration of activity, and then it 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 if, Stern, if you can tee those up because I do want to give the people who have asked questions online that we answer those. Maybe you could either bring them up now or you could on your mic. Christina, if you could just read some of those.
Yeah, sure. 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 in 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 3 trial that had retreatment criteria. I don't know if Regenxbio's phase 3 does. Charlie, you may know better than I. What we tried to do with our criteria was acknowledge that you can have increased fluid, including subretinal fluid, but not affect the vision. You may recall that in the refillable port phase 3, 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 five letters. Other than refillable port, I'm not aware of any other program that has had retreatment criteria to phase 3. Charlie, are you?
Yeah. Thanks, Jay. I agree with all your comments, and if you broaden it to look at other development programs that aren't in phase 3, 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 outcome are paramount. What we don't wanna do is to try to game the system such that you allow patients to lose vision and then be able to claim durability. 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 slide, the bullet point at the bottom of the retreatment criteria was, I think maybe the most important one, which was there is some level of investigator discretion. 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 'cause there are other programs that don't allow that. They don't allow an investigator to say, "Hey, for a safety reason, I wanna re-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?
Yeah. I have one more question from online. 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 endpoint, and we do not expect that to change. Look, at the end of the day, it's all about vision. In the real world practice, I'll ask Dr. Wykoff if you wanna comment. Even though the FDA won't accept that as a endpoint, how that impacts in real world practice.
Yeah. It is quite relevant. If you can't hear me, tell me. I think the battery just died. You know, I think diabetic retinopathy is a great example here, and we briefly talked about it before, where, right, the approvable 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 approvable endpoint. Right, what's approvable is obviously extremely relevant to development programs. Clinically, clinicians will look at a drug like this, potentially slightly differently. Reduction of treatment burden in the real world is of paramount importance. It's of paramount importance from a patient perspective. Just ask them, "Would you rather get fewer injections?" They will 100% say yes.
Even more important at 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.
Yeah. 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 non-inferiority 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. In 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.
Yeah. If I may add, I'm having worked with the FDA for many years, absolutely. The primary objective is non-inferiority here. At the end of the day, they really do an assessment based on benefit to risk. You know, granted that this is a safe product, and is non-inferior in terms of BCVA, reducing the burden for the reason we said can only improve that ratio in favor of the product.
I just want to follow up. 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 a nine-month. Can you just talk about that?
Yeah. Let me just repeat the question. The question is, what about the primary endpoint timeframe? Most studies had a 12-month endpoint. We've been talking about an eight to nine-month endpoint. Dario, why don't you answer that?
Yeah. Absolutely, I mean, we want to learn from the, you know, single injection study, the duration. We unmasked, as I mentioned, six months after the insert, eight months, essentially. 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. To be more specific, they, you know, given the three induction injections, they specifically say you have to wait 1 month after the last Eylea injection, which takes you to three months. Add nine months, that makes it 12. We anticipate that 12 months will be probably, yeah, the primary endpoint.
Yeah. Let me just clarify, 'cause this can get a little confusing. Right now, remember, our phase 2 is not aimed for pivotal. Once we get to phase 3, we expect that you will have a readout nine months after the last injection. Because we plan to do three induction doses, that takes you to 12 months. Does that make sense?
Yes.
Yeah.
Okay.
One more follow-up. For the DAVIO 2 study, are you using a blended efficacy measure at, you know, month five to six after the last injection? Or are you doing exactly six months after?
For the W2, we unmask at eight months, right? We plan actually to unmask at eight months, so we blind the seven and eight months.
Seven.
Yeah. The blinding, 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 two 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? Yeah, Yale.
Maybe just a quick question to follow on to the previous one, which is that if for the pivotal study you talk about as the endpoint, do you anticipate a fixed six months subsequent EYP-1901 injection or retreatment for DME?
Jay, why don't you answer that? This is on for the phase 2 study. Should we anticipate a retreatment at six months or not? Then we can
Phase 3.
Phase 3. Thank you. Thank you for clarifying. Phase 3.
That's the plan at present.
The answer is yes, Yale. For phase 3, we plan on doing a re-injection at six months.
I would add, though, that I say it's the plan. We really have to get a little more dosing and longevity information.
Yes. Yes.
Before we make that definitive.
Okay. I don't wanna 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. Would management be willing to discuss the potential applicability of tech to other targets such as complement inhibitors and thinking about geographic atrophy?
Yeah. I'm gonna 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. I personally believe that both C3 and C5 are validated targets in geographic atrophy. So the tricky part right now is finding the optimal C3 or C5 blocker or perhaps another blocker in the complement system that would benefit from being in Durasert. The company has been extraordinarily active in the last nine months looking for such a partner.
Okay. Any other last questions? All right. I wanna 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. I also wanna 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. 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.
Then George Elston, who really helped spearhead all of this, thank you, and the entire executive team who was very involved. It's a lot of hours that get put into this. We hope you found it useful. I appreciate your questions. Very insightful. We look forward to continuing to bring EYP-1901 through the clinic and hopefully, providing some real benefit to patients. Thank you very much.