Good morning. My name is Michelle, I'll be your conference operator today. At this time, I would like to welcome everyone to the EyePoint Fourth Quarter 2025 financial results and recent corporate developments conference call. There will be a question and answer session to follow at the completion of the prepared remarks. 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. Sir, please go ahead.
Thank you. Thank you all for joining us on today's conference call to discuss EyePoint'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. Jay will begin with a review of recent corporate updates and discuss our clinical programs for DURAVYU and wet AMD and DME. I will close with commentary on the fourth quarter and full year 2025 financial results. We will 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, www.eyepoint.bio.
Before we begin our formal comments, I'll 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 and 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. You should not rely on these forward-looking statements as representing our views as of any date subsequent to today. I'll now turn the call over to Dr. Jay Duker, President and Chief Executive Officer of EyePoint.
Thank you, George. Good morning, everyone, and thank you for joining us. 2025 was defined by significant progress and achievement for EyePoint as we made important advances that set the stage for success and potential value creation for the year ahead. As a result of our exceptional clinical execution driven by our de-risked and patient-centric programs, our lead asset, DURAVYU, 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 DURAVYU 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 III DME trials.
With a strong cash position that is expected to fund operations into the fourth quarter of 2027 and multiple inflection points on the near-term horizon, we are entering a transformative period for EyePoint with significant momentum. Our conviction in DURAVYU's blockbuster potential is underpinned first and foremost by its compelling clinical profile. In our Phase II trials in the largest retinal disease markets, a single dose of DURAVYU demonstrated durable efficacy with improved vision and tight anatomical control. Importantly, DURAVYU 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 III 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 that 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 TIE-2 inhibition are the key drivers of its differentiated profile. This unique profile positions DURAVYU 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 DURAVYU's development. Our Phase III wet AMD program was intentionally designed to inform real-world practice and generate meaningful data for the retinal community by comparing DURAVYU to on-label aflibercept as the control.
Additionally, we will be evaluating statistical superiority in treatment burden reduction and six-month redosing to support a compelling and relevant label. Based on the success of our large phase II DAVIO 2 trial and with our proven regulatory pathway and strong execution to date, we believe our wet AMD program is uniquely de-risked 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 DURAVYU for multiple indications. We are pleased that randomization is now underway for both COMO and CAPRI, our two pivotal phase III trials in DME, where we expect to drive rapid enrollment by leveraging our preexisting clinical trial infrastructure and investigator network.
In line with our wet AMD program, our DME program follows an established non-inferiority design with an on-label standard of care control and redosing every six months. It was similarly informed by impressive phase II data from the VERONA trial, where eyes treated with DURAVYU demonstrated meaningful visual and anatomic improvements as early as four weeks. We anticipate top-line data in the second half of 2027 and look forward to building upon our strong track record of clinical execution as we advance DURAVYU through our phase III DME program. We believe that DURAVYU 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. We remain focused on building DURAVYU 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. DURAVYU'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 long-standing 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'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 DURAVYU 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 our planned new drug application, or 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 DURAVYU to patients if approved. Before passing it over to George to review our financials, I'd like to thank the entire EyePoint 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 research 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 December 31st, 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 December 31st, 2025, total net revenue was $0.6 million, compared to $11.6 million for the quarter ended December 31st, 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 the second quarter of 2023.
Operating expenses for the quarter ended December 31st, 2025 totaled $71 million, compared to $57 million in the prior year period. This increase was primarily driven by the ongoing phase III trials for DURAVYU 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 December 31st, 2025, total net revenue was $31 million, compared to $43 million for the year ended December 31st, 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 the second quarter of 2023.
Operating expenses for the full year ended December 31st, 2025 totaled $275 million versus $189 million in the prior year period. This increase was primarily driven by the ongoing Phase III trials for DURAVYU in wet AMD and DME. Net non-operating income totaled of $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 December 31st, 2025 totaled $306 million compared to $371 million as of December 31st, 2024.
We expect the cash and investments on December 31, 2025 will enable us to fund operations into the fourth quarter of 2027, well beyond key milestones and NDA preparation for the Phase III wet AMD program in 2026 and fully funding the Phase III pivotal DME program. In conclusion, we are incredibly pleased with EyePoint's progress in 2025 and are well capitalized to continue advancing DURAVYU 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'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 de-risked, 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 III LUGANO trial anticipated in mid-2026, with LUCIA data to closely follow. Completing enrollment in our pivotal Phase III DME program in the second half of 2026, and preparing for regulatory filing in wet AMD, assuming positive Phase III data. Thank you all for your attention this morning. I'll now turn the call over to the operator for questions.
Thank you. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. As usual, we'll 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 Q&A roster. Our first question is going to come from the line of Tessa Romero with JP Morgan. Your line is open. Please go ahead.
Good morning, guys. Thanks so much for taking the question.
Good morning, Tess.
Jay, George, can you clarify the rate of ocular AEs that you have seen across your cumulative safety database with DURAVYU, in particular around the incidence of vitreous floaters and cataracts? Relatedly, what specifically has the physician feedback been around your safety profile? Thank you.
Sure, Tess. Happy to address that. As you probably recall, we've treated over 190 patients in completed trials. That's one phase I and III phase II trials. The number of cataracts that were measured by the investigators in those 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%. 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 DURAVYU patients reported floaters, which is again consistent with what you might see in any type of study that has injections into the eye. 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 II data to evaluate both the efficacy and the safety of our drug. I think that gave them a great confidence in enrolling patients. I think again, I'd like to make one more note on the 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. Again, just to remind the listeners, in the DAVIO 2 trial, our treated patients in wet AMD gained vision. 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 gained. The Eylea arm, again, at that point, was getting three injections over that timeframe because it was on label Eylea. That to summarize, we're very comfortable with our safety. We've 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.
Hey, guys. Thank you for all the details. 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. Jay, I appreciate your comment on the safety. Clearly has been pretty good across phase II studies and also phase III 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. For the first question, the regulatory front, yeah, I think in general, we would all welcome a more rapid and less expensive pathway to drug approvals. As you heard this morning, and as I think most listeners know, we have two identical phase III 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. Overall, I don't 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 the fourth quarter of 2027.
Given that other regulatory agencies around the world are probably still not aligned with single trial, we don't believe we have any reason to alter our approach for these two indications. Future indications, of course, we will, you know, discuss with the agency. With respect to single trial in retina studies, I think that it's 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. 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's single trial. Of course, in the case of rare diseases, there are exceptions that are made.
wet AMD, DME, unfortunately are not rare diseases. With regard to, the regulatory pathway, we think our pathway is de-risked. We have taken the non-inferiority approach, which is, you know, the approach essentially the five of the last approvals have taken. We've got 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's a blockage in their ability to look into the eye, either in the back of the eye, in the vitreous, from the front of the eye, 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 DURAVYU in any of the treated eyes. We wouldn't have expected it. DURAVYU is designed to hold the drug until the drug is fully eluded. We have no free-floating drug particles. We've had 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'd like to remind everybody, our scientists have been able to upgrade the inserts so that they're 94% payload. They're only 6% matrix. We haven't seen any anterior chamber opacity, and we wouldn't expect to. The vitreous opacity percentage is low.
Thank you. 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.
Hi, Jay and team. Thank you. I'm just curious with regard 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've got Ramiro on the line, our CMO. Ramiro, feel free to answer that question about continued safety looks in the wet AMD trials.
Hey, Yigal. Good to hear from you. We have, as a safety monitoring body for these studies, both internal mask review that we do as ongoing basis, as well as the independent Data Safety Monitoring Committee that reviews the unmasked data. The last DMC meeting was in 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 DURAVYU so far has been consistent with our previous experience in the phase I, phase II studies, with nothing new to be aware. Our next DMC meeting is scheduled in May. That's going to be the next opportunity for that group of physicians to review the MS data and provides updates to us.
Okay. Thank you. Just one question on biomarkers. I know you identified IL-6 recently. I'm just wondering what additional biomarker work may you be doing to further explore the activity profile of vorolanib?
Yigal, thanks for that question. Additional biomarker work around the JAK1 receptor and its ability to block downstream effects of IL-6. We have additional data on that that we're 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. We didn't discover at the time any other significant receptors involved in retinal disease either positively or negatively that vorolanib was active against.
Got it. Thank you.
Thank you. One moment for our next question. Our next question will come from the line of Clara Dong with Jefferies. Your line is open. Please go ahead.
Hi. Good morning, guys. Thanks for taking my question. Just in terms of the DURAVYU and multi-mechanism profile beyond the JAK inhibition, so how prominently do you expect this mechanistic differentiation to really be featured in your regulatory discussions and maybe eventual commercial messaging as well? Is there any plan for you to report more preclinical evidence of the IL-6 inhibition MOA in the future? Thank you.
Yeah, Clara, great question. Thanks for it. 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. The, the great thing about what we do is eventually it's all about the data. 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's what we showed in the VERONA data. If you recall, as early as week four, the treatment arms with DURAVYU had already separated from EYLEA. We were already four to five letters better and about 40 microns drier than EYLEA.
We believe most likely that's 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. I certainly wouldn't 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 W2 that was not rescued ended up with slightly better vision than on-label Eylea. With respect to regulatory, I'm going to let Ramiro Ribeiro take a stab at that. With respect to commercial, Michael Campbell's here, and maybe Mike can try to take a stab at how that might affect us commercially. Ramiro Ribeiro, why don't you go ahead first?
Yeah, sure. Thanks, Clara, for that question. The regulatory path that we're following with both the wet AMD and the DME studies is a non-inferiority approach. 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 BCVA. As Jay mentioned, there are body of evidence suggesting that IL-6 has a role in both DME as well as wet AMD. We're going to be investigating that in our phase III clinical studies.
Thanks, Romero. Mike, if we're 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, Clara. 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's 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 a marketplace.
Thank you. 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.
Good morning. Thanks for taking my question. Congrats on first dosing in your DME Phase III 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 DURAVYU, what are the key steps that are needed, you know, at EyePoint over, like, the next six, 12, 18 months to ensure an optimal U.S. commercial launch, especially, you know, when you might be going head-to-head, you know, in a competitive landscape versus another competitor? Thanks.
Go ahead, Mike.
Yeah. Thank you, Greg. You know, there is a complete, go-to-market strategy and approach for sure. As we think about the opportunity here, and to your point, potentially even having a competitor in the marketplace, there's a lot of precision that goes into a go-to-market approach, especially in the specialty retina marketplace. It's 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, if you can't really get good at allowing patient access through coverage and reimbursement, then it can really hinder you.
There's a lot of effort that we're putting behind making sure we have the right rigor to come to market and make it easy for doctors to be able to use DURAVYU but also easy for patients to access DURAVYU. I would also add that there's 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've done.
Jay, if I could just quickly follow up here.
Sure.
Phase III trial designs in DME are just slightly tweaked or different from the phase III trial designs in wet AMD. Just wondering if you could point us to reasons why they're slightly different in terms of kind of loading doses, maybe maintenance doses, just things like that?
Sure. Go ahead, Romero.
Yeah, Greg, thanks for the question. When we look at our DME study comparison to our wet AMD program, there are two main difference. The first one is on the control arm. For non-inferiority studies, the FDA mandate that you use on-label medication, and the on-label regimen for aflibercept in DME is five loading dose followed by every eight weeks. That's how we're gonna be dosing patients in the control arm. The other difference is that for a DME study, we are now dosing DURAVYU at day one. If you recall from the wet AMD study, we actually dosed DURAVYU after the three loading dose at week eight. The reason for doing what we're 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 II study.
If you recall from the Phase II study, we dosed patients on day one with aflibercept plus DURAVYU compared to aflibercept alone. Then in that study, we show a greater improvement in DVA and CST early on in the study at week four. We believe one of the reasons is could be because of the role of IL-6 JAK1 in the DME disease. We believe that if we can replicate those findings in the Phase III study, providing patients an earlier improvement in DVA and CST, is gonna be something that is gonna be advantageous for our patients.
Thank you very much.
Thank you. One moment for our next question. Our next question comes from the line of Debanjana Chatterjee with JonesTrading. Your line is open. Please go ahead.
Hi. Thanks for taking my question. One more on safety. We saw a handful of cases of uveitis and iritis in our competitor trials. Could you just and tell me again about your broader clinical experience in terms of these kind of inflammatory signals, even if mild or moderate in, on DURAVYU. Also is there anything intrinsic to your insert design, injector or the overall product profile that you believe mitigates these kind 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, you know, there are 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. 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 and resolved quickly without any sequelae. We had no reported cases of uveitis, no reported cases of vitritis. The overall intraocular inflammation rate is just those two patients, about 1%. We're optimistic and confident that our drug shouldn't cause inflammation to any large degree because vorolanib, of course, is a small molecule. It's not a biologic. We're not gene therapy.
The matrix that we're using, that 6% matrix in the inserts, that matrix has been used in our prior FDA-approved products. There was virtually no, very low rates of inflammation reported in those previous products. Given that, and given the safety profile we've obviously seen in humans, which I just reported, the safety we've seen in animals, intraocular inflammation is not something we're very concerned about.
Thank you.
Thank you. 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.
Great. Good morning. Thanks for taking our questions. I know we still have a number of months still before the top-line readouts of the wet AMD studies. 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, you know, on the math there and just what our expectations should be for reduction treatment burden. Just an addendum to that, you know, 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. In the first year of the trial, the DURAVYU patients mandated should receive two DURAVYU injections. The EYLEA arm, the control arm, has a mandated five injections. If there's no supplementation in the entire study, we would expect that 60% reduction in treatment burden in the DURAVYU arm. I can tell you that our expectations, there will be some supplementation probably in both arms, just like there was in the DAVIO 2 trial.
Although we do believe it's likely that there will be less supplementation in the phase III for various reasons. If you apply the supplementation rates that we saw in DAVIO 2 to the phase III, we would have an approximate 40% reduction in treatment burden, which is excellent. I think from the perspective of what the doctors wanna see, I think any kind of significant reduction in treatment burden, will be welcome because I, a supplementation with a TKI in the real world is not a failure. Doctors don't mind doing injections. They just wanna 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. The concept of sustained release is not about reduction in treatment burden. That's a positive side effect.
What we really wanna 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 blocker TKI at the same time, and that may prove to be better for long-term visual acuity results. 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. As part of the trial, I think, Romero, maybe can you comment on the superiority testing that we'll be doing about treatment burden?
Sure, Jay. Our, our hierarchical testing, number one is gonna be, as I mentioned before, the non-inferiority on BCVA. The next one is gonna be superiority on treatment burden. The study, you know, of course, is well powered for the primary endpoint, the non-inferiority BCVA. For this key secondary endpoint, the treatment burden, the study is also, well powered, and we should be able to detect a difference even if the difference is 10% or 7%.
Great. Thanks.
Thank you. One moment for our next question. Our next question will come from the line of Lisa Walter with RBC. Your line is open. Please go ahead.
Hi. Good morning, Jay. 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 LUCIA as it relates to DAVIO 2. I believe in DAVIO 2, the 2-milligram arm performs better on things like eye pain, cataract, and floaters versus the 3-milligram arm. 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? How might this impact safety in LUGANO LUCIA, where two inserts are being used like the 2-milligram arm in DAVIO 2, but the amount of drug is closer to the 3 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 rolipram so far. We dosed animals with approximately 10 times higher dosing than we have ever done in a human. We don't believe there will be any sign of vorolanib toxicity at the current doses that we're using, even with reinjection. No, I don't believe any of the AEs reported have been due to vorolanib. I'd extend that to say, you know, so far, all the TKIs that have been used for wet AMD, as far as I know, there's no AEs that have been suggested to be due to the drug itself. These drugs at the doses we're 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's not something we, you know, really essentially considering. There was a higher incidence of floaters in Phase II with a 3-milligram three insert versus a 2-milligram two insert. It, you know, maybe it had to do with the number of inserts, but given that we're using two inserts in the Phase III and ongoing, it's 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 to have the inserts removed. From a clinical outcomes perspective, we're really not concerned either about the number of inserts we're using or the doses of vorolanib that we're achieving.
I think that, the safety, in the entire cohorts really speaks for itself.
Thank you. One moment for our next question. Our next question will come from the line of Yale Jen with Laidlaw & Co. Your line is open. Please go ahead.
Good morning, and thanks for taking the questions. I recall in the press release you have, that you have mentioned that there's a floater and the mechanism of actions of the drug could potentially reduce that. Could you elaborate a little bit more on that?
I'm sorry, Yale. You asked about the mechanism of action reducing-
Of the drug. Of the drug that potentially could reduce the floater.
Reducing floater.
Something of the nature.
No, I'm not sure I follow that, Yale. The mechanism of action of vorolanib, again, 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 results in visual acuity. I don't think the MOA would have any effect on patient's perception of floater. Again, given that the rate of floaters for the whole 191 patients was 5.2%, I just don't think it's a concern.
Okay. Yeah. I just met read. It says to prevent the free-floating drug particles. Okay.
That's not MOA. That's the design of the inserts. Once again, the design of the insert, as is already stated, we design these inserts so they control drug release until the drug is gone. That's the whole purpose of a sustained release insert, is to control the drug release at therapeutic levels for an extended period of time. We would not expect free-floating drug particles. We haven't 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. That is a more of an effect of the delivery system, not the MOA of vorolanib.
Okay, great. That's very helpful to clarify that. Then maybe a quick one. How many sites for the COMO and the CAPRI study in total, and are some of those are ex-U.S., U.S. Versus in or in the U.S.?
Yeah. Romero, why don't you take that question, please?.
Yeah. We have both studies are 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. We are leveraging a lot of the infrastructure that we use for our wet AMD program. A lot of the sites that are part of DME, most of them were also part of our wet AMD program. Which 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, they agreed to be part again, of the DME program, which again, I think highlights the confidence of the investigators in our clinical program.
Okay, great. Thanks a lot. I very appreciate.
Thank you. One moment for our next question. Our next question comes from the line of Daniil 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 hyperton? Second part is, how do you expect the steps or requirements to affect the adoption of vorolanib? Thank you. Thanks, Daniel.
First of all, with respect to patient selection, I think, we're all speculating a little here because we don't have the phase III data in the label. If one extrapolates from the phase II 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. As doctors get comfortable with its therapeutic profile and its safety, I think it will get expanded.
I'll 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're anti-fibrotic, or we have neural protection, other benefits that are potentially that we might see, then I think the adoption will be much broader than that. I mean, if we can show that we're anti-fibrotic, I think retinal physicians will acknowledge the fact that fibrosis in the long term is an important cause of visual loss. If you can prevent it from happening, you will result in improved vision over the years. 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 wouldn't anticipate it would be an issue. First of all, again, we don't know what our label will look like, of course, but our study in wet AMD is being done with a three-injection load. If the label contains use of DURAVYU 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's 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. Of course, that's all dependent on the data we show in the pivotal trials.
Okay, great. Thank you.
Thank you. I'm showing no further questions in the queue at this time. Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may now disconnect. Everyone, have a great day.