EYPT - NASDAQ

Good morning. My name is Michelle, and I will be your conference operator today. At this time, I would like to welcome everyone to the EyePoint Pharmaceuticals, Inc. Fourth Quarter 2025 Financial Results and Recent Corporate Development Conference Call. There will be a question-and-answer session to follow. Please be advised that today's conference is being recorded at the company's request. I would now like to turn the call over to George Elston, Executive Vice President and Chief Financial Officer of EyePoint Pharmaceuticals, Inc. Sir, please go ahead.

Thank you, and thank you all for joining us on today's conference call to discuss EyePoint Pharmaceuticals, Inc.'s Fourth Quarter and Full Year 2025 financial results and recent corporate developments. With me today is Dr. Jay Duker, President and Chief Executive Officer of EyePoint Pharmaceuticals, Inc. Jay will begin with a review of recent corporate updates and discuss our clinical programs for DuraVu in wet AMD and DME. I will close with commentary on the fourth quarter and full year 2025 financial results. We will then open the call for your questions where we will be joined by Dr. Ramiro Ribeiro, our Chief Medical Officer, and Mike Campbell, our new Chief Commercial Officer. Earlier this morning, we issued a press release detailing our financial results and recent corporate developments. A copy of the release can be found in the Investor Relations tab on the company website at ipoint.bio. Before we begin our formal comments, I will remind you that various remarks we will make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. These include statements about our future expectations, clinical developments, regulatory matters and timelines, the potential success of our products and product candidates, financial projections, and our plans and prospects. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent Annual Report on Form 10-K, which is on file with the SEC, and in other filings that we have made or may make with the SEC in the future. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so, even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. I will now turn the call over to Dr. Jay Duker, President and Chief Executive Officer of EyePoint Pharmaceuticals, Inc.

Thank you, George. Good morning, everyone, and thank you for joining us. 2025 is defined by significant progress and achievement for EyePoint Pharmaceuticals, Inc. as we made important advances that set the stage for and potential value creation for the year ahead. As a result of our exceptional clinical execution, driven by our derisked and patient-centric programs, our lead asset DuraVu is on track to deliver top-line data in wet age-related macular degeneration, or wet AMD, beginning in mid-2026. In parallel, we advanced DuraVu as the only tyrosine kinase inhibitor, or TKI, program in diabetic macular edema, or DME. We are pleased to report that as of last week, the first patients were dosed in both pivotal Phase 3 DME trials. With a strong cash position that is expected to fund operations into 2027, and multiple inflection points on the near-term horizon, we are entering a transformative period for EyePoint Pharmaceuticals, Inc. with significant momentum. Our conviction in DuraVu’s blockbuster potential is underpinned first and foremost by its compelling clinical profile. In our Phase 2 trials in the largest retinal disease markets, a single dose of DuraVu demonstrated durable efficacy with improved vision and tight anatomical control. Importantly, DuraVu has a favorable safety profile with no safety signals in over 190 patients across four completed clinical trials. The safety profile so far remains consistent in the ongoing Phase 3 Lugano and LUCIA trials for wet AMD, based on continued masked internal safety review and two interim reviews conducted by the independent data safety monitoring committee. In addition to its robust clinical profile, we continue to believe in the potential for every six-month dosing via standard in-office intravitreal injection, a best-in-class delivery technology, and a novel multi-MOA that inhibits VEGF, PDGF, and IL-6 via the JAK1 receptor with no Tie2 inhibition, which are the key drivers of its differentiated profile. This unique profile positions DuraVu to address both VEGF-mediated vascular leakage and IL-6–mediated inflammation that contribute to disease pathogenesis in wet AMD and DME, thereby potentially enabling improved long-term outcomes for patients with fewer injections. Our confidence is also grounded in our established and clinically rigorous approach throughout DuraVu’s development. Our Phase 3 wet AMD program was intentionally designed to inform real-world practice and generate meaningful data for the retinal community by comparing DuraVu to on-label aflibercept as the control. Additionally, we will be evaluating statistical reduction in treatment burden and six-month redosing to support a compelling and relevant label. Based on the success of our large Phase 2 DAVIO-2 trial, and with our proven regulatory pathway and strong execution to date, we believe our wet AMD program is uniquely derisked and optimized to support success. We look forward to reporting top-line data beginning in mid-2026. The clinical and regulatory rigor that defines our approach also extends beyond wet AMD as we work to position DuraVu for multiple indications. We are pleased that randomization is now underway for both COMO and CAPRI, our two pivotal Phase 3 trials in DME, where we expect to drive rapid enrollment by leveraging our preclinical trial infrastructure and investigator network. In line with our wet AMD program, our DME program follows an established noninferiority design with an on-label standard-of-care control and redosing every six months. It was similarly informed by impressive Phase 2 data from the VERONA trial, where eyes treated with DuraVu demonstrated meaningful visual and anatomic improvements as early as four weeks. We anticipate top-line data in 2027 and look forward to building upon our strong track record of clinical execution as we advance DuraVu through our Phase 3 DME program. We believe that DuraVu is well-positioned to be the first to market among all current investigational sustained-release programs in both wet AMD and DME with a potential best-in-class profile, and we remain focused on building DuraVu into a durable franchise targeting the largest retinal disease markets. With a combined current global market of $10 billion and growing, wet AMD and DME make up the vast majority of the global branded retinal disease market. DuraVu’s unique MOA, robust clinical data package, proven release technology, and attractive storage and administration benefits offer a compelling value proposition that we believe will address the longstanding need for innovation and support strong commercial positioning. As part of our ongoing commercial readiness efforts, we are thrilled to welcome Michael Campbell as our new Chief Commercial Officer. Mike is a seasoned commercial leader with a proven track record of successful product launches and oversight of prominent ophthalmology franchises, including Lucentis and Xiidra. As we prepare to deliver on EyePoint Pharmaceuticals, Inc.’s next milestones, including potential approval and transformation into a fully integrated commercial organization, Michael’s deep commercial expertise will be instrumental as we position DuraVu for a successful U.S. launch. In addition to strengthening our commercial leadership, we continue to expand operations at our 41,000 square foot cGMP manufacturing facility in Northbridge, Massachusetts. The facility has been online for over a year, supported by about 60 full-time employees, and continues to not only support the CMC submission for a planned New Drug Application (NDA) but also commercial supply. As we near regulatory submission, we are preparing for pre-approval inspection, underscoring our growing independent commercial readiness and commitment to ensuring that we are well equipped to deliver DuraVu to patients if approved. Before passing it over to George to review our financials, I would like to thank the entire EyePoint Pharmaceuticals, Inc. team for your continued dedication to improving vision and patient outcomes. We are proud to advance our therapeutics for the benefit of the entire retina community and grateful to the patients, study coordinators, and clinical investigators who make our progress possible. As we look ahead, we are excited about the upcoming milestones and the opportunities in store for us to extend our leadership in sustained ocular drug delivery. I will now turn the call over to George.

Thank you, Jay. We ended 2025 with a strong balance sheet of $306 million in cash and investments, driven by continued stewardship of our resources and a $173 million follow-on financing in October. As the financial results for the three months and full year ended 12/31/2025 were included in the press release this morning, my comments today will be focused on a high-level review of the quarter. For the quarter ended 12/31/2025, total net revenue was $600,000 compared to $11.6 million for the quarter ended 12/31/2024. The decrease was primarily driven by the recognition of remaining deferred revenue related to the company's agreement for the license of YUTIQ product rights in 2023. Operating expenses for the quarter ended 12/31/2025 totaled $71 million compared to $57 million in the prior-year period. This increase was primarily driven by the ongoing Phase 3 trials for DuraVu in wet AMD and DME. Net non-operating income totaled $3 million, and net loss was approximately $68 million, or $0.81 per share, compared to a net loss of $41 million, or $0.64 per share, for the prior-year period. Turning to the full year ended 12/31/2025, total net revenue was $31 million compared to $43 million for the year ended 12/31/2024. The decrease was primarily driven by the recognition of remaining deferred revenue related to the company's agreement for the license of YUTIQ product rights in 2023. Operating expenses for the full year ended 12/31/2025 totaled $275 million versus $189 million in the prior-year period. This increase was primarily driven by the ongoing Phase 3 trials for DuraVu in wet AMD and DME. Net non-operating income totaled $12 million, and net loss was $232 million, or $3.17 per share, compared to a net loss of $131 million, or $2.32 per share, for the prior-year period. Cash and investments on 12/31/2025 totaled $306 million compared to $371 million as of 12/31/2024. We expect the cash and investments on 12/31/2025 will enable us to fund operations into 2027, well beyond key milestones and NDA preparation for the Phase 3 wet AMD program in 2026 and fully funding the Phase 3 pivotal DME program. In conclusion, we are incredibly pleased with EyePoint Pharmaceuticals, Inc.’s progress in 2025 and are well capitalized to continue advancing DuraVu through both of our late-stage development programs. I will now turn the call back over to Jay for closing remarks.

Thank you, George. EyePoint Pharmaceuticals, Inc.’s progress in 2025 reflects the strength of our programs and our consistent execution. As we prepare to drive value through transformative catalysts in 2026, we will continue to be guided by our derisked, clinically rigorous, and patient-centric approach. We are well positioned to deliver on our near-term priorities, including reporting top-line data for the Phase 3 Lugano trial anticipated in mid-2026 with LUCIA data closely following, completing enrollment in our pivotal Phase 3 DME program in 2026, and preparing for regulatory filing in wet AMD assuming positive Phase 3 data. Thank you all for your attention this morning. I will now turn the call over to the operator for questions.

Thank you. As usual, we will try to get to as many questions as we can through the course of the call. Please limit the number of questions you ask to one, to give others a fair chance to participate. One moment while we compile our queue. Our first question is going to come from the line of Tessa Romero with JPMorgan. Your line is open. Please go ahead.

Good morning, guys. Thanks so much for taking the question. Jay, George, can you clarify the rate of ocular AEs that you have seen across your cumulative safety database with DuraVu, in particular around the incidence of vitreous floaters and cataracts? And then, relatedly, what specifically has the physician's feedback been around your safety profile? Thank you.

Good morning, Tess. Sure, happy to address that. As you probably recall, we have treated over 190 patients and completed trials of one Phase 1 and three Phase 2 trials. And the number of cataracts that were measured by the 191 patients is 5.8%. In contrast, if you just look at the DAVIO-2 data, the cataracts in the DAVIO-2 study in the study arms was approximately 8%. In the EYLEA control arm, it was numerically higher; it was 9%. So this is an elderly population. You do expect cataracts. But, of course, in the controlled DAVIO-2 trial, there was no mismatch between the cataracts at all. With respect to vitreous floaters, once again, in the entire population, 5.2% of the DuraVu patients reported floaters, which is, again, consistent with what you might see in any type of study that has injections into the eye. So I think to answer the second part of the question, which is how do the clinicians perceive it, I think one of the main reasons that we were able to enroll the wet AMD trial so rapidly is the doctors had really good Phase 2 data to evaluate both the efficacy and the safety of our drug. And I think that gave them great confidence in enrolling patients. I think, again, I would like to make one more note on safety and efficacy. We think of visual acuity as the primary efficacy endpoint, which it is for all of these studies, but visual acuity also is a safety outcome. And, again, just to remind the listeners, in the DAVIO-2 trial, our treated patients in wet AMD gained vision. And, in fact, in the unsupplemented eyes in DAVIO-2, the treatment arms gained 2.1 letters over the course of the trial, which is actually numerically greater than the EYLEA arm gain. The EYLEA arm, again, at that point was getting three injections over that time frame because it was on-label EYLEA. So, to summarize, we are very comfortable with our safety. We have had no ocular or systemic SAEs attributed to our drug, and in those four prior trials, no safety signals. Thank you.

Thank you. And one moment for our next question. Our next question comes from the line of Yatin Suneja with Guggenheim. Your line is open. Please go ahead.

Just a quick one on the regulatory front. Just love to hear from you how are you thinking about recent sort of FDA chatter around single study–driven regulatory approvals. Does that change your strategy? Just curious what is possible. And then, Jay, I appreciate your comment on the safety. Clearly, it has been pretty good across Phase 2 studies and also Phase 3 blinded review that you have provided. Anything on opacity that you can comment? Like, how are those numbers relative to what we see with other TKIs in development? Thank you.

Thanks for the question, Yatin. So for the first question, the regulatory front, yes, I think in general, we would all welcome a more rapid and less expensive pathway to drug approvals. But as you heard this morning, and I think most listeners know, we have two identical Phase 3 wet AMD trials underway that are reading out this year. If, in fact, the FDA would allow us to file with a single trial, our second trial is only two months behind, and so overall, I do not know that that would give us any particular advantage in the single trial. In DME, we have two simultaneous trials that we expect to read out in 2027. And given that other regulatory agencies around the world are probably still not aligned with single trial, we do not believe we have any reason to alter our approach for these two indications. Future indications, of course, we will discuss with the agency. With respect to single trial in retina studies, I think that it is certainly something the agency may be considering in the future. Of course, there are rules around single trial filing that the FDA updated in 2023. Those rules are already out there, and in order to do that, you not only need to have a large trial but you need confirmatory evidence that your drug is active if it is single trial. Of course, in the case of rare diseases, there are exceptions that are made, but wet AMD and DME, unfortunately, are not rare diseases. So with regard to the regulatory pathway, we think our pathway is derisked. We have taken the noninferiority approach, which is, you know, the approach essentially that five of the last approvals have taken, and we have two trials in each of those large indications already in motion. With respect back to safety for a second, opacity is a sign that the masked investigator can see when they look into an eye. They see if there is a blockage in their ability to look into the eye, either in the back of the eye in the vitreous or the front of the eye in the anterior chamber. In our DAVIO-2 trial, we had about a 1% rate of vitreous opacity. We had no rates of anterior chamber opacity. That has not been seen at all with DuraVu in any of the treated eyes, and we would not have expected it. DuraVu is designed to hold the drug until the drug is fully eluted, so we have no free-floating drug particles. We have not seen any migration of the inserts. The inserts so far, at least, have not been reported in humans to break up into pieces. They just slowly bioerode and release their payload, which again, I would like to remind everybody, our scientists have been able to upgrade the inserts so that they are 94% payload; they are only 6% matrix. So we have not seen any anterior chamber opacity, and we would not expect to. The vitreous opacity percentage is low.

Thank you. And one moment for our next question. Our next question comes from the line of Yigal Nochomovitz with Citigroup. Your line is open. Please go ahead.

Yeah. Hi, Jay and team. Thank you. I am just curious, with regards to the conduct of the wet AMD trials before they read out this summer and into the early fall, will there be additional looks at masked safety? What will the cadence of those be, and will you be reporting that to us as you proceed? Thank you.

Thanks, Yigal. We have got Ramiro on the line, our CMO. So, Ramiro, feel free to answer that question about continued safety looks in the wet AMD trials.

Hey, Yigal. Good to hear from you. So we have, as a safety monitoring body for the studies, both internal masked review that we do on an ongoing basis as well as the independent data monitoring committee that reviews the unmasked data. The last DMC meeting was November. At that point, they reviewed the data from patients, and I remind you that at that point, we had over 25% of patients getting the second dose. The safety profile of DuraVu so far has been consistent with our previous experience in the Phase 1, Phase 2 studies with nothing new to be aware of. Our next DMC meeting is scheduled in May, so that is going to be the next opportunity for that group of physicians to review the unmasked data and provide updates to us.

Okay. Thank you. And just one question on biomarkers. I know you identified IL-6 recently. I am just wondering what additional biomarker work may you be doing to further explore the activity profile of vorolanib.

You know, thanks for that question. Additional biomarker work around the JAK1 receptor and its ability to block downstream effects of IL-6. We will have additional data on that that we are presenting at ARVO in May. We have additional ongoing studies to really try to assess the impact of that in humans. With respect to the rest of the potential receptors, we did a very extensive evaluation of the kinome last summer at the time that we discovered that vorolanib was a potent inhibitor of JAK1 with an IC50 of about 80 nM, and we did not discover at the time any other significant receptors involved in retinal disease, either positively or negatively, that vorolanib was active against.

Thank you. And one moment for our next question. Our next question will come from the line of Claire Dong with Jefferies. Your line is open. Please go ahead.

Hi, good morning, guys. Thanks for taking my question. So just in terms of the durable and multi-mechanistic profile beyond VEGF inhibition, how prominently do you expect this mechanistic differentiation to really be featured in your regulatory discussions and maybe eventual commercial messaging as well? And then, is there any plan for you to report more preclinical evidence of the IL-6 inhibition MOA in the future? Thank you.

Yeah, Claire, great question. Thanks for it. And a bit complicated because, you know, the story, I think, is still unfolding. Ultimately, what we all want is better visual acuity—our patients certainly, and the physicians who treat them. And so the great thing about what we do is eventually it is all about the data. And what we hope to show, and really, if we can show it, I think, primarily in our DME trials, is that that additional IL-6 blockage does give a more rapid onset of visual acuity improvement. That is what we showed in the VERONA data. If you recall, as early as week four, the treatment arms with DuraVu had already separated from EYLEA. We were already four to five letters better and about 40 microns drier than EYLEA. And we believe most likely that is the effect of the IL-6. IL-6 has also been implicated in wet AMD. I think it may be perhaps a little more difficult to winnow out the effects of IL-6 in the wet AMD population. But I certainly would not rule out that we might end up with better visual acuity in the wet AMD population overall. Again, I mentioned earlier with respect to subgroup analyses, the subgroup in DAVIO-2 that was not rescued ended up with slightly better vision than on-label EYLEA. With respect to regulatory, I am going to let Ramiro take a stab at that. And with respect to commercial, Mike Campbell is here, and maybe Mike can try to take a stab at how that might affect us commercially. Ramiro, why do you not go ahead first?

Yeah. Sure. Thanks, Claire, for that question. So the regulatory path that we are following with both the wet AMD and the DME studies is a noninferiority approach. So if we show that BCVA are similar to the control arm, that, of course, might be sufficient for regulatory agencies. With that, for both wet AMD and DME study, as part of our analysis plan and hierarchical testing, we are going to be testing for superiority on the BCVA. And as Jay mentioned, there is a body of evidence suggesting that IL-6 has a role in both DME as well as wet AMD. So we are going to be investigating that in our Phase 3 clinical studies.

Thanks, Ramiro. And, Mike, if we are able to show this additional benefit of IL-6, can you perhaps comment on the commercial aspects of that?

Yeah. Thank you, Jay, and hi, Claire. The commercial approach, specifically with visual acuity and safety—and as Jay mentioned, our unique MOA—gives us a real opportunity here with IL-6 as part of that complete package. I mean, the messaging around this and the opportunity to commercialize gives patients and providers a real opportunity potentially to have a best-in-class, durable approach to treating wet AMD and DME. As Jay mentioned, if there is an opportunity to be able to show the benefit of IL-6 in the DME population, that has a real meaningful commercial opportunity to really separate yourself in the marketplace.

Thank you. And one moment for our next question. Our next question will come from the line of Graig Suvannavejh with Mizuho. Your line is open. Please go ahead.

Hey, good morning. Thanks for taking my question, and congrats on the first dosing in your DME Phase 3 studies. Maybe a question for Mike as the new Chief Commercial Officer. As you come into the company, how are you thinking about commercial prep for the potential launch of DuraVu? What are the key steps that are needed at EyePoint Pharmaceuticals, Inc. over, like, the next six, twelve, eighteen months to ensure an optimal U.S. commercial launch, especially when you might be going head-to-head in the competitive landscape versus a competitor?

Yeah. Thank you, Graig. You know, there is a complete go-to-market strategy and approach, for sure. And as we think about the opportunity here—and to your point, potentially even having a competitor in the marketplace—there is a lot of precision that goes into a go-to-market approach, especially in the specialty retina marketplace. So it is areas, for example, around not only positioning and messaging, the market research, the pricing research; all of that is priority, along with patient access and services. I mean, we can have a fantastic—and we believe we will have a fantastic—opportunity here, but if you cannot really get good at allowing patient access through coverage and reimbursement, then it can really hinder you. And so there is a lot of effort that we are putting behind making sure we have the right rigor to come to market and make it easy for doctors to be able to use DuraVu, but also easy for patients to access DuraVu. And just lastly, I would also add that there is a lot of really good work that is going on and will continue to go on around coverage with the payers, and good payer research that we have done.

Jay, if I could just quickly follow up: your Phase 3 trial designs in DME are just slightly tweaked or different from the Phase 3 trial designs in wet AMD. Just wondering if you could point us to reasons why slightly different, in terms of kind of loading doses, maybe maintenance doses—just things like that.

Sure. Go ahead, Ramiro.

Great. Thanks for the question. So when we look at our DME study in comparison to our wet AMD program, there are two main differences. The first one is on the control arm. For noninferiority studies, the FDA mandates that you use on-label medication, and the on-label regimen for aflibercept in DME is five loading doses followed by every eight weeks. So that is how we are going to be dosing patients in the control arm. The other difference is that for the DME study, we are now dosing DuraVu at day one. If you recall from the wet AMD study, we dosed DuraVu after the preloading dose at week eight. The reason for doing what we are doing in the DME study—which is to dose at day one—is to try to replicate the findings that we had in our Phase 2 study. If you recall from the Phase 2 study, we dosed patients on day one with aflibercept plus DuraVu compared to aflibercept alone. And then in that study, we showed a greater improvement in BCVA and CST early on in the study at week four. And we believe one of the reasons could be because of the role of IL-6/JAK1 in the DME disease. So we believe that if we can replicate those findings in the Phase 3 study, providing patients an earlier improvement in BCVA and CST is going to be something that is going to be advantageous for our patients.

Thank you. One moment for our next question. Our next question comes from the line of Debanjana Chatterjee with Jones. Your line is open. Please go ahead.

Hi, thanks for taking my question. One more on safety. So we saw a handful of cases of uveitis and iritis in a competitive trial. Could you just tell me again about your broader clinical experience in terms of this kind of inflammatory signals, even if mild or moderate, in your view? And also, is there anything intrinsic to your insert design or the overall product profile that you believe mitigates these kinds of events?

Sure, Debanjana. Thank you very much for the question. With respect to intraocular inflammation, the study is usually divided into iritis, which is inflammation in the front of the eye and, while somewhat troublesome, not typically sight-threatening; vitritis, inflammation in the back of the eye, a little more serious; and uveitis, which usually refers to inflammation in both those cavities. We do know historically biologics can cause inflammation, and there are various rates to the biologics. When they were first out, there were papers that were written that up to, you know, 10% or more of patients at certain times were getting at least mild inflammation. Obviously, inflammation is not ideal, and one of the real issues, even in mild inflammation, is the concern that it might actually be an infection, which can be much more serious. So with respect to the 191 patients that we have treated in those four studies, we had two cases of iritis, and both cases were mild, treated with topical drops, resolved quickly without any sequelae. We had no reported cases of uveitis, no reported cases of vitritis. So the overall intraocular inflammation rate is just those two patients, about 1%. We are optimistic and confident that our drug should not cause inflammation to any large degree because vorolanib, of course, is a small molecule. It is not a biologic. We are not gene therapy. And the matrix that we are using, that 6% matrix in the inserts—that matrix has been used in our prior FDA-approved products, and there were virtually no, very low rates of inflammation reported in those previous products. So, given that, and given the safety profile we have obviously seen in humans, which I just reported, and the safety we have seen in animals, intraocular inflammation is not something we are very concerned about. Thank you.

Thank you. And one moment for our next question. Our next question comes from the line of Colleen Kusy with Baird. Your line is open. Please go ahead.

I know we still have a number of months before the top-line readouts of the wet AMD studies, but just a clarifying question on the reduction in treatment burden, the secondary endpoint. How do you plan on measuring that? Would that include the loading doses, or is that measured after the loading doses? Just curious on the math there and just what our expectations should be for reduction in treatment burden. And then just an addendum to that, what would be clinically meaningful? Thank you.

Colleen, thanks for the question. First of all, the reduction in treatment burden is to be measured after the load. Since all the patients in the wet AMD trials get loaded with three monthly injections, the treatment burden clock, so to speak, starts after that. So in the first year of the trial, the DuraVu patients mandated should receive two DuraVu injections. The EYLEA arm, the control arm, has a mandated five injections. So if there is no supplementation in the entire study, we would expect that 60% reduction in treatment burden in the DuraVu arm. I can tell you that our expectation is there will be some supplementation probably in both arms, just like there was in the DAVIO-2 trial, although we do believe it is likely that there will be less supplementation in the Phase 3 for various reasons. But if you apply the supplementation rates that we saw in DAVIO-2 to the Phase 3, we would have an approximate 40% reduction in treatment burden, which is excellent. So I think from the perspective of what the doctors want to see, I think any kind of significant reduction in treatment burden will be welcome because supplementation with a TKI in the real world is not failure. Doctors do not mind doing injections; they just want to do fewer, number one. And, obviously, the more important thing is they want to get better visual acuity for their patients in the long term. So the concept of sustained release is not about reduction in treatment burden. That is a positive side effect. But what we really want to see is better vision control in the long term, and we believe we can provide that. I think some doctors may be excited about the possibility of using two MOAs, having a ligand-blocker biologic and having a receptor-blocking TKI at the same time. And that may prove to be better long-term visual acuity results. So this whole idea of supplementation, it has a strict definition within the trials, but in the real world I think the doctors will approach it a little bit differently. Now, as part of the trial, I think, Ramiro, maybe can you comment on the superiority testing that we will be doing about treatment burden?

Sure, Jay. So our hierarchical testing, number one, is going to be, as I mentioned before, the noninferiority on BCVA. The next one is going to be superiority on treatment burden. This study, of course, is well powered for the primary endpoint in noninferiority BCVA. For this key secondary endpoint, the treatment burden, the study is also well powered, and we should be able to detect the difference even if the difference is 10% or 7%.

Thanks. One moment for our next question. Next question will come from the line of Lisa A. Walter with R. Your line is open. Please go ahead.

Hi. Good morning, team, and thanks for taking our question, and congrats on the progress. Maybe just one on safety. Wondering how we should think about the safety profile in Lugano and LUCIA as it relates to DAVIO-2. I believe in DAVIO-2 the two milligram arm performed better on things like eye pain, cataract, and floaters versus the three milligram arm. But my question is, how much of the safety differences in DAVIO-2 are due to the two arms using a different number of inserts versus a different amount of drug? And how might this impact safety in Lugano and LUCIA where two inserts are being used, like the two milligram arm in DAVIO-2, but the amount of drug is closer to the three milligrams that was used? Any color here would be helpful. Thanks.

Sure, Lisa. First of all, with respect to dosage, we have animal data that shows no maximally tolerated dose of vorolanib so far, and we dosed animals with approximately ten times higher dosing than we have ever done in a human. So we do not believe there will be any sign of vorolanib toxicity at the current doses that we are using, even with reinjection. So, no, I do not believe any of the AEs reported have been due to vorolanib. And I would extend that to say, you know, so far, all the TKIs that have been used for wet AMD, as far as I know, there are no AEs that have been suggested to be due to the drug itself. So these drugs at the doses we are using appear to be very safe in the back of the eye. With respect to insert number, the numbers are too low to really know, and that is not something we, you know, are really essentially considering. There was a higher incidence of floaters in DAVIO-2 with the three milligram/three insert versus a two milligram/two insert, and, you know, maybe it had to do with the number of inserts. But given that we are using two inserts in the Phase 3s and ongoing, it is not much of a concern. And especially because the rates were low, and we had nobody report decreased vision due to the inserts. We had nobody leave the trials due to the inserts. Nobody has had to have the inserts removed. So from a clinical outcomes perspective, we are not concerned either about the number of inserts we are using or the doses of vorolanib that we are achieving. I think that the safety in the entire cohort really speaks for itself.

Thank you. And one moment for our next question. Our next question will come from the line of Yale Jen with Laidlaw & Company. Your line is open. Please go ahead.

Good morning, and thanks for taking the questions. And I recall in the press release, you mentioned that there is a floater and the mechanism of action of the drug could potentially reduce that. So could you elaborate a little bit more on that?

I am sorry, Yale. You asked about the mechanism of action reducing the floater—something of that nature? No. I am not sure I followed that, Yale. The mechanism of action of vorolanib includes its anti-VEGF effect, potentially the anti-PDGF effect to give a benefit to fibrosis, and potentially the anti–IL-6 effect to give a better and quicker result in visual acuity. I do not think the MOA would have any effect on patients' perception of floater. And, again, given that the rate of floaters for the whole 191 patients was 5.2%, I just do not think it is a concern.

Okay. Yeah. I just meant it says the preventive free-floating drug particles.

Okay. That is the design of the inserts. And once again, the design of the insert, as we have already stated—we design these inserts so they control drug release until the drug is gone. That is the whole purpose of a sustained-release insert: to control the drug release at therapeutic levels for an extended period of time. And so we would not expect free-floating drug particles. We have not seen free-floating drug particles in any of the animal studies, and so far, there have been no reports of free-floating drug particles in the eye. So that is more of an effect of the delivery system, not the MOA of vorolanib.

Okay. Great. That is very helpful to clarify that. And then maybe a quick one. How many sites for the COMO and the CAPRI study in total? And are some of those ex-U.S. versus in the U.S.?

Yeah. Ramiro, why do you not take that question, please?

Yep. So we have both studies as global studies. So we have sites in the U.S. as well as outside of the U.S. We are planning to have approximately 140 sites across both studies, and we are leveraging a lot of the infrastructure that we used for our wet AMD program. So a lot of these sites that are part of DME—most of them—were also part of our wet AMD program. And what was very interesting and very encouraging for us is that all sites from the wet AMD program that we invited to participate in the DME studies agreed to be part again of the DME program, which, again, I think highlights the confidence of the investigators in our clinical program.

Thank you. And one moment for our next question. Our next question comes from the line of Daniil V. Gataulin with Chardan. Your line is open. Please go ahead.

Hey, good morning, and thank you for taking my question. In your conversations with KOLs, what are you seeing in terms of which patients they would initially be willing to focus on when considering vorolanib? For example, are they thinking more of stable patients versus newly diagnosed patients or patients with high burden? And second part is, how do you expect the steps or requirements to affect the adoption of vorolanib? Thank you.

Thanks, Daniil. First of all, with respect to patient selection, I think we are all speculating a little here because we do not have the Phase 3 data and the label. But if one extrapolates from the Phase 2 data, I think that at the beginning, where most doctors will try it, is their patients who are being treated more frequently than they would like—every four weeks, every six weeks, every eight weeks. I think that will be the initial adoption of it. And as doctors get comfortable with its therapeutic profile and its safety, I think it will get expanded. Now I will modify that a bit, which is if we can show in the clinical trials that we can deliver better vision than EYLEA on-label, or that we are antifibrotic, or we have neuroprotection—other benefits that are potentially going to, that we might see—then I think the adoption will be much broader than that. I mean, if we can show that we are antifibrotic, I think retinal physicians will acknowledge the fact that fibrosis in the long term is an important cause of visual loss, and if you can prevent it from happening, you will result in improved vision over the years. So I think it will start off with the eyes that likely need a lot of treatment, but it may expand well beyond that. With respect to step therapy, we would not anticipate it would be an issue. First of all, again, we do not know what our label will look like, of course, but our study in wet AMD is being done with a three-injection load. So if the label contains use of DuraVu after three injections of an anti-VEGF, for example, then that automatically puts us beyond the initial injections into a branded drug. I will say we are looking into the possibility of our different MOA and our six-month efficacy, if it is there, in the IL-6 blockage—if we can show a benefit there—to be considered different than the ligand blockers, which may also be advantageous to us in the long term. But, of course, that is all dependent on the data we show in the pivotal trials.