Good day, everyone. Thank you very much for coming to Oculis R&D Day. My name is Sylvia Cheung, Chief Financial Officer at the company. We'll spend the next two hours reviewing our pipeline and highlighting some of the key developments that we're particularly excited about. We're also extremely pleased to have the world's renowned leading ophthalmology, neuro-ophthalmology, and neurology experts with us. I look forward to hearing their insightful perspectives on our data and the opportunities for each of our leading assets. This slide shares our standard cautionary statements and forward-looking statements. I would encourage everyone to read it as a refresher. Next one. On the next three slides, I'll briefly introduce each of our speakers and guests of honor, and then I'll run through the agenda. In addition to myself, three Oculis executives will present today. They are Dr. Riad Sherif, Chief Executive Officer of Oculis, Snehal Shah, President of R&D, and Dr. Sharon Klier, Chief Development Officer. It is with deepest gratitude that we have nine KOLs joining us today. They are the top minds in ophthalmology, neuro-ophthalmology, and neurology fields in the world. Due to our rich agenda and compact contents, I'll provide brief introductions. The four retina experts are Dr. Arshad Khanani, a member of our Board of Directors, the chair of our Retina SAB and DIAMOND Steering Committee. He's also a clinical professor at the University of Nevada, Reno School of Medicine. Dr. Barry Kuppermann, Professor of Ophthalmology, Neurology, and Neurosurgery at McGill University. Dr. David Boyer, Professor of Ophthalmology at the University of Southern California. Dr. Sebastian Wolf, Professor of Ophthalmology at the University Hospital Bern. Our expert in anterior segment and in ocular inflammation, who will speak about our dry eye and our development plans for Licaminlimab, is Dr. Anat Galor, Professor of Ophthalmology at Bascom Palmer Eye Institute at the University of Miami. The three thought leaders who will speak about the neuro-ophthalmology-related topics are Dr. Len Levin, Professor of Ophthalmology and Neurology and Neurosurgery at McGill University, Dr. Mark Kupersmith, here with us, Professor of Neurology, Ophthalmology and Neurosurgery at Mount Sinai, and Dr. Pablo Villoslada, who's also here with us, Department Chair of Neurology at Hospital del Mar, Pompeu Fabra University. We also have the privilege to be joined by Professor Stephen Hauser, Head of Neurology at UCSF. Dr. Hauser has received numerous awards and honors for his work in neuroscience and neuroinflammation, as described on this slide. As I said, we have a very exciting agenda today, and we'll start with Riad's corporate overview. He will highlight our strategic evolution of our innovative pipeline, and then we'll move on to our three leading assets. First on our agenda is OCS-01. It is for diabetic macular edema, and it's our most advanced asset. We will cover the phase III DIAMOND Program and its latest updates. Following that, we will discuss Licaminlimab, or OCS-02. It aims to be the first personalized medicine for dry eye disease. This asset is ready to move into our first pivotal trial later this year, following the successful phase II-B trial and the recent FDA discussion. Finally, we'll spend the most time on Privosegtor, or OCS-05, which truly is a novel neuroprotective asset. It showed very positive phase II data in the ACUITY trial on acute optic neuritis, and it has incredible potentials given the neuroprotective properties. We will first share a summary of the ACUITY trial results, as well as some expanded data from that trial, followed by the development plans for the Privosegtor. I'll remind you that we'll have a Q&A session at the end of each of the presentations, which will be facilitated by Riad, and he will also provide a closing remark at the end of the meeting. Without further ado, I would now turn the podium over to our CEO, Dr. Riad Sherif. Thank you, Sylvia. Thank you to all our guests and to the Oculis management to be here. Thank you also for all attending physically and via Zoom. Very pleased to be here and very, very happy to give the first R&D Day for 2025. 2025 starts for Oculis extremely strong, actually, with the first Privosegtor positive result in ACUITY trial, which was in acute optic neuritis. We will go into the details in terms of selecting AON or acute optic neuritis in terms of indication, but also what it means for neuroprotection. The second good news was our meeting with FDA, which for the first time in dry eye and perhaps in ophthalmology, actually, we are going to have a genotype-based development program for dry eye. This is a result of spending time to understand the disease, spending time to understand also the risks in terms of development, and coming with a potential solution which is transformative in terms of how to develop drugs in the future. The third milestone was raising $100 million in the March timeframe, and I would like to thank all our investors and new investors who join us for your support and trust. The last, which is also very important for us, was the OCS-01 completion of enrollment for the phase III. Both trials, DIAMOND 1 and DIAMOND 2, are fully enrolled with more than 800 patients in both trials. Sharon will go into the details. Enrollment was very fast, much faster than expected, and extremely happy with where we are. As you know, Oculis has three major clinical assets: OCS-01, which is the first and the only product in phase III in DME as an eye drop. It is designed to address two unmet medical needs which are not addressed today. One is early intervention for patients who are starting the disease. In common practice, because of benefit-risk, because it is a needle into the eye for standard of care, we tend to wait. There are hundreds of thousands of patients, even a million in the U.S. and multimillions elsewhere, who are not treated. The first segment is early intervention, and the second segment is patients who are not responding to the standard of care. Sharon will give more details, and we are privileged to have experts who will be sharing their experience in terms of DIAMOND 1 and DIAMOND 2 execution. The second asset is Licaminlimab. As I said, this is really for the first time where we are going to have a genotype-based development in dry eye. This will allow us to be much more efficient in terms of phase III, reducing the risks and reducing the cost, but also offering a very different and innovative TPP to address a highly unsatisfied market, which is dry eye. The third Privosegtor is a true breakthrough, actually, in neuroprotection. First time ever where we see a result which is consistent in terms of anatomy, in terms of biology, and we will see them later. This is a new data point we'll be sharing with you. In terms of function in acute optic neuritis, which is the first indication, and it was really designed as a multiple shot on goal AON as a proof of concept in neuroprotection. It is a difficult indication, but we have been able to show benefits in acute optic neuritis, which really opens the door. As we always say, if it works in acute optic neuritis, it will open the door for multiple clinical applications. This is where we are. Therefore, this means for us to prioritize our portfolio and to focus on where we can drive value and have the best return on investment in terms of resource deployment, internal and cash we have in hand. This is really the thinking and the mindset we have in terms of portfolio prioritization. There are programs or there are indications which we will postpone, and we will go into the details. Where the company is going to focus are three key core indications, which the three of them can create a multibillion business. OCS-01 would be the first topical treatment for DME if approved. As we said, enrollment is finalized, and now we have the next 12 months to be focused on making sure that we deliver the highest quality possible trial in phase III in DME. The readout is planned in Q2 2026. The second program is Licaminlimab with the genotype-based development to deliver a personalized medicine in dry eye. A market which is driven by trials and error, where Licaminlimab will be the first, which will be differently prescribed, not by trials and error, but by making sure to go to the patient who will be highly responders to this biology. The last, Privosegtor neuroprotection in acute optic neuritis, which is the core program now we have. We have data in phase II, and our plan is to full steam go into the next steps, and we will go into the details. In terms of expansion and really the thinking based on the pathophysiology of acute optic neuritis and acute treatment, there are two indications where we would like to initiate programs. One is called NAION, which is an orphan indication. We are speaking about 20,000-30,000 patients in the U.S. It is a high unmet medical need. No treatment is approved. The second indication, which will be relapses in MS. We will go into the details about what we envision. We are in parallel exploring internally multiple in vivo proof of concept based on the biology, on Privosegtor biology, and we will be communicating once we have the result further on, but expect a lot to come from OCS-05 biology. Now I will invite my colleague, Sharon, to go through the OCS-01 in DME. Thank you. Thank you, Riad. We had positive results in the DME OCS-01 studies as soon as the exploratory studies that we conducted a few years ago, as well as a phase II study and the phase III stage I study that was conducted and shared last year. On the right, you can see an example of a patient in the phase II study that came in without treatment, without being previously treated, with edema of up to 700 microns and 40 letters on BCVA. After 12 weeks of treatment, you can see the bottom image here. After 12 weeks, the edema went markedly down, down to 300 microns in thickness, and his BCVA increased to 56, a 16-letter increase. There was a highly responsive patient. This is an example of what this drug can do. In this, the stage one of the phase III DIAMOND programs, we saw statistically significant improvement in vision and reduction in DME in edema, 7.2 letters and 7.6 letters at week six and week 12, respectively. Over 25% of the patients gained 15 letters or more. Both treatment-naive and previously treated patients had similar results and similar efficacy. I'm happy to share that both DIAMOND 1 and DIAMOND 2 phase III studies completed enrollment, and we announced this just last week. These are adequate, well-controlled pivotal studies. Those patients who are enrolled are both previously treated and treatment-naive. The design is similar to the stage I of the phase III that I just showed, with the only difference being that the treatment is being given up to 52 weeks. The primary endpoint is change in BCVA letter score at week 52. Similar to stage one, patients instill OCS-01 or vehicle 6x a day for the first six weeks, followed by the maintenance phase of one drop 3x a day for the duration of the study, in this case, 52 weeks, up to 52 weeks. With completion of enrollment of over 800 DME patients, about three-quarters of whom were enrolled in the U.S., we are well-positioned to have top-line results in the second quarter of 2026. Enrollment was rapid, faster than industry standards, with the help of DIAMOND committees, experienced investigators, strong Oculis team, and highly motivated patients. We are fully focused on the execution and oversight of this study to drive strong adherence to the protocol, ensure compliance, retention, and high-quality data, and continue to collaborate with the experienced investigators and committees. With us on the phone is Dr. David Boyer from Los Angeles. Dr. Boyer was an investigator in the phase I study as well as currently in DIAMOND 1. Can we have Dr. Boyer on? Oh, okay. Perfect. Hi, Dr. Boyer. Good morning. Thank you for calling very early in the morning. As an investigator in the DIAMOND program, can you please share your experience with enrolling into the study? Secondly, please share how you would use an eye drop versus intravitreal injection or implant in patients with DME. Thank you. As you pointed out, Klier, it was very easy to enroll patients. If you think about it, if you give the patients an option between giving injections or taking a topical drop, I think almost all of us, except for some pseudo-masochistic people, would probably favor the idea of taking an eye drop. One of my concerns in the beginning was, would they take it 6x a day? And the answer was yes, they would to avoid a shot. Enrolling patients in the trial and keeping patients in the trial, I think, is much easier than I expected. One of the things that people always ask, well, here is an eye drop. We had glaucoma patients that compliance was not good. In this case, they actually get visual improvement, and they actually have a reason to take the eye drop. Compliance was much, much stronger. I think the patients will continue to do this. I think that using this in practice, I think this is probably the strongest steroid I've ever seen. I would certainly say that in patients who I think require treatment, this would probably be my first choice. In those that do not respond well, I would continue the treatment and add an anti-VEGF. In patients that I'm currently treating with an anti-VEGF that I cannot extend, or simply even with monthly injections or every six-week injections, I think the addition of the eye drop would be extremely helpful in reducing the edema. As you pointed out, I've had a patient and know of another patient in the trial that actually had the response that you showed on the screen, that when we stopped the study, we gave them anti-VEGF and they did not respond. They actually were doing better on the steroid injection or steroid topical drop than they did with intravitreal injection. I think that we'll keep patients in the trial and hopefully be able to get an approval. I would use this as first line in some patients or as an add-on in other patients. I think it has a wide range of benefits to the diabetic macular edema population. Also to patients, this is the strongest steroid I've ever seen in patients with uveitis. I think that is a natural drug to be used in that situation. Thank you very much, Dr. Boyer. We have the honor and the privilege to work closely with world-renowned retina specialists and clinical trialists who are part of the DIAMOND Steering Committee and the Central Review Committee. With us on the phone today are the chairs of these committees, Dr. Arshad Khanani, the chair of the Steering Committee, and Dr. Barry Kuppermann, the chair of the DCRC. That's the Central Review Committee. Dr. Khanani? Hello, Sharon. It's great to be here. Can you hear me? Yes, we can. Yes, now we can see you too. Good morning, Dr. Khanani. Can you please share your perspective on the execution of the study and specifically on the importance of having a Steering Committee? Absolutely. Any program that I've been involved with that has successfully executed and got into approval has really involved the retina community globally to get guidance. Here we have Steering Committee members that are clinical trialists that are very experienced in drug development globally. The idea here is to get a protocol that is practical, come up with a regulatory plan in terms of protocol that will be accepted by the regulatory agencies, and then use the Steering Committee to generate excitement, obviously, about this program. I'm happy to report that all the members of the Steering Committee have really recruited and helped us get this trial recruited in a very, very efficient and fast fashion. I just want to mention the reason for that, obviously, is this is the first novel topical treatment for diabetic macular edema. When people think about drops, as David said, sometimes people think patients are not going to take it or there will be compliance issues and things like that. What we have seen is that patients always ask for a non-invasive treatment first. We have many patients who actually do not want intravitreal injections, or many of the physicians are not giving them intravitreal injections because they are too early in the disease. In addition, I would like to thank you, Sneh, Riad, and the whole team for partnering with us and listening to our advice. Sometimes companies do not listen to the advice they get. It is a team effort where we are here on a mission to bring the first novel treatment for our patients. Obviously, I want to thank all the Steering Committee members that have been part of it, many of them high recruiters because they're so excited about this program. Thank you, Dr. Khanani. Now a question for Dr. Kuppermann. Thank you for calling in this morning. Can you please share your thoughts on the use of DCRC and its importance in the successful execution of the study? Sharon, again, I'm glad to see everybody. The DCRC plays an important role in a placebo-controlled trial. Now we have a situation where diabetic macular edema can tolerate edema for a while and still have good recovery. We have a highly expert committee: myself, Mar k Barakat from Arizona, Tim Lai from Singapore and Hong Kong, Thomas Wolfensberger from Switzerland, and Sebastian Wolf. We meet on a weekly basis to review all the cases that are showing signs of potential progression. We review any potential 15-letter loss, which is the futility criteria. We review the OCTs together. It's a thoughtful process. We interact with all the investigators on a regular basis and on every single case. It's a thoughtful process for each of the potential rescues. We go through it together to make sure that it all meets criteria. We have collaboration with the investigators who have been very supportive of this process. In fact, I have a call later today with an investigator. Diabetes has the advantage of being able to move a little more slowly. We do meet weekly and review each case. With that, we follow the guidance of the protocol. We have been able to adhere very nicely to the protocol and maintain patients in the trial until, as needed, futility criteria is met on those few that that happens to. It has been a successful process. This has had the support. The committee meets together with other members as well. Sharon meets with us, Snehal Shah meets with us, others as well. It is a committee of retina experts together with the other consultants as well as the actual company. It's a thoughtful process, meeting on a weekly basis to review each case. Thank you, Dr. Kuppermann. We will now turn it to a Q&A session on the OCS-01. Can I make a comment? Is this on? I'm a non-retina specialist, of course, but I'm a trialist. The compliance in this study seems to be quite robust. This sort of suggests that the drug is effective, in my opinion, because the problem with compliance in other trials with topical drops, that being glaucoma, is because patients do not know whether the drug is working or not because treatment of glaucoma is designed to prevent vision loss. No one sees any better with anything that you do for glaucoma. You have to watch the grass grow and prevent progressive vision loss. Here, I would say that the participants must be seeing that there is a benefit to the drop, and that is why they are compliant. Mark, thank you very much for saying it. I have been saying it for the last five years. We never talked about OCS-01, and you are saying exactly. Therefore, thank you so much. No, it's exactly correct, actually. This is what Dr. Boyer shared with us and the rest of the investigators. Patients see the benefit. As soon as you see the benefit, you keep the drug because the symptoms drive compliance, actually. Thank you. No, thank you so much. Thank you, Sharon, for a great presentation. Yes, yes, please, please, Barry. Of course. Just as an emphasis on this, this is a critically important point. Diabetic macular edema is a macular disease. It's a central visual effect. Glaucoma is a loss of peripheral vision. Historically, that's been the main disease that's treated with topical drop therapy. Because it's invisible to patients, they're losing peripheral vision. That's why compliance there is mixed. They know that they should be taking their medicine, but they don't always think of it. This is radically different because it's right in the middle of their vision. They see the benefit. Macular disease should not be subject with an effective therapy to any lack of compliance because it's right in the middle of their visual field instead of loss of peripheral visual field, as Mark mentioned. Again, this needs to be thought of in a very, very different frame of mind than everything that we've experienced with glaucoma drops. Thank you. Thank you, Barry. We will take questions from the room now. Yeah, please. Pavan Patel, Bank of America. The first question is, I guess, in terms of given the DME market is dominated by anti-VEGFs and steroid implants, how do you envision OCS-01 carving out its niche? What's the severity of disease threshold before using in first-line treatment or as an add-on to anti-VEGF? Yeah, thank you. If I had to focus just on the U.S. market because we have all the data. In the U.S. market, approximately, we have 1.8 million patients who are diagnosed. Into the 1.8 million diagnosed patients on DME, 500 are receiving anti-VEGF, basically. You have 1.4. steroid implant, OZURDEX mainly. You have 1.3 million who are not treated or inadequately treated because they might be receiving but not responding. Therefore, really, when you think about it, if you make it very simple, you have three segments. One segment, which is early, as soon as you have the disease. Imagine you have a heart disease. We are saying to patients, let's wait to be worse and come back and I treat you. If you have an accessible, easy treatment to prescribe immediately and the patient will be willing to take it even if it is not very severe, then they will take it. This will be the case with OCS-01. This is for early intervention. The second segment where we really do not have any competition, actually, is, as Dr. Boyer said, these patients who are on anti-VEGF and not responding on anti-VEGF. Actually, this part is well published. We are speaking about around 40% of patients who are not responding to anti-VEGF. This patient, when you add a steroid, and there is a publication on combination, it has a synergistic effect. It is almost double BCVA gains, double responders of 15 letters and more. Therefore, these are really the two segments. We are speaking, in fact, if you consider the market of DME or around $4 billion, in terms of patient pool, if we address the two groups, early and combination, we are speaking about a patient pool which is bigger than the current market. OCS-01 can create a bigger market, at least in terms of patient pool, as the current market. We are really speaking about huge unmet medical need where this product will be a new tool for the retina specialists to adapt their treatment, actually, and deliver better outcomes. I think, yeah, I think you please, she had actually questions. Sorry, I do not remember your first name. Hi, this is Suzanne from Kempen. On behalf of my colleague, Sushila, for the DME study, can you share the split of treatment naive and previously treated patients? For those doctors involved in the trial, have patients indicated that they take all six drops on average? A second question is for the company. Can you elaborate on your portfolio prioritization and how you currently think about OCS-01 in that front? Sorry, I didn't hear well the second question about. On your portfolio prioritization, can you elaborate on your current thinking on OCS-01? Okay, thank you. Yeah, on the split, our clinical trials were always all-comers, and we always ended up with a good balance between naive patients and patients already treated with anti-VEGF. I would say the balance currently is more or less similar. Therefore, we should have a similar balance between naive versus previously treated. I would say the good news, if you come back to our previous data and you see the benefit in both groups, the product brings benefit in both groups, naive and previously treated. Now, in terms of prioritization, on OCS-01, our decision is to focus on DME. Ocular surgery, which is ready to be submitted, will not be submitted now. It will be submitted only after DME. This is a decision we took, we took to make sure that we deploy our resources into the private sector, which we believe will create huge value for investors, actually. Therefore, on OCS-01, the focus will be only DME for the time being. Yeah, Colleen and Annabel. T hanks for taking my question. Just regarding the first question, how are you going to tap these patients? Can you tell us where the majority of the naive patients are sitting? We have a lot of retinal specialists here, but are they sitting at the ophthalmologist's office? Are they sitting at the optometrist's office? How do you plan on commercializing it? Are you going to tap into the retinal specialists first, or are you able to go earlier in treatment? Yeah, perhaps I will leverage our experts. They are in the retina. I am not, so they know more than me. Barry, please, could you share with us from your point of view where the patient, the naive patient, are seated versus patients who are already receiving anti-VEGF? I will just complement after. Please, Barry, you can address. That's a good question because currently, when patients develop macular edema or certain levels of diabetic retinopathy, the general ophthalmologist or optometrist will tend to refer it up the food chain to the retina specialist because the treatment is typically intravitreal injections, and that's by and large administered by a retina specialist. What this would do theoretically, though, and again, I value what David Boyer's and Arshad Khanani's input as well to this, and Sebastian's with us as well, is what that would look like in the future, potentially, because the general ophthalmologists do have OCT machines in their office, and they may choose to initiate therapy with topical drops, for example, as a prescription earlier in the sequence before then. And then those that, for example, that might have persistent macular edema despite the drops might then be referred to the retina specialist for intravitreal injections. It's an interesting question. What the current reality is, is it's still very much in the hands of the retina specialist. The referral goes from optometry/general ophthalmology to retina, and treatment tends to be initiated by retina specialists because it's intravitreal injections. In the future, with an effective topical therapy, as this may turn out to be, hopefully will be, that would potentially be a paradigm shift. Arshad, your thoughts? Totally agree with you, Barry. I think we are also busy in our clinic. A DME patient may take several weeks to get in. The optometrist or the ophthalmologist can initiate the therapy, and then I can see that patient, or they can see the patient, and if they need an injection, send us our way. This is going to open up a new market that currently doesn't exist. Many of the patients with very mild DME with good vision, optometrist or ophthalmologist may just watch because they mention the word injection, and patients don't want to do it, especially the ones that don't have significant vision loss. Completely agree with you, Barry. It's going to be a paradigm shift where we will be managing these patients with the help of our ophthalmologist and optometrist colleague. I also want to highlight one point about compliance, as mentioned by Mark and David and Barry, that these patients actually see benefit, and we see the benefit on OCT. This drug works very quickly, and that's what I learned as an investigator in the stage one, that it works very quickly, and patients are improving in vision, and we are seeing an anatomic benefit. Sometimes when you do not see an anatomic benefit and vision is changing, you are not sure if there is a real drug effect. Here, we are seeing both. I think that is why patients are excited. The second thing is their second option, if drop does not work, is to get an injection. Patients absolutely do not want an injection. When you mention taking drops 6x a day or 3x a day versus getting a needle in the eye on a frequent basis, I think it changes the paradigm. Very, very different. Totally agree. It's going to open up a new path, new patients that we are currently not treating. David? I agree with everything. I have a different take on this. I think this is going to be rolled out. When the drug's approved, I think that the retinal specialists will be the first to embrace this and use it. As times are changing and optometry is gaining in a lot of states the ability to do many things, I think you're going to find that over the next three to five years after this is approved that there will be optometrists that will be treating, as was pointed out by Dr. Khanani. They have OCT machines, so they can follow just as well as we can. It also will allow us to send some of these patients back to the optometrist and continue for them to follow and then send it back to us if at some point they need additional treatment. I think in the beginning, it's going to be completely retinal specialists because they're not going to be used to following these patients. They'll need some special training. I think that the ability for the optometrist in the future will probably be the first-line people that will treat this or in conjunction with the retinal specialist. Thank you. Sebastian, any different view or similar view from the European landscape? Yeah, I think in the European landscape, we have less really retinal specialists, more general ophthalmologists. I think this will be in the hands of the general ophthalmologists after they have learned from the retinal specialists how it works. I see a fantastic chance for this to treat more patients and to have better care for them. Thank you. Thank you. Just to Annabel, the current trial is only with retina specialists. The previous trials were only with retina specialists. We always ended up with something around 60% naive, 40% treated. More or less, it will be the same. Therefore, this naive versus treated are already in the retina specialists. As the expert group said, we will be able to broaden, actually, the patient pool by being able to treat early, but also broaden the prescriber pool by having general ophthalmologists with OCT to treat this patient. Thank you. I think Colleen has a question, and we have the last two minutes. Colleen, go ahead. Yeah, Dr. Boyer, would you like to share your experience? Colleen is asking about IOP monitoring and how you are doing it and what is your experience. There are two things. Steroids in general that work have two side effects that people have to realize. One, obviously, is the intraocular pressure, which you're referring to. The other is formation of cataract over a long period of time. I think that as far as the glaucoma or the elevated pressure, it may not be glaucoma, but elevated pressure, it's much safer than any other steroid. First of all, only about 20% of patients will develop an increased intraocular pressure, even if given 4x a day a strong steroid. You're dealing with a very small number of patients. In contrast to the other steroids that are available, this can be stopped. Or if it's a low pressure rise, you can actually add a glaucoma drop to reduce the pressure and keep them on it. I don't think that monitoring the patient as far as the pressure and the patients that I've seen, we haven't had any significantly severe elevations, unlike some of the other drugs, ILUVIEN and even OZURDEX in the past. I'm sure we will see those over a period of time. Unlike the other drugs, we have the ability to just reduce the number of drops or to add something. Certainly, we're very conscious of who this drug is. There's not one size fits all for any treatment, any diabetic macular edema or proliferative disease. There's always a bunch of different things. We try to take into account if the patient is phakic and how old they are. A lot of these patients come in, and they already have cataracts, and they already know they're going to have them removed. I would certainly use it in those patients. I may not take a 20-year-old with diabetic macular edema and use this as a first line, though. Thank you. Thank you very much. I think we are on the time. I might take more questions in the end if possible. Thank you. I just would like to thank the Oculis team leading this trial, Snehal, and Sharon, and Kate. I would like also to thank all the experts who are helping us. As Arshad said, this is a teamwork, and success is always a teamwork. I really would like to thank you all for an excellent job. Let's continue to focus on disciplined execution. Thank you. Now, I will invite my colleague Snehal to speak about Licaminlimab. Thank you, Riad, and welcome, everyone. It's a pleasure to speak to you today. Dry eye disease is a multifactorial disease with significant unmet need, an opportunity for genotype-based development with precision medicine. Only 13% of patients experience relief with current treatment options. 85%- 90% of patients are dissatisfied with their treatment and discontinue treatment within six months. Sorry, I was the first guy to mess up the slides. It always happens once. Today, it's our pleasure. We have leading dry eye disease expert, Dr. Anat Galor, with us online. Hello, Dr. Galor. How are you? I'm good. Thank you for having me. Thank you. It's an absolute pleasure. I have a question for you, Dr. Galor. Can you please help us crystallize the unmet need for dry eye disease and why treatment is so challenging today? I think there is a huge unmet need. The first thing is dry eye is such a common condition where many people in the population have symptoms or signs that fall under the umbrella of dry eye disease. The problem is dry eye disease is an umbrella. People have different symptoms, different signs driven by different pathophysiological mechanisms. The punchline is not everyone needs the same treatment. We have no way right now of predicting which patient will do best with which treatment. You can imagine that this leads to a lot of frustration, both on the side of patients and the side of physicians who say, "Let's try a trial and error approach." As we get new products approved, we have more trial and error approaches. You can see that reflected in these beautiful graphs you made that people oftentimes switch therapies, and most people are unhappy with this trial and error approach. You can imagine that this is amplified because somewhere between 15%-20% of the population, this is the healthy population, not the hospital-based population, has a sign or symptom of dry eye. A huge unmet need with a disconnect between diagnosis and treatment options. Thank you for your insight, Dr. Galor. Can you also tell us a little bit, what are the principles of precision medicine? Do you think this type of approach would help address the unmet need in dry eye disease? First of all, I have to say that I'm so happy that this is happening in the dry eye world because it seems like the retina people have all the new ideas. Here for us, this idea of precision medicine is really revolutionized or revolutionary in ophthalmology. Of course, in cancer treatment, we would never try a trial and error approach when it comes to cancer. Yet, we do it all the time in terms of different therapeutics for ophthalmic conditions. The idea of being able to find a diagnostic biomarker that predicts treatment response is not just novel in dry eye. It's novel in ophthalmology. To me, especially in dry eye, which there's such a need for this, it would really make the whole pathway from diagnosis to treatment better if we're able to figure out which patients need which therapies. Thank you, Dr. Galor. The development program for Licaminlimab, or OCS-02, consists of three positive phase II studies in dry eye disease. Results showed meaningful and rapid efficacy in both signs and symptoms of dry eye disease in the general population. Additionally, there was a more profound effect in TNFR1 genotype-positive patients, 5x greater in signs and up to 7x greater in symptoms. OCS-02 was well tolerated with a drop comfort similar to artificial tears. Dr. Galor, as our dry eye disease expert today, based on the phase II data with OCS-02, can you please comment on its potential as a precision medicine for dry eye disease patients? I think that the data are compelling. Number one, it's not just a marginal improvement. There is a huge difference between people with a certain genotype versus people without it. That is already very exciting to me. Some other caveats are that looking at therapies that are already out there, one issue is the time course of treatment. Many of the therapies we have take months to show an effect. In addition to not knowing whether they're going to work, it takes months to figure out that they're not going to work. The fact that there is a rapid treatment effect is very promising. The other issue with many of the currently available therapies is comfort, whereas there's distillation site reactions. Having a drop that is comfortable and well tolerated is also a huge difference. While obviously, as a scientist, I'm most excited about the diagnostic biomarker, a huge area of need are products that work quickly and are comfortable. I'm excited about the prelim data. Thank you for your comments, Dr. Galor. Earlier this year, we met with the FDA and received agreement for genotype-based development with OCS-02 as a precision medicine. We also received agreement on registrational trial design. FDA agreed the primary endpoint can be in TNFR1 genotype-positive patients, while the full population can be evaluated as a secondary endpoint. We're planning our first registration study with OCS-02 in dry eye disease the second half of this year. Genotype-based development leads to higher probability of success and efficient capital deployment. As agreed with FDA, we can enroll 2/3 genotype-positive patients and 1/3 genotype-negative in our registration studies. The primary endpoint will be change in mean global ocular discomfort at day 29 in the genotype-positive patients. We anticipate only needing about approximately 80 patients per treatment arm with over 100 patients TNFR1 genotype-positive. OCS-02 genotype-based development is the first of its kind in ophthalmology and dry eye disease. It has the potential to bring a very differentiated target product profile and truly meet the unmet need in dry eye disease with precision medicine. We'll now take questions. Thank you very much. Thank you. Thank you, Snehal, and thank you, Anat. Who would like to start? Yes, please. Thank you. How many patients are actually genotype-positive in real-world practice? In the U.S., the data tells us that it's around 18%-20%. In our previous clinical trial, it was 19%. So 20%. 20%. If you take now in terms of market and sizing, we have around 30 million-40 million dry eye in the U.S. 10 million are moderate to severe. 10 million would need medication, and 30 million are fine with artificial tears. If you take 10 million and you apply the 20%, we are speaking about 2 million patients who are needing a drug and positive to the TNFR1. How easy is it to conduct the biomarker test? What's the typical turnaround time? The turnaround time, it's a qPCR test. It's a very simple test in saliva sample. It's very simple. Today, it's done in the lab. I need 24 hours. You send the sample, and you have a response. Therefore, it's very easy. It's not expensive at all, actually, which is good and simple to implement. What is the turnaround time? It's 24 hours the time to send the sample and to get the result. During the meantime, what would the doctor give the patient? It is on the screening phase when you see the running phase. We will be screening patients, and we will be randomizing based on the TNFR1. I mean, in the real-world practice, before the test gets active, what would the doctor give? In the real-world practice, we will come back actually with our pre-commercial and commercial plan. We are working on it and preparing it. Yeah. In the real world, they just give a graph for the meantime. Any other question? Yes, please. For these genotype-positive patients, are they typically, is there a difference in the prevalence in the moderate to severe patients, or is it 20% across the board? No. Actually, Dr. Galor published about it, and it is really similar. The TNFR1 receptor is not related to the dry eye itself. It is really related to the inflammation pathway. Therefore, it is really similar. It is similar in dry eye, similar to all population. It is the same. It is the same presence of this receptor in 20% of the population in the U.S. today. It is slightly higher in Europe, but in the U.S., it is 20%. Good. Thank you very much. We will be during the year informing about the start of our study. As soon as the study is finalized and we have the data, we will be talking then about the launch plan and so on. Okay? Thank you. Thank you very much. Now let's go to Privosegtor. Privosegtor really opens a new era, or for the first time, an era of neuroprotection, which has been something where many companies, even I learned from one of our senior advisors that even in the 1990s, the U.S. president declared that neuroprotection and neurology will be an important area of investment. For the first time, we have something which showed in a first trial in patients meaningful benefit. In the session, we will be talking about three topics. One is a phase II ACUITY expanded data analysis. We will go into new data. We'll be sharing them with you. Next, we will be talking about what the company is going to do on acute optic neuritis. The last point, we will be talking also about beyond acute optic neuritis in terms of clinical application with this biology. In terms of takeaways, and just if we summarize this in five takeaways, Privosegtor is a new class, first of drug, potentially unlocking neuroprotection therapy era. Privosegtor is a small molecule peptide that penetrates blood and retina barrier. In preclinical data in various animal models, in vivo models, in three, glaucoma, multiple sclerosis, acute optic neuritis, the product showed that it preserves or protects or promotes survival of neurons and axons. In acute optic neuritis, which was chosen not only because of the indication where we do not have anything approved, but also it is a very pure model in terms of showing neuroprotective benefit. You will see the translation and how this can be translated in something else on top of developing a drug for acute optic neuritis. Positive equity phase II showed a positive result in terms of anatomy, biology, and we will go through it, and LCVA as the function, the visual function. We will be advancing acute optic neuritis now with a very clear plan, which we will be discussing with FDA. We will be also initiating two new programs in NAION and relapses of MS. I will be sharing a few slides, which we already shared in the beginning. I will be faster in this part, and I will spend more time in the new data and the next steps. If you recall, we discussed about how this product was selected. Privosegtor, again, is a small molecule which crosses peptide which crosses blood-brain barriers, selected by high-throughput screening for neurotrophic and neuroprotective effect. In fact, the product is an activator. It activates SJK pathway to activate FOXO3, which is well known to promote survival of the neurons. The product, as I shared with you, was tested in actually seven in vivo animal trials in three models: glaucoma, acute optic neuritis, and multiple sclerosis, and consistently showed really that it does three things which are important. It promotes and preserves retinal ganglion cells from dying. It protects and promotes axons, and it improves function. The function was measured in multiple sclerosis model. Why acute optic neuritis is a predictive model for neuroprotection is really focus on think about it is that you look for a model where you have retinal ganglion cells/axon injuries. As soon as you have this trigger, which is the injury of the retinal ganglion cell and the axon, you have the retinal ganglion cell here, which is the neuron in the retina which is in distress situation, and it dies. We see it in MS relapses, and in fact, acute optic neuritis is considered similar to MS relapses. It is the same process, which is a neuroinflammatory process. This injury can be mechanistic like glaucoma. It can be inflammatory like MS, or it can be an injury. Here, acute optic neuritis, if you show that you can promote survival or preserve retinal ganglion cells and axons from dying, that the translation to something else, which could be relapses of MS, or it could be NAION, and I will show you the pathophysiology of it, we can easily have the hypothesis that this product will be able to protect the retinal ganglion cells and the neurons and axons, and this is what we would like to do. In fact, in all our now exploration for new clinical applications, think about it really in a very simple way. Any disease where retinal ganglion cell or axon is suffering, this product can protect retinal ganglion cells/neuron and axons from the injury of the insert. Now, acute optic neuritis, you remember, is an orphan indication. We are speaking about 65,000 patients in the world. Half of them are in the U.S. It's an inflammation of the optic nerve. The cell is in distress, and then it dies, and then we have symptoms, which are pain and loss of vision. Today, we do not have anything approved here, and we just use steroids to reduce inflammation. The prognosis is we end up with patients who could potentially improve LCVA. However, LCVA will not be back to normal, and this is what we are addressing here. The way to measure the efficacy of the product is easy, actually, and good because you can measure by OCT RNFL thickness, which gives us the status of the axon. We measure GCIPL thickness, which gives us the health of the retinal ganglion cell. You see them there. Then we measure the function by measuring LCVA, which is an FDA regulatory endpoint. As you recall, the study was a multicenter double-masked trial comparing steroid alone versus steroid plus OCS-05. The key endpoint where primary endpoint was focusing on cardiac safety. This is a new class and new molecular entity is normal, and the company will continue to monitor safety, which is a normal process to do with FDA and with the regulatory bodies. The secondary endpoint are focused on efficacy, the two imaging, and the function. This is the baseline characteristics, which show balanced groups between the 3 mg and the steroid alone on all parameters. Nothing really to highlight here. The only perhaps thing is, as I said, this is a disease which is directly linked with MS, and therefore you see MS patients. We are speaking about a really young population, which makes it even more important to find the solution. As you may recall, we shared this data previously. The primary endpoint of cardiac safety showed no difference in percentage of patients that had the change in ECG outside of normal and all the events were mild and transient. We will continue, of course, to do this monitoring till NDA for a new molecular entity. In terms of safety also, at the dose given, the product showed safety in this trial, no AE leading to drug withdrawal and no drug-related serious adverse events. In terms of safety also, we monitored MS relapses. We see here that in the Privosegtor plus steroid, we see less relapses. Of course, the numbers are small. The study was not an MS study. It was an AON study. However, it is encouraging, and the company will continue to assess this data point, but very encouraged to see this. Now, back to the efficacy. In the Privosegtor, 3 mg arm, we see less GCIPL thickness decrease, which means we basically protected the retinal ganglion cells from dying, basically. We protected functional cells from dying, which and then the question you ask yourself, okay, are you seeing better? We will see. We protected also the axon by achieving less RNFL thickness decrease, and it was at three months and sustained like in GCIPL at three months and sustained. Extremely encouraging anatomical structural benefit with the two main endpoints, GCIPL and RNFL. Then the function, which is patient with Privosegtor arm, achieved clinically meaningful improvement in visual function by 18 letters difference at month three, sustained at month six, which is extremely encouraging. Now, of course, when you have this data, which are amazing data, and extremely pleased with the data, you ask yourself, is it driven by a group of patients? Months overall, MS, non-MS, and HCVA higher or lower than 60. Regardless which group you say, this product is bringing benefit at month three and sustained at month six, which tells us that the population we addressed in phase II is representative of the AON population. When we go into the details and we see the benefit, the benefits are consistent across the groups. I say to you, I said, yes, we went into other endpoints. The last endpoint really we wanted to measure, very encouraged actually by the neurologists. As you recall, just three months ago, we were only an off-tar company, so therefore we are learning from experts who are here with us in the room and on Zoom. We went into the neurofilament. What is a neurofilament? Neurofilament is actually found in the cytoplasm of the neurons, and they are like proteins, polymers. They form the neuronal cytoskeleton of the neuron. When the neuron is suffering, they are released into the blood or the CSF. In fact, there are products which were approved based on the neurofilament. It is a material regulatory endpoint. Here is a very nice curve you see here where the group receiving OCS-05 is having less neurofilament being released into the blood, which means they have less retinal ganglion cells and axons dying. You see it very clearly. Of course, there is back to normal after month six because the crisis is behind us. In the beginning, it is very clear the group who is losing retinal ganglion cells and axons versus the group who is not losing. This gives us even more confidence that this product can act in situations of neuron/axon injuries to protect neuron/axons. This is really the first hypothesis, and I am very happy to say it because I was not into the design of the trial, but I would like to thank the expert who designed it, and one of them is with us, is Pablo Villoslada, who designed this trial and went into acute optic neuritis. I think it was very smart. I can tell you many people told us rightfully that it was a very difficult indication. I am very happy to say that we succeeded in a very difficult indication, which shows the efficacy of this product and what this product could deliver for patients. This is an amazing result, which is just built on what we have in terms of anatomy, function, and biology. In conclusion for the ACUITY trial, Privosegtor achieved primary safety endpoint, which is important. As I said, this is a first-in-class new molecular entity, and we will continue anyway to monitor this. Second, which is very important, is the efficacy. The product showed consistently vision improvement, showed anatomy improvement in terms of GCIPL and RNFL, and showed biological positive effect, showing that actually in the active, the patients are losing less retinal ganglion cells and less axons. On the safety, no difference in percentage of patients, shifted post-baseline ECG, no drug-related serious adverse event. Good news, even if it is a small number of patients, again, is lower incidence of new relapses of MS in the active versus steroid alone. Therefore, in the next step, what is our plan? Our plan is to meet with FDA and other regulatory bodies to review ACUITY result and discuss full development program to support acute optic neuritis registration plan. Our base or current plan in terms of next registrational trial will be the primary endpoint will be LCVA at month three. The similar regiment and trial design will be close, perhaps not 100%, but very close to what we did. It worked, so therefore we like to be consistent. Because this is a new molecular entity, the study duration will be 12 months. This is at least our assumption. Of course, we'll discuss with FDA, and we will have clarity in terms of next steps. We start global registration study in the first half of the next year in 2026, of course, pending FDA feedback and clarity in terms of design. This is what I had to share with you on ACUITY. Before going to Q&A, I would like to talk about NAION and relapses of MS, and then we will go into the Q&A. MS, what first, I think, and I have been actually involved in MS a long time ago with the launch of Gilenya, which is fingolimod, which was one of the most successful launches 15 years ago. What we saw in MS, it is a dramatic change actually and very good treatment, all of them immunomodulators, which have the benefit to reduce relapses and improve progression of MS. However, we do not have anything which treats relapses. When we have a relapse, we give steroid and we wait, and we hope that disability will be not bad. This is really what we do. Therefore, we end up still, we end up with disabilities which are related to relapses. We are speaking, of course, about a bigger market than acute optic neuritis in terms of patients. We have in the U.S. around 850,000 patients. We are speaking about huge markets, more than $20 billion. Still, we do not have a treatment to improve progression, treatment to reduce relapses, and we have been able to reduce relapses, which is good, but we do not have a treatment for relapses. We give them steroids so far to reduce inflammation. This is what we do. Therefore, there is a need like AON, and really think about it like AON, there is a need to protect axons and neurons which are suffering during the relapse acute period. If we go to relapse, we are speaking about around 170,000 relapses in the U.S. only. What happens, and it can be a symptom including a loss of vision like acute optic neuritis. It can be severe weakness or poor balance interfering with mobility. It's a multiple-dimensional disease, and we have experts here, and I will ask them to give their opinion. They are experts. I am not. When you see the unmet medical need in MS, really one of the last unmet medical needs is how we can treat relapses to reduce relapse-associated worsening. This is the goal. If I can extrapolate about the data in LCVA and you take the data in AON and you have this LCVA, if we can apply the same thing we applied in LCVA, reducing the Relapse-Associated W orsening, which is like reducing the impact in LCVA, it's a huge benefit for patients because instead of losing step by step or having permanent disability, we would reduce permanent disability. This is our hypothesis based on the acute optic neuritis trial, and this is what we would like to assess. Now, what it would like, so here you have a typical relapse and remitting multiple sclerosis where you have relapse and you have Relapse-Associated Worsening, and step by step, the disability goes high. What a treatment of relapse, if I extrapolate what we saw in acute optic neuritis, if I extrapolate into MS, it will basically create this benefit. Instead of having a high Relapse-Associated Worsening, it will be lower. Take LCVA as the same model in acute optic neuritis in relapse of MS. What will happen also, the next relapse will be less severe because the baseline will be better. Step by step, we are basically reducing overall relapse-associated worsening and improving the life of patients. This is our hypothesis. It's based on the biology we know about the product. It's based on ACUITY data and all ACUITY data, all the data set, what we see in the anatomy in terms of preventing retinal ganglion cells from dying and axons, what we see in biology by having the biological proof, which is again a regulatory endpoint, which is neurofilament, which shows that actually retinal ganglion cells and axons were protected, and of course, the function, which is LCVA. This is our hypothesis. We will be meeting with FDA to initiate the program here. Next indication is an NAION. NAION stands for Non-arteritic Anterior Ischemic Optic Neuropathy. It is an orphan indication. We are speaking about around 30,000 patients in the U.S. It's very severe. Actually, more than 60% of patients have significant visual impairment. We do not have any treatment for this disease. Nothing. Even steroids, which are magic, they don't do anything here. We do not have anything. Nothing. We just tell them that we are very sorry. This is what we say to them. What happens, it is again a hypoperfusion of the optic nerve, which leads to retinal ganglion cells and axon suffering. The patient loses vision. It's mainly affecting patients who are 50 and above, affecting both sexes in the same way, which is different from AON. Risk factors include diabetes, include hypertension, include sleep apnea, and use of certain medications, which is well published actually. Here, as I shared with you, we do not have anything in this disease. Therefore, the hypothesis here is we will be able to protect retinal ganglion cells and axons from the injury they are having. Therefore, we would like to initiate a program here. These are the two new programs we would like to initiate on top of acute optic neuritis. In terms of what are next steps, for AON, it's meet with FDA in the second half of this year to discuss next steps, to discuss all what we need to do. On top of that, of course, to discuss the registrational trial, which we aim to start the next year. The second is to expand into NAION and relapses of MS with pre-IND interaction with FDA to support application relying on existing Privosegtor data sets we have. This is planned toward the second half of this year in terms of preparing it with FDA. In conclusion, we are extremely pleased with the portfolio we have in hand. After the ACUITY data and the result, we decided to, as I said to you, to be extremely focused and laser-focused on three indications we are going to pursue now. One is OCS-01, and Sharon shared with you the DIAMOND 1 and DIAMOND 2 status. As you heard, our only focus on DIAMOND 1 and DIAMOND 2 is execution. This is the only focus. I am extremely thankful and pleased to see the support we have from the medical community and from the experts. This is a team work, and we will be succeeding it as a team. I am extremely thankful for a great Oculis team we have and great KOLs and experts and advisors supporting us. Second, only Licaminlimab for a disease which is known for two things: high failure in phase III and not commercially successful product since Restasis, which has 20 years. This is like each time I speak about dry, people say to me, "Yes, phase III does not work," and actually commercially it does not work. It is true actually. I'm in agreement with you. This is why we took the time to analyze, and this is why we are coming with something completely different to address the risk in phase III and to address the fact that we do not want to be a me-too. We want to have an efficient phase III, which is successful. I learned in the past from an advisor who always said to me, "A good trial is a positive trial." This is what we try to do, even if we do not control biology. We strongly believe we are confident with our genotype-based development approach. We will be able to reduce the risk materially in phase III and come up with a very differentiated product in terms of precision medicine. The last, which, as you could hear today, really opens a huge door for Oculis and for the medical community in terms of neuroprotection, we'll be focusing on acute optic neuritis, which is the core. After expanding into NAION and relapses of MS, we will be coming to you in a few months with our data on new in vivo data. We are validating the biology of OCS-05 in multiple huge clinical applications. You could see, and this is additive, this is not cumulative. You can see the size of the market we are aiming to address, which is if you add them all, we are basically addressing a size of a market which is around $50 billion in the end of the period. You can imagine how much we are excited, motivated, and at the same time, we need all your help to make it happen for patients. Just in terms of next catalysts, OCS-01, DME top-line result is planned in Q2 2026. DME NDA submission will follow immediately after. Ocular surgery NDA will be postponed and will be done only after DME. The decision was to take these resources and to deploy them in Privosegtor. We believe that the return on investment will be much higher, and this is why we made this decision. Dry eye, it's a very, I would say, laser-focused genotype-based development, which we will be doing for Licaminlimab. For Privosegtor, we have an upcoming meeting with FDA to discuss acute optic neuritis. After, we will have IND enabling on NAION and relapses of MS. At the same time, as I shared with you, we are doing multiple in vivo validation studies to validate the biology of OCS-05 in other clinical applications. Really, the very simple way to think about them is think about any situation where the neuron or the axons are suffering due to inflammation, injury, mechanistic. This is what we are addressing. Thank you very much, and very happy to open up to the questions. Yes, Marc? Yeah. Can we hear from the experts on the neuroprotection and just talk about whether the endpoints that were in the trial, were those important endpoints? Should there have been other endpoints that the company should go after next time? We have never seen the RNFL data today. What your thoughts are on the RNFL data? Have we ever seen RNFL improvement before in a neuroprotective agent for the eye? Yeah, okay. If we can have also, I think we have Sebastian and Len. Yes, okay. I would say I will ask Mark if you would like to talk about the endpoint and then on in neuroscience. I thought it would be instructive just for a moment just to say who I am a little bit better. I am a neurologist and an ophthalmologist. I have developed, along with a whole lot of colleagues, the clinical trial network that runs trials for both NIH and pharma in the few neuro-ophthalmological disorders. Because of a need, I have become a little bit expert in imaging of the back of the eye because it did not really exist before for all of these acute optic nerve injuries. We could do a lot of research in this, including AI and biomechanics of the optic nerve. I've sort of like wear a few different hats in this situation besides still being in active practice. I also was one of the people who developed and ran the original optic neuritis treatment trial. That goes way back. Mark, could I add just one thing actually? We have the three people who led the biggest NAION trial ever: Len Levin, Mark Kupersmith, and Sharon. Actually, they ran and led the biggest NAION trial. They know very well NAION as well. That's NAION. Now we're talking about optic neuritis, right? Is that the question for you, Marc? Right, okay. For this study, I would have used the same metrics for outcome because for the audience, I'm not sure how well-versed every audience is on optic neuritis, but high-contrast vision tends to get markedly better with or without therapy in patients. Very few people are left with high-contrast vision loss, probably 10% or less. The low-contrast vision, no matter what you do, about 60% of patients will have incomplete recovery and will still have that. We'll always say, "Well, that eye is just a little bit fuzzy. That eye is cloudy. I can't see. I can't read the newspaper with that eye because of the gray print on a gray background," just to give you the concept of what low contrast means. We do know that in 90% of patients who have optic neuritis, they'll have significant thinning of the macula ganglion cell layer. Most of the neurons that make up the optic nerve are centered around the macula. There certainly are neurons in the inner layer of the retina all the way out, but most of them have to do with the central vision because the brain supports central vision more than peripheral vision in terms of overrepresentation. I think looking at the macula ganglion cell layer change, which is a very—Marc and I have already talked about this—but it's a very stable baseline measure to get an accurate measurement for loss. I think that's a very good structural marker. The retinal nerve fiber layer, which is the axons of those retinal ganglion cell cell bodies that form the optic nerve, that's a less stable measurement because it's perturbed by the original inflammation behind the eye, causes axonal swelling and interstitial edema. What you're looking at is not just axons in the RNFL at the beginning, but you're looking at just axons at the end. There's a lot that goes into that. The low-contrast vision marker, which was developed by a whole team of MS experts led by Laura Balcer, has shown that that correlates extremely well with quality of life and actually long-term actually correlates very well with disability in MS. There's a whole literature on all of that. I think they picked the right metrics. If I had designed the study, I would have said, "Let's design and look at the central 10° of visual field, 10:2 visual field," but I would have been wrong because we've done subsequent work to show that isn't as good a marker as the low-contrast vision for an outcome of optic neuritis. That's what I would have chosen at the time of the study based on our prior research, but I would have been wrong. I hope I answered that question. Have you seen RNFL lowering before? I've never seen that with any—I've never seen in—as in Marc as I meant in Payham, but I've never seen this in any phase II human trial, a correlation with both the structural preservation. Because remember, it's not improving. It's just reducing the loss in both the retinal nerve fiber layer, ganglion cell layer, and a visual outcome metric, a functional metric. That's what makes, for me, and that's the reason I'm sitting here, it was a unique situation I haven't seen in any drug development. Yes, please. Oh, I thought you were going to answer. Please, Daniil. For AON—sorry, Daniil from Chardan. Sorry, I'm looking for AON. Yeah, my name is Daniil from Chardan. For AON, I know it's a small sample size for a 2 mg group, but can you comment on the efficacy results for that group and how confident are you in 3 mg group moving forward or 3 mg dose moving forward? Yeah. On the balanced group, when you compare where is balanced, there is actually a drug effect. Now, as you said, we are speaking about a small number of patients. We are speaking about four patients. But four patients on GCIPL and LCVA, you see a very nice dose response. You do not see it in RNFL because the baseline was really unbalanced, so it's very hard to compare. But with GCIPL and LCVA, you see it very nicely. Now it's four patients. Yeah. I think there is another question in the— Thank you. This is [Alexandra] from Kempen. I just have a question because FOXO3, I know it exists at the interplay of metabolism and insulin signaling downstream of insulin, actually. So I'm just curious, is there anything you can say about a potential food effect or dietary considerations? Is a food effect—can you repeat, please, the question? Sorry, you said FOXO3, and then if you can have the mic very quickly. Yeah, so FOXO3, because it's downstream of insulin signaling, is there anything you can say about potential food effect or dietary considerations? Okay, this drug has been developed trying to mimic the activity of the trophic factors we were discovering years ago. We pursued the discovery with a phenotypic screening, and after observing the efficacy, is when we did the convolution and identified that the main target was this specific kinase. This specific kinase, SJK, is overexpressed during stress, meaning it's, in addition to mediate the activity of trophic factors, it's also activating stress, meaning it's part of the natural stress response. It's doing several activities, but the main one is the activation of FOXO3, which is the master protein that helps neurons to survive. It's surprising that this needs to be the case because in biology of the brain, neurons need all the time this constant signaling, this cortisol signal in order to be healthy, let's say. What we are doing here is stimulating the neurons to survive, to maintain the functioning in the presence of this stress, waiting for better times that they arrive because the inflammation disappears. After that, we have preserved the neuron, we have preserved the axon, and the reason we are preserving the—we decrease the disability is the point. I'm answering your question? Yes, thank you. Thank you. Just for a reminder, the current formulation is an IV formulation. Yeah, okay. I think we have a new guest joining us. Good morning, Dr. Hauser. Thank you so much for joining us. We are not hearing the speakers on this. Can you hear me now? Yes, yes. Sorry. Good morning, all. No, no. Perhaps I will ask you a question because I remember we did not know each other, and when you saw the data, you asked me to visit you, and thank you very much for the invitation. I learned a lot from you. Dr. Hauser, can you please share with us your read on the data and how you extrapolate the benefit we see with the previous sector in acute optic neuritis in MS and other indications, perhaps focusing on MS? Of course. On the relapse of MS, basically. I was extraordinarily excited by these data. When we planned the study, when Pablo took the lead in planning the study with our colleagues, we were hoping to see a—we were hoping to see safety and, of course, a small effect that we could then fuel to design subsequent studies. I think that the biology of the effects that we've seen in the early phase II study, and that has already been presented, is that correct, Pablo? Yes. Yeah, I think that was so remarkable and convincing. It is one of those examples where the real-world results in patients have sent us back to the laboratory, armed with many questions, including the question about diet that you asked. I think I agree with Pablo that the IV formulation we believe mitigates any effects of diet, although in longer-term studies, this will be an important variable in MS trials for the BTK inhibitors, of course, especially with ivermectin. Diet appears to be important. I don't think that with this IV formulation, it is important, but as we move to different formulations, it could be. What was most remarkable to me about the phase II trial was not only that we saw biomarker evidence of disease across a variety of secondary endpoints, but we actually corroborated this with clinical benefits to vision. This was really spectacular. The world has been looking for neuroprotective therapies that work for a very long time, as we know, and there have been ups and downs in the way that these therapies have been assessed. Some of the problems are the difficulty with the system, and others are access and making sure that the PD and PK work in the pathologic state. I think this data is incontrovertible. Another thing that we've learned from MS and optic neuritis trials is that the phase II are pretty good predictors of what the phase III will look like. I'm extraordinarily excited that for the first time, we may have something that could be added on to our current roster of protective therapies for optic neuritis and MS with something that could actually improve neuronal and glial outcome. That second, the implications for a variety of other brain diseases, both inflammatory and non-inflammatory, are awfully compelling. Thank you. Thank you. Thank you, Dr. Hauser. If I may ask Dr. Len as well, Len has been helping us to assess the data, to have a good understanding of the readout, and to understand the next step. Len, you have been also with Mark and Sharon also involved in the biggest NAION trial. Could you share with us your take from the results and also your conclusion and next steps, and how do you see them with this biology? Sure, Riad. I share with Dr. Hauser, the idea that this is truly a remarkable step forward in neuroprotection trials. I've been involved in this area for what is now more than three decades, and there really has not been a success in neuroprotection in neurological disease or neuro-ophthalmic disease or ophthalmic disease beyond relatively small amounts and small changes in perhaps what is actually neuroenhancement. This is based on the phase II data, pretty profound. I think the thing to keep in mind here is that we've studied in the ACUITY trial with optic neuritis and axonal disease. This pretty convincingly shows at the phase II level that there's a preservation both of function and structure and a biomarker. The combination of all three makes a kind of an error based on false positive unlikely because these are two disparate measures that, however, correlate very strongly. It's in an axonal disease, and so I think the company is correct in looking at other axonal diseases, of which, of course, multiple sclerosis is the biggest one. Ischemic optic neuropathy, in particular in this case, non-arteritic anterior ischemic optic neuropathy, or NAION, the most common ischemic optic neuropathy, is a wonderful target, especially because there is no approved therapy for it. The prognosis, as was pointed out in the lectures, was very grim, is very grim. The development of a potential pathway to a drug that actually could be helpful for ischemic optic neuropathy would make a huge difference to a large number of people that suffer from this. Once the damage is done, they suffer lifelong. I share the happiness that there has been finally a convincing neuroprotection development in a phase II study. I think that the target of looking at these axonal diseases is a wonderful one and pretty likely to succeed. Of course, we never know when there's a phase II to phase III translation gap that can always occur. Nonetheless, I'm pretty encouraged. Thank you. Sebastian, you have been also involved in not the biggest NAION, but the biggest AON trial. Can you share with us your take? You are the head of the reading center. Can you share with us your take for the conclusion of equity and how do you see it implemented in AON, but also NAION? You are the retina expert as well, so please go ahead. Yeah. I think these results are really compelling, and it's very nice that we see in the retina, the ganglion cell layer going the same direction like visual acuity, what we expect. Low contrast visual acuity improves, and there's less loss of the ganglion cells. I never have seen this in any of the studies we are looking at. We have looked at many studies on ganglion cell layer thickness, and the results are remarkable. Everything points towards the same direction. I'm echoing Len and the others before me, but I think we had the big luck that we looked at the fovea, the central field of the ganglion cells, where the ganglion cells are thickest. We found a big difference between placebo and treatment group. Thank you. Thank you. If I may ask Stephen, Dr. Hauser, on the translation between AON and relapse of MS, I remember you were one of the first raising it. Could you share with the group how you see this translation and the hypothesis made on treating relapse? Yes, I think that as our diagnostics have improved, the proportion of patients with AON who have either multiple sclerosis or an MS-like illness has increased. One of the, I think, important differentiators that we will use in the phase, or that we probably will use in the phase III, will be patients with other silent lesions who have acute optic neuritis or with symptoms or signs that suggest they have MS. The majority of patients with AON have an MS-like disease. I think that these results will—we will have a similar population in the phase III trials. I'd also point out that one reason for selecting optic neuritis is that the natural history and markers of outcome from acute optic neuritis are very well established so that we can compare not only with—we can model the trial easily, relatively easily, and also compare with valid historical as well as contemporaneous data about expectations. Because MS, the M in multiple sclerosis means multiple, the outcomes for the other long tracts that are affected by MS—motor, sensory, cerebellar, bowel-bladder, cognitive coordination—are less well quantitated than optic neuritis. Of those other symptoms of the disease, perhaps the motor system would be most amenable to therapy in terms of being able to predict and monitor outcomes. I think optic neuritis, in my view, is a surrogate for MS and benefits in optic neuritis, and especially in people who are high risk for MS or have MS with optic neuritis, that should lead to widespread use for other attacks in MS. This is our most easily quantitated MS attack parameter. I would also say that it is very important to remember that there are other autoimmune inflammatory visual optic nerve disorders that are even more devastating than multiple sclerosis. Here we have spoken about some of the non-inflammatory disorders, but remember that neuromyelitis optica due to aquaporin IV autoantibodies and their cousins due to autoantibodies against proteins called GFAP or MOG, as well as sometimes as a cancer-related optic neuritis. These are devastating in terms of visual outcome and an important cause of blindness. I would hope that once we are moving on the phase III in optic neuritis, we will begin to think about other terrible visual disorders as we think of other disorders that have an element of inflammation and certainly tissue damage, like traumatic brain injury, like other neurodegenerative diseases, like acute stroke. Worth remembering that 3.4 billion people on the planet suffer from a brain disease, and many of these involve axonal loss. Thank you. Thank you. I will perhaps ask each expert here to give a last word before making the conclusion, unless we have a last question. Okay, we are on time. I will ask Pablo, Mark, and then Sebastian, Stephen, and Len, your last word about the previous sector, and I will be making a conclusion in the end. Thank you. You know, I would like to say that this is happening on my chance, but because it has been based on more than a couple of decades of research investigating how the central nervous system of the retina is being damaged, the trophic factor history I was explaining to you, but also developing these models of optic neuritis for testing neuroprotection, the introduction of OCT, which is not so old. We proved that it's so useful. Development of this clinical endpoint, low contrast visual acuity here in New York and U.S. especially. Now these biomarkers, RNFLs, neurofilaments that, you know, they were new for long, but in the last five years, they became validated as a biomarker, blood biomarker of brain damage, was the basis of approval for a drug in ALS, for example, meaning altogether is what is putting us in the good position of developing a drug that is truly preserving the retina, the optic nerve, the brain, and decreasing disability. This gives us a great opportunity to help people with these kinds of diseases. Thank you. I'll give a more practical—this is a global entry, but a practical about people haven't asked—how are we going to do such a study? I think it's very important to understand that, as Riad said to me last night, she said, "People with optic neuritis have pain, and that's a gift." It means that people with young people lose their vision, they may—old people lose their vision, they may sit around. Young people do not sit around. They go right to the eye doctors or emergency rooms and get treated right away, driven in addition by the pain. The practicality of running such a trial is not quite so difficult as in other trials like we had for our NAION trial because it's driven by the patients coming in. The other issue is they get referred to referral centers right away, and we can recruit patients quite quickly. I reminded everyone that when we ran the optic neuritis treatment trial 30 years ago at 21 sites, we recruited 457 patients in two years. I do not think there is a problem with getting people into the study. What we will set up will not be an onerous, difficult process to get through, to get into a study, and all the data collection really does not have to weigh upon some of these trials that are so top-heavy that the sites cannot get through them. I do not see difficulty with recruiting for such a study and getting it accomplished. Thank you. Thank you, Mark. Sebastian, and then Stephen. And then—for me, ACUITY is really a door opener for neuroprotection. In ophthalmology, neuroprotection would be very important not only in optic nerve disease, but in glaucoma and other diseases as well. If you think further about this, brain disease, any other disease with neurological problems with loss of neurons would be a target. I think it's really a big step. We haven't seen something like this before. I'm really excited. Thank you. Stephen, and then Len, your last word you would like to say or to share? Maybe I would say that I've been caring for patients with optic neuritis and other brain diseases for a half century, for 50 years. From that vantage point, I feel and mentioned this to Riad and Pablo multiple times, we have an obligation to carry this program forward. There are uncertainties, as Sebastian and others have said. There are always uncertainties when we advance from phase II to phase III. The heft of the data that we see makes this a social obligation for us to find a path forward. Thank you. Len, please. I was just thinking as I was listening to my wonderful colleagues, you know, the phrase, you know, if it walks like a duck, it quacks like a duck, it tastes like a duck, it's probably a duck. You know, if you think about the actual data that's really around what we're talking about, there's preservation of the ganglion cell layer and IPL, which is a sign that the ganglion cells are somewhat preserved, very well preserved, and they're connected to their afferents. There's preservation of the retinal nerve fiber layer, again, relatively, and that's a sign that the fibers, the axons are preserved. There is preservation of the low contrast visual acuity, which means that the connection is not just of the axons, but the onward connections are also preserved. You have all the three parts that basically show that the drug was neuroprotective in this trial. If that can be extrapolated onto a larger phase III study, but also, as we've discussed now, fairly carefully to other axonal diseases within the central nervous system, then this may have huge implications for human health, especially with those related to visual function and neuronal function and cognitive function. I think this is a fantastic opportunity to go out and have a good duck-a-larange tonight. Thank you. Thank you all for a great R&D Day. I just would like to thank all the organizers, our partner LifeSci, our internal people, and really say bravo to the Oculis team for great work they are doing. I am very thankful and privileged really to work with such an amazing expert group who joined us for retina, for anterior segment, and for neuroprotection. I think, as Dr. Hauser said, we have the obligation to bring these new solutions to patients, and I can assure you that we have the patients, the passion, the energy, and the drive to make it happen. Everything in our hand, we will make it to do it to make sure that these drugs reach the patient as soon as possible. Thank you all for your support to our investors as well and all the stakeholders supporting us in this nice ecosystem. Thank you. Have a very good day. Thank you very much. Bye. Thank you. Bye-bye.