EyePoint Pharmaceuticals, Inc.

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 iPoint fourth quarter and full year 2024 financial results and recent corporate development conference call. There will be a question and answer session to follow the completion of the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to George Elston, Executive Vice President and Financial Officer of iPoint. Please go ahead, sir.

Thank you, and thank you all for joining us on today's conference call to discuss IPoint's fourth quarter and full year 2024 financial results and recent corporate developments. With me today is Dr. Jay Duker, President and Chief Executive Officer. Jay will begin with a review of recent corporate updates and discuss the ongoing clinical trials for DuraView. I will close with commentary on the fourth quarter and full year 2024 financial results, and we will then open the call for your questions. 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.ipointpharma.com. 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. Therefore, 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 iPoint.

Thanks, George. Good morning, everyone, and thank you for joining us. 2024 was a year of continued execution and exceptional results for iPoint on all fronts, bringing us closer to delivering on our goal of bringing life-changing treatments to patients with severe retinal diseases. On today's call, We will review why we're the leader in ocular sustained drug delivery and how we are uniquely positioned to improve patients' lives with strong data in two potential multi-billion dollar blockbuster indications. We've advanced our best-in-class therapy, DuraView, into phase three clinical trials in wet age-related macular degeneration, or wet AMD. And we've reported positive 24-week Phase II results in diabetic macular edema, or DME, supporting a second Phase III opportunity. DuraView is the only sustained delivery program with robust data for an investigational six-month therapy in both of these indications, highlighting how a differentiated TKI with a new mechanism of action may improve patient outcomes compared to the standard of care. I want to emphasize the safety of our DuraCert technology, beginning with the four products already approved by the FDA and continuing with the strong safety data from the four clinical trials of bioerodible DuraCert E, consisting of over 190 patients treated with DuraView. This superb safety profile coupled with the excellent efficacy data we saw in W02, the largest intravitreal Phase II sustained delivery clinical trial in WET-AMD to date, has driven significant patient and physician interest in our ongoing pivotal trials, with both of our Phase III WET-AMD trials, Lugano and Lucia, surpassing enrollment expectations. I'm pleased to report that we are exceeding historical enrollment rates of comparable wet AMD trials by a substantial margin. The Lugano trial is now well over 50% enrolled, and the Lucia trial is tracking ahead of schedule as well. We continue to expect completion of enrollment in both trials in the second half of 2025, with top line data anticipated in 2026. The tried and true non-inferiority trial design of Lugano and Lucia in wet AMD represents a clear pathway to regulatory approval should the results be positive. In the sustained release space, we anticipate being the first investigational six-month intravitreal wet AMD program to submit a new drug application, or NDA, allowing us to potentially reach patients first. Our patient-centric trial design should enable a broad product label with an optimal dosing interval, thereby providing physicians flexibility and allowing us to capture more of the market share. As part of our preparation for success, our commercial manufacturing facility in Northbridge, Massachusetts is now online with DuraView registration batch manufacturing underway to support an NDA filing. We recently reported positive efficacy, safety, and subgroup data from our Phase II Verona clinical trial for DuraView in DME. Verona met primary and key secondary endpoints, firmly establishing DuraView as the only sustained release TKI program with an active DME program. DME is currently a large market, but has a significant need for sustained delivery options. I will discuss the Verona data in more detail later in this call, but based on the compelling phase two data, we expect to hold an end of phase two meeting with the FDA around pivotal trial design in the second quarter of this year. We remain in a solid financial position. We ended 2024 with a noteworthy balance sheet of $371 million in cash and investments and no debt. This was bolstered by a $161 million oversubscribed follow-on equity offering in the fourth quarter. Turning to our science, DuraView consists of Virolanib, which is a patent-protected, best-in-class tyrosine kinase inhibitor, or TKI, formulated in proprietary bioerodible Duracert E. Duracert has been safely delivered to tens of thousands of eyes across four FDA-approved products. meaning both patients and physicians are exceptionally comfortable with this delivery system and its established safety record. DuraCert E uses a bioerodible matrix that allows for the sustained delivery of drug via zero-order kinetic release for at least six months. Zero-order kinetics means that the drug is delivered at a steady rate so that small payloads can give an extended therapeutic effect with constant tissue exposure. In addition, DuraCert-E allows for immediate bioavailability and, by design, prevents uncontrolled release of free drug floating in the eye. Virolanib is not another anti-VEGF, and DuraView is not just another anti-VEGF program. Virolanib is a potent and selective TKI that brings a new mechanistic approach to the treatment of VEGF-mediated retinal diseases. through intracellular blocking of all VEGF receptors. It therefore blocks all isoforms of VEGF, including VEGF-C and D. Virolanib has demonstrated neuroprotection in a validated retinal detachment animal model and may have an anti-fibrotic benefit as it blocks the PDGF receptor. At tissue exposure achieved with Duravu, Virolanib does not block Ti2. Blockage of the TIE2 receptor is associated with retinal vascular instability. The review is packaged in a pre-filled sterile syringe injector. It is administered by a standard intravitreal injection in the physician's office, similar to the current standard of care anti-VEGF biologic treatments and consistent with current retinal practice dynamics. Unlike currently approved biologics and other sustained release programs in development, however, DuraView can be shipped and stored at ambient temperature. We have strong patent protection for DuraView in both the United States and outside of the U.S. This allows us to protect our innovation and provides us flexibility with our strategic partnerships. In summary, with an excellent safety profile, a distinct mechanism of action, zero-order kinetics that allows for sustained microdose delivery for at least six months, great patent protection, and convenience for physicians, we believe DuraView is well-positioned as an excellent treatment option for patients with VEGF-mediated retinal diseases. Turning to the Phase II Verona clinical trial on DME, we recently announced positive 24-week safety and efficacy data for DuraView, with both DuraView arms meeting the primary endpoint of longer time to first supplement versus control. DuraView 2.7 milligram demonstrated an early, sustained, and clinically meaningful improvement in best corrected visual acuity, or BCVA, with a gain of 7.1 letters compared to baseline, and a central subfield thickness, or CST, improvement of 75.9 microns on OCT measurement. This represents 74% more drying effect versus the Aflib Recept control. Visual and anatomic gains were observed as early as week four and were much more robust than those achieved by the Aflibricep control eyes, demonstrating the immediate bioavailability of DuraView and its differentiated profile as a sustained release TKI. Both DuraView treatment arms showed a favorable safety and tolerability profile with no DuraView-related ocular or systemic serious adverse events reported to date. Yesterday, we presented subgroup analyses from the Phase II Verona clinical trial of the supplement-free patients through week 24. The data demonstrated that for those eyes that went 24 weeks with no supplementation, DuraView 2.7 mg had a significantly better improvement in BCVA and anatomic control compared to the Aflibrocept control group. BCVA improved 10.3 letters compared to baseline versus only three letters improvement for the Aflib-RCEP control group. DuraView 2.7 milligram also demonstrated concomitant structural improvement with CST improvement of 117 microns versus only 31 microns for the Aflib-RCEP control. This result confirms that the positive data from the Phase II Verona trial were driven by DuraView as an active agent, continuously released over six months, and that the unsupplemented eyes had improved visual acuity of about two lines on the eye chart. The highly positive Phase II data supports our plans to engage in discussions with the US and ex-US regulatory agencies to solidify the plans around a pivotal program. As a company, we are highly focused on the successful completion of our Phase III wet AMD program for DuraView. In wet AMD, our goal is to provide a product that maintains stable vision and retinal anatomy for the majority of wet AMD patients within every six-month label. This could represent a significant improvement compared to the current anti-VEGF treatments, that are typically dosed on average every two months in the United States. And it may allow patients and practitioners the flexibility to reduce the number of visits without sacrificing visual outcomes. As previously mentioned, enrollment is ongoing in both of our pivotal phase three wet AMD trials, Lugano and Lucia, with rapid enrollment rates that are exceeding our expectations. Enrollment completion in both trials is expected in the second half of 2025. Both trials have received exceptional investigator and patient enthusiasm to date, driven by an established and familiar trial design. The two essentially identical non-inferiority trials with six-month redosing provide a clear and recognized pathway for global regulatory and commercial success, positioning Duravue to become a potential blockbuster franchise. To close, I'd like to thank the entire I-Point team for an incredible year and a strong start to 2025. The dedication and execution capabilities demonstrated by our team to reach these milestones reflects the entire organization's commitment to improving patients' lives. On that note, I'd also like to thank the patients and the clinical investigators for their participation in our ongoing trials. Without you all, the progress we've made advancing Duravue would not be possible. With our compelling clinical pipeline representing multi-billion dollar product opportunities, our best-in-class sustained ocular delivery, DuraCert E technology, along with a strong balance sheet, we have further established our role as the leader in sustained ocular drug delivery and are well on our way to bringing impactful therapies to patients suffering from serious retinal diseases. I will now turn the call over to George to review the financials. George?

Thank you, Jay. As Jay noted, we ended 2024 with a very strong balance sheet driven by continued stewardship of our cash and an oversubscribed $161 million follow-on financing in October, ending the year with $371 million in cash and investments. As the financial results for the three months and full year ended December 31, 2024, I were included in the press release issued this morning, my comments today will be focused on a high-level review for the quarter. For the quarter ended December 31, 2024, total net revenue was $11.6 million compared to $14 million for the quarter ended December 31, 2023. Net product revenue for the quarter ended December 31, 2024 was $0.8 million compared to net product revenue for the quarter ended December 31, 2023 of $0.7 million. We expect net product revenue to continue at immaterial levels as we will no longer be supplying UTEEQ to ANI Pharmaceuticals, our US partner, as of May 31st, 2025. This follows the non-renewal of a supply agreement that accompanied the sale of UTEEQ commercialization rights to Alamira Sciences, now ANI, in 2023. Consistent with our strategy, our forward manufacturing focus is on our review program to support clinical trials and NDA filing and future commercial launch. Net revenue from royalties and collaborations for the fourth quarter ended December 31, 2024, totaled $10.8 million compared to $13.3 million in the corresponding period in 2023. The decrease was primarily driven by lower recognition of deferred revenue from the license of UTIC product rights. Operating expenses for the quarter ended December 31, 2024, totaled $56.8 million compared to 30.4 million in the prior year period. This increase was primarily driven by the two ongoing phase three trials for Duravue. Net non-operating income totaled 3.9 million and net loss was 41.4 million or 64 cents per share compared to a net loss of 14.1 million or 33 cents per share for the prior year period. Turning to the full year ended December 31st, 2024, Total net revenue was $43.3 million compared to $46 million for the year ended December 31, 2023. Net product revenue for the full year ended December 31, 2024 was $3.2 million compared to net product revenues for the full year ended December 31, 2023 of $14.2 million. This decrease was driven by the license of Utique Product Rights sold in May 2023, completing iPoint's exit from its commercial business. Net revenue from royalty and collaborations for the full year ended December 31st, 2024 totaled $40.1 million compared to $31.8 million in the corresponding period in 2023. The increase was primarily driven by full year recognition of deferred revenue in 2024 from the license of UT product rights versus a partial year in 2023. Operating expenses for the full year ended December 31st, 2024 totaled $189.1 million versus $121.1 million in the prior year period. This increase was attributed primarily to a $26.6 million increase in clinical trial costs related to the Phase III clinical trials of Duravue, $28 million of increased personnel costs across the organization, including $24.7 million increase of non-cash stock compensation, $16.7 million in Duravue non-clinical and license expense. These increases were offset by $3.3 million decrease in other sales and marketing expenses due to discontinuation of UT commercialization in 2023. Net non-operating income totaled $15.1 million, and net loss was $130.9 million, or $2.32 per share, compared to a net loss of $70.8 million, or $1.82 per share, for the prior year period. Cash, cash equivalents, and investments in marketable securities on December 31st, 2024 totaled $371 million compared to $331 million as of December 31st, 2023. We expect the cash and investments on December 31st, 2024 will enable us to fund operations into 2027 beyond top-line Phase III data for Duravue and WED-AMD expected in 2026. Accordingly, Based on our solid cash position, we currently have no plans to access the equity capital markets this year. In conclusion, we are incredibly pleased with iPoint's progress in 2024 and are well-capitalized to advance our Duravue program through Phase 3 trials in wet AMD. I will now turn the call back over to Jay for closing remarks.

Thank you, George. As we've discussed, iPoint continues to be a story of a superior product strong execution, and focused leadership in the retinal disease space. We've accomplished our clinical milestones efficiently and aligned with our guidance, and we plan to continue this in 2025 and beyond. Key upcoming catalysts include enrollment completion in the Phase III Lugano and Lucia clinical trials of DuraView and WET-AMD in the second half of 2025. top-line data for these Phase III trials in 2026, and an end-of-Phase II meeting with the U.S. FDA to discuss the first pivotal Phase III trial of DuraView in DME. This remains an incredibly exciting time for I-Point, as we are well-positioned to execute on our upcoming milestones and continue to transform the treatment landscape with innovative, long-term solutions to improve both the vision and the lives of patients with serious retinal diseases. Thank you all very much for listening this morning. I will now turn the call over to the operator for questions.

Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. We ask that you please limit the number of questions that you ask at once. It will 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 Tess Romero with JP Morgan. Your line is open. Please go ahead. Hi, Jay and team.

Thank you for taking our questions this morning. For your wet AMD pivotal program, how many clinical sites have been activated across the trials of your overall target so far? I think you were at over 100 sites activated across the trials as of our conference in January. And for Lucia, can you remind us how many ex-US sites do you have open and are you aiming to open? Thanks so much.

Good morning, Tess. Thanks for your questions. I'd like to introduce our chief medical officer, Romero Ribeiro, who's also on the call. Dr. Ribeiro, do you want to answer those questions first of all about our wet MD trials, the current sites open, and ex-US sites planned?

yeah no thanks jay and good morning everybody thanks for the question just um so we we have most of the sites already activated in the us the ones that are not activated yet are usually the ones that have more length process like academic centers that takes a little bit longer to be activated but i think as as we show with our enrollment numbers we are very pleased with the progress of the studies, and we have most of the sites already activated, especially the strong ones. In terms of XUS, we are planning to have between 60 and 80 sites per study, which should be coming later this year.

Thank you. Can you just clarify your numbers of active sites currently in each trial?

So we have approximately active about 60 sites per study.

Okay. Thanks so much. Thank you. And one moment as we move on to the next question. Our next question comes from the line of Yigal Notumovitz with Citigroup. Your line is open. Please go ahead.

Hi, Jay and team. Thank you for taking the questions. I just had one on the analysis you presented yesterday on the supplement-free. It was interesting that you got a very, very strong separation with the 2.7 milligram versus Flibirsep, though for the 1.3, it seems like it didn't separate as much as one may have expected. I was just curious if you could comment on the trend there relative to what was observed with the overall population of the 26 patients. Thanks.

Yeah, thanks, Yigal. Terrific question. And again, I think that evaluation of the subgroup analysis, in particular the subgroup of the non-supplemented patients, really shows you how powerful DuraView was in this DMV population. So these were the eyes that made it the whole 24 weeks without anything else other than Duravue in our group. And they improved over 10 letters and had 117 microns less fluid, which was significantly better than the unsupplemented eyes in the control. I think what we're seeing essentially is evidence of dose response between the 2.7 and the 1.3 doses. And, of course, the 2.7 dose is what we're using in the current pivotal trials, what we plan on using in the pivotal trials in DME, and what our go-to-market dose is. But we interpret it with, you know, there is some individual variability within those numbers, but we think this represents a dose response. So what it shows you is that when DuraView works in this population, it works exceedingly well. And the supplement-free rates that were achieved by the 2.7 milligram dose were not clouded by the fact that those supplement-free eyes were slowly losing vision, were slowly gaining fluid, but didn't meet the criteria. In fact, when you look at those curves, they are flat. So these eyes that were supplement-free were extremely well controlled. I will bring up the point, too, that the supplements in the 2.7 group, with one exception, didn't really seem to change the vision or the fluid much, suggesting that we had breached perhaps a ceiling effect in most of these eyes. So, yes, that analysis is very strong, and I think to try to explain the differences, I think, again, it's dose response between the two doses with a little bit of individual variability there.

Okay, thanks. And just one very quick one on the timing of the Phase 3s. Will there come a point perhaps later this year where you'll be able to provide a little bit more granularity on sort of which half of 2026 we may expect the Phase 3 top-line data?

Oh, the Phase 3 top-line data, sure. I think we will be able to give you more granularity certainly as we approach last patient into Lucia. I think that'll be obvious. So, So, yeah, we do expect sometime, I suspect, early second half of the year to give you some more granularity around that. Oh, perfect. Thank you so much.

Thank you. And one moment as we move on to the next question. Our next question comes from the line of Yatin Suniha with Guggenheim. Your line is open. Please go ahead.

Hey, guys. Thank you for taking my question. I mean, now that, you know, the study is 50% enrolled, are you able to characterize, you know, the type of patients you are able to recruit right now, how they might be? I know there are differences versus W2, but, you know, anything you can just comment on? So that's one. The second one is on the DME side. I mean, now that you have a little bit more time to analyze the data, could you maybe talk about the development plan, especially the phase three, how you are thinking about what sort of a load we should expect from center of care? Yeah, thank you.

Thanks, Yann. First, the first question about the patient population, I think at a high level, we have said that we're capping the previously treated patients at approximately 25%. And we have reached that cap in Lugano. So the majority of patients obviously at this point, since we're over 50% enrolled, are treatment naive patients. But we don't expect in that trial to be enrolling any more previously treated patients. So that's really kind of the high-level understanding of where we're at with the type of patients we've recruited. Beyond that, there's really been no kind of analysis done yet, and we don't expect to be doing any analysis before the studies are done on any kind of other details around that. With respect to the Phase III DME trial, you know, we have a lot of options here. I think probably Romero is the best person to give you a little bit more specifics, but the truth is we don't know yet exactly what we're going to do. We really need to get some important questions answered by the agency around this. But the top line here is the data was so robust, I think we have a lot of options that would give us a pathway to approval. Romero, any more detail you wanna add on that?

Yeah, I think as you mentioned, Jay, the data from the Phase II study does show immediate benefit on BCVA on day one. So that type of result give us flexibility while we think about designing the Phase III studies for DME. The first option, of course, is always gonna be something similar to what we're doing for wet MD, right? We have the loading dose, which for DME in this case is five loading dose of a Flibercept, and then we would give to review. But again, based on the results from the phase two study, I think we might have an opportunity to design a study that is more efficient, meaning we would dose to review earlier, do a study that could be a little bit shorter, And overall, happy results sooner.

Very helpful. One more question. This one is for George. Could you maybe help us model the R&D expense going forward at least in 2025? Yeah.

Pardon me. Yeah, sure. Yeah. And so, remember, we did see that fairly meaningful increase in Q4. And that was really related to the initiation of both the Lugano and Lucia trials in the fourth quarter. You know, I think that's probably a good barometer of how you roll forward 2024. You know, as we clarified yesterday and again today, we are laser focused on execution of those trials. And that's going to be the focus for our burn on the R&D side in 2025. Thank you.

Thank you. One moment as we move to the next question. Our next question comes from the line of Kambiz Yazi with Jefferies. Your line is open. Please go ahead.

Morning, Jay and team. Congratulations on the enrollment progress. While Lucia and Lugano remain the laser focus near term, I was wondering if you have considered any opportunities to conduct post-marketing studies for DuraView long term? If so, what information would be valuable to glean from such studies and help further differentiate DuraView and the WebAMD marketplace? Thank you so much.

Thanks, Kempis, for that question. And obviously, we've already started to think about what other studies might enhance the value of DuraView and WebAMD. And the one we've talked about, I think, for a while, that is most obvious, would be post-approval to run a study in WET-AMD of DuraView against whatever the current industry leader for ligand blocker is at the point, whether it's high-dose ilea or vabizmo. In the study, instead of the primary endpoint being change in visual acuity, the primary endpoint would be supplement-free rate up to six months or percentage of eyes unsupplemented or time to first supplement, that sort of thing. The obvious reason for doing that is we're going up against two milligram ilea in the pivotal trials, which is a regulatory requirement. And while two milligram ilea remains a very, very good treatment as a ligand blocker with terrific short-term efficacy, Uh, the, the, the market seems to be moving, uh, into Vivisimo and suspect high dose eventually. So it makes sense to, to prove our longevity against those two products. We think we would do very well against that. Uh, and obviously then, uh, give us some more strength in the marketing argument. Uh, I can ask, you know, Romero, you know, any other thoughts you might have on, on, uh, post-approval studies that would be interesting and helpful.

Yeah, I think we are just learning about the effect of TKI in wet TMD. And, of course, the Phase III studies are later focused on getting our regulatory approval, but as Jay mentioned, we're going to do studies comparing to other ligand blockers. exploring additional benefits that ATK inhibitors could have, such as prevention of atrophy in this type of wet MD patient. So that's something that we're also going to be looking for as a post-market study.

Thank you. And one moment as we move on to the next question. Our next question comes from the line of Jennifer Kim with Cantor Fitzgerald. Your line is open. Please go ahead.

Hi, thanks for taking my question and congrats on all the strong execution. Maybe first to start in DME, can you give a bit more color on your plans to meet with both U.S. and ex-U.S. agencies next quarter, including what you're hoping to take away from both? Should we expect an update by next quarter or will that come shortly after and then understanding that when AMD takes center stage, what would sort of trigger a decision to advance a pivotal program? Is it contingent on sort of that accelerated pathway that Romero was talking about?

Thanks, Jennifer. Terrific questions as usual. So, I'm going to let Romero give a little more details around what type of interaction we'd expect and hope for with the regulatory agencies. Typically, what we've done in the past, and I suspect what we'll do for this as well, is after we get the written minutes, we would have a public announcement about what our plans are and how they obviously sync with what the agencies have told us. As for acceleration of DME, that, again, We do not, at this point as a company, want to put anything at risk with wet AMD. We really are delighted with how it's going. We want to continue to make sure that we have the resources within the company, both people resources and financial resources, to have a strong cash runway after the wet AMD data. And therefore, decisions about the structure of DME after regulatory meetings and the timing of DME is really going to be secondary to this first principle, which is make sure that WET-AMD is successful. So over to Romero again. Any color on what we really hope to accomplish with the 2Q meeting with the agencies?

Yeah, so we are planning to have a meeting both with the FDA as well as with EMA to ensure we gather regulatory feedback globally. In the end of the day, the questions are going to be around the design of the study. So, of course, I think we're going to propose something that, as I mentioned before, would make a study efficient and then get feedback from the agencies if they agree with that approach.

Okay, and if I could ask one question on the wet AMD programs. Since you talked about the 60 sites per study roughly, should we think about, I guess given the enrollment we've seen with Lugano, should we think about Lucia in the same way, or is there sort of a split in high enrollers tapping into Lugano before they move into Lucia? I'm just trying to think through what the cadence looks like.

The number of sites in Lugano at this point is slightly higher than Lucia. We do expect more Lucia sites to come on over time. Remember, Lucia started approximately, I think it was perhaps first patient in six, seven weeks after Lugano. So there's naturally going to be, I wouldn't call it delay, but a little separation between the rise in the recruitment. So what we're seeing, though, in recruitment rise in Lucia is mirroring what we saw at the beginning of the Lugano trial. So we are optimistic and confident that the type of enrollment we saw in Lugano will be matched by Lucia.

All right, that's helpful. Thanks, guys.

Thank you. One moment as we move on to the next question. Our next question comes from the line of Greg Suvanovich with Mizuho Securities. Your line is open. Please go ahead.

Good morning. Thanks for taking my question. Congrats on the progress in the year and the quarter. I just wanted to ask a question about your Northbridge manufacturing facility. Manufacturing, obviously, is something that we on the south don't get a lot of visibility into, but maybe can you talk about, you know, how... you are anticipating the manufacturing progress to continue and maybe some color on, I guess, kind of the quality of the site that you've built out there and potentially anticipating any potential CMC issues, which obviously we always worry about because we can't get visibility to that. Thanks.

Sure. Thanks, Greg. George, do you want to answer that question of Yeah, sure. How we did it and how it's going.

Yeah, Greg, you know, really great question. And thanks for that because, you know, we've been out ahead of this for several years. I think just to remind the audience. We opened our Northbridge facility last fall, state-of-the-art 41,000 square foot facility. We're focused not just on clinical execution, but being ready for registration batches, pre-approval inspections, and ultimately commercialization. The team's really done a remarkable job getting that site up and running. And we've really pivoted all the review manufacturing forward to that site. And the team has already started activities to get ready to start registration batches this year to support an NDA filing. The site was actually built to our specifications by the landlord. It didn't involve any cash investment, so it's really worked out incredibly well for us. And importantly, to your point, we've had FDA involved early in the design and execution of that site. And our quality team has had that in mind the entire way. So we're feeling really positive and really prepared as we get on the other side of data that we're going to have not just product for clinical, but also be able to support a successful commercial launch with positive data.

If I may tell a little anecdote about the site, too, which I think reflects the team that we have and how focused we are. I've obviously been out there many times. And right before we were ready to have an official opening, I went out to inspect. And I walked around the site. It's in the middle of the woods, actually. It's a beautiful area. I walked around the site, and there's a sidewalk all the way around the building. I went to the head of the building, and I said, why did we put a sidewalk all the way around the building? And his response was, so when the FDA comes to inspect us if it's a rainy day, they will have a sidewalk to walk on. That is the type of foresight that the team has, putting it together to make sure that this site will be up and running on time into both FDA and EMA specifications. And we expect, from a commercial perspective, to be able to supply the entire global supply for Duravue from this site.

Thanks for the anecdote, Jay, and thanks, George.

Thank you. One moment as we move on to the next question. Our next question comes from the line of Colleen Cussie with Baird. Your line is open. Please go ahead.

Great. Good morning. Thanks for taking our questions and congrats on all the progress. We've seen with other retina studies, talking about GA studies, a difference in results in XUS versus US sites. Can you speak to whether you'd expect a meaningful difference in the type of patients you're enrolling in Lugano and Lucia? Any differences in the standard deviation for patients and how that might impact the top line results?

Great question, Colleen. And I have the best person next to me to answer that question, Dr. Ribeiro, who, of course, was quite involved in one of the international GA studies. So, Ribeiro, what do you think?

Yeah, no, good question. And I think if we go back on the GA trials, I think that was something that could be one of the hypotheses, but I'm not sure if it was truly confirmed that the geographical difference were one of the reasons for the difference in the results Regardless, WES-MD studies are much more mature than GA trials across the globe, right? So clinical sites have been doing these WES-MD studies for many, many years. I think we nailed down our inclusion-exclusion criteria to accommodate a global study. So I don't expect to see baseline characteristics being much different between the U.S. and ex-U.S. sites.

Great, that's helpful. And one quick one, if I can. On DME, does the FDA have the same non-inferiority margin of minus four and a half letters on the lower bound of the confidence interval as they do in what AMD?

Roberto, do you know historically how the non-inferiority margin has been calculated in DME?

Yeah, so for DME, of course, it's going to be part of our discussion with the FDA EMA. But I think if you look back of some of the previous studies, they tend to use four letters. instead of 4.5, but of course, it's going to be one of the questions we ask in our interactions.

Great. Thanks for taking our questions and congrats on the progress.

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

Hi. Thanks for taking my question. So in terms of future market positioning, how would you review potential every six-month label compared to AXPAC's potential every six months, every 12-month label that Ocular has guided to?

Thanks for the question. I think an every six-month label is what the physicians, I think, prefer. I think that's been made clear not only by us but by quite a bit of market research. And of course, that's how we designed DuraView to consistently deliver therapeutic levels of virolinib for six months in virtually everybody. So that we like our label, we like our study design, and we think the six-month label will deliver that flexibility to patients and physicians to help tailor their individual treatment to maximize the vision, maximize the drawing effect, while minimizing the necessary visits and injections.

Thank you. As a quick follow-up, the way things are stacking up, ZeroView could still be the force to market durable TKI. How would you use this lead time over to capture the market?

Well, that's a really interesting question because it's quite broad, and of course, First-to-market, there is an advantage, as I think you all know, and we strongly believe that we are still in a position to be first-to-market, especially driven by this great enrollment that we've talked about today. In saying that, we've had an early program work done here for the past two years on exactly how we are going to position DuraView. It is a shift in the market, a true six-month repeatable, safe, tolerable treatment for VEGF-mediated diseases. You could argue there really is nothing like that right now. So that the idea of how to get physicians comfortable with it is a process that we are doing right now. and it will certainly accelerate internally as we get closer and closer to data and closer to eventual launch. So I think we could spend two hours on the details of what that might entail, but suffice it to say that just like we've been on the forefront of figuring out manufacture for commercial, we've been testing the market interviewing KOLs, talking to payers, talking to the business people at the retina groups in order to best position ourselves.

Thank you. Thanks for the insight. Thank you. And one moment as we move to the next question. Our next question is going to come from the line of Greg Harrison with Scotiabank. Your line is open. Please go ahead.

Hey, good morning. Thanks for taking the question. I wanted to ask about your cash runway guidance and whether that includes assumptions for or what assumptions that includes for work in DME and the earlier pipeline. And then separately, you know, what is the current status of the RASA Protofib program and when could we see additional data there?

Thanks, Greg. I'm going to let George take both those questions.

Sure. So, Greg, our cash guidance is into 2027, and I think, as Jay said, we want to have meaningful cash on hand on the other side of the Phase III data. And so our guidance includes, obviously, everything associated with Duravue and WET-AMD. It includes our ongoing work in preparation internally for an eventual DME study, but not the study itself. As far as Razaprotafib goes, our preclinical activities will continue there. Obviously, with our focus on wet AMD, that's gone to a lower priority, but it continues to move forward as we look at some additional enabling studies to ultimately move that forward for an IND. But I would say that's on percolation mode. The organization remains laser focused on wet AMD execution this year and really conserving cash.

Thanks, that's helpful.

Thank you. One moment as we move on to the next question. Our next question comes from the line of Yael Jin with Laidlaw & Co. Your line is open. Please go ahead.

Great, and thanks for taking the question and congrats on all the progress. Just two from us. The first one is that you suggested that you guys might be the first to market. And given the ocular sort of mentioned a few days ago, they may have the top line result in the first quarter of 26. Any read through from these two statements? And then I have a follow up questions.

Sure. First to market, of course, is going to be highly dependent on that last patient in the second trial. whether the first trial, which was not run concurrently, reads out in the fourth quarter of this year, the first quarter of next year, doesn't affect the last patient in the second trial, and for us, of course, last patient in for Lucia. Once again, as we look at the rate that we're recruiting, we remain confident that Lucia will recruit as rapidly as Lugano is, and therefore... we think that taken in total, we are confident we will be first to market.

Okay, great. That's very helpful. Maybe one more follow-up here, which is that a few days ago you reported the supplement-free patient subgroup analysis. I know the number is small, but just curious, have you guys dissected the patient which do not need supplement versus those needs? Any characteristic differences and being able to maybe apply to your current phase three study?

Yeah, great question, Yale. I'm going to let Romero answer that.

Yeah, no, good question. And I think you already mentioned the limitation of this study being a small study. So I think with this sample size, it's a little bit hard to predict. which patients are going to be suplement of three. Of course, once we have a larger database with the phase three program, then that's something that we might be able to look at.

Okay, great. That's very helpful. Again, congrats on all the progress. Thank you.

Thank you. And one moment for our next question. Our next question comes from the line of Yee Chin with HC Wingright. Your line is open. Please go ahead.

Thank you for taking my question. Could you talk about whether you currently have a plan to initiate a phase three trial in DME at this point, potentially late 2025 or 2026? If not, do you plan to find a partner potentially moving this indication forward? And what would be the target enrollment suggested by the Verona results in a potential phase three trial setting? Thank you.

All great questions, and I can say that we have currently no plans to initiate the pivotal trial in DME in 2025. We believe that it will be a 2026 event at this point, and we would certainly welcome a potential partner, but we're not going to partner in indication individually. A partnership that might include clinical program development in DME would have to be a much larger partnership or we really wouldn't be interested in it. So that's something that I think we would consider at the right time, but as I said, it would have to be a much larger structured partnership than just DME. As for the target Again, I think maybe Romero, you might be able to answer that better about how we would approach the targets.

Yeah, and I think we have a great benefit of having the wet MD study in a lot of the learnings, as well as the relationship we're building with the sites now. So we know that for DMEs clinical sites, they would be very likely the same ones as we are using for RETMD trials. So I think in terms of enrollment rates, we would also be optimistic for a DME trial.

All right. Thank you.

Thank you. I am showing no further questions in the queue at this time. Ladies and gentlemen, thank you for participating in today's conference. This does conclude your program, and you may now disconnect. Everyone, have a great day.