Good morning, and welcome to the Oculis Analyst and Investor Call. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentation. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Oculis website following the conclusion of the event. I'd now like to turn the call over to Sylvia Cheung, Chief Financial Officer at Oculis. Please go ahead, Sylvia. Thank you, Tara, and thank you all for joining today's call. Before we start, I would like to point out that there is a slide deck which accompanies today's presentation. It can be viewed using the webcast link provided on the Investors and Media page of the Oculis website. Also posted on this webpage is a press release issued earlier today, announcing top-line data from Oculis' phase II-B RELIEF trial of licaminlimab, or OCS-02, in patients with dry eye disease. Before moving on to the presentation, I'll first note that during the course of this conference call, company management may make forward-looking statements within the meaning of the U.S. Federal Securities laws regarding future events or performance of the company. Actual events or results could differ materially. We refer you to the documents the company files from time to time with the SEC. The company's filings contain and identify important factors that could cause actual results to differ materially from those contained in any forward-looking statements. Please note that the forward-looking statements made during this call speak only as of today's date, and we undertake no obligation to update them to reflect subsequent events or circumstances, except to the extent required by law. The words anticipate, continue, estimate, expect, intend, will, and similar expressions are intended to identify forward-looking statements. Now, let's move to the next slide. Joining today's call are Oculis CEO, Dr. Riad Sherif; Oculis President of R&D, Snehal Shah; and two experts and thought leaders, Dr. Victor Perez and Mr. George Ousler. Dr. Victor Perez is a professor of ophthalmology and currently serves as Director of Cornea Research at the Bascom Palmer Eye Institute at the University of Miami. Dr. Perez is an expert in inflammatory diseases of the eye, severe dry eye, ocular surface diseases, ocular graft versus host disease, high-risk corneal transplantation, and ocular surface reconstruction. Mr. Ousler is a Senior Vice President of Anterior Segment at Ora, where he oversees clinical programs. He has over 20 years of experience in pharmaceutical development and played a pivotal role in development and successes, and also oversaw successes of a number of FDA-approved products for dry eye treatment. Riad will detail the data from the company's phase II-B RELIEF trial, which evaluated licaminlimab for the treatment of dry eye disease. Following the presentation, we will open the call to a Q&A session with Riad, Snehal, Victor, and George. After the Q&A session, Riad will wrap up the call with a brief concluding remark. Thank you again for joining us, and with that, I'll pass the call off to Riad. Thank you very much, Sylvia, and hello, everyone. Good morning and good afternoon. Extremely pleased to share the results of the RELIEF phase II trial, which was successfully executed with positive result in dry eye. In terms of efficacy, Licaminlimab, OCS-02, showed a rapid onset and meaningful improvement in multiple signs efficacy endpoint in full trial population. Furthermore, TNF Receptor 1 genetic biomarker, which previously was identified in the Phase II symptom trial, showed a predictive and pronounced effect in signs, paving the way for precision medicine in ophthalmology. The safety of Licaminlimab was well-tolerated, with a low incidence of adverse event similar to vehicle. Furthermore, because it is important in this population, no burning or blurred vision event were reported in the treatment group. With this result, positive phase II RELIEF trial defines clear pathway for licaminlimab to advance to phase III as potentially the first precision medicine to address both signs and symptoms of dry eye. Now, before going into the details of the study, and because dry eye, as you all know, is a complicated disease, I would like first to share with you the full data set of what we have now with OCS-02 or licaminlimab, and then to speak about dry eye, and then to go into the details of the study. A rapid recap of what we did with licaminlimab. Three clinical trials in dry eye: DED1, DED2, and DED3. DED1 was with the predecessor of OCS-02 or licaminlimab. DED2 and DED3 are with licaminlimab. Licaminlimab showed efficacy in symptoms in the two previous trials in ocular discomfort. But furthermore, in DED2, we identified a TNF receptor 1 genetic biomarker, which showed predictive and pronounced response in symptoms in this population. In the DED3, which is a RELIEF trial, which was on signs on 122 patients, Licaminlimab showed improvement in signs, in corneal and conjunctival staining, and we were able to validate TNF receptor 1 genetic biomarker in signs, and I will show you the result. So for the first time, we can truly dream that with Licaminlimab, we can drive precision medicine approach to apply in dry eye, which will mean significantly de-risking phase III clinical program with a product which allows us predictive and profound response, and also after commercially, offering a transformative product profile for doctors and patients. Let's speak about dry eye, and then we go into the detail of the study. So as you all know, dry eye is an important market, a big market, $4 billion, expected to double in the next 5 to 10 years, mainly driven by inflammation, because inflammation is the core component in dry eye. However, as reported in 2024 by AAO, still, almost 9 out of 10 patients are not satisfied with their treatment. And this, despite the launches of many products recently, we see that 85%-90% of discontinuations occurred in the first six months, and the primary documented reasons for switches are lack of efficacy and adverse events. And in recent surveys, when you ask the prescribers what they want to have in this syndrome, which is dry eye syndrome or dry eye disease, is they want to be able to customize their treatment. And this is what potentially Licaminlimab could offer. What is Licaminlimab? It is an anti-TNF inhibitor, antibody fragment, specifically formulated for the eye for a topical delivery. First, the mode of action is anti-inflammation, anti-apoptosis, which is specifically designed to address the two biggest issue in the vicious circle of dry eye, which is inflammation and then apoptosis. The second, it is specifically designed for the eye. It is a fragment which allows the product a good ocular penetration, and it allows us a high concentration of the product. And furthermore, and this is what we will see as well, is the product comes with a proprietary genetic biomarker, which showed a very high association between high response and the presence of the genetic biomarker TNFR1 in symptoms, and we will see it in signs now. Licaminlimab is a product which act on inflammation and act on apoptosis, which is what is happening in the cornea, in fact, in dry eye. Licaminlimab is a product which is highly potent, and you can see here the comparison of the potency vis-à-vis Humira and vis-à-vis infliximab. Now, what we learned previously with the two previous trials, in terms of efficacy, licaminlimab showed significantly reduced ocular discomfort in patients treated with licaminlimab versus vehicle at day 29. It showed a rapid onset of action, with relief of symptoms starting on day 15. The safety, the product was well-tolerated, with low incidence of adverse events related to the study treatment, similar to vehicle. And we were able to show that the TNFR1 genetic biomarker showed significant association between licaminlimab response and ocular discomfort, which was sevenfold higher than the response with full population. Furthermore, we saw that we could reduce the inflammatory cytokines in the tear film observed in Licaminlimab-treated patients.... So let's now go to the RELIEF trial. Before going into the data, let me remind us the objectives of the trial. We had three objectives. First objective was to evaluate the efficacy of Licaminlimab in the treatment of signs of dry eye disease. The third objective was to confirm the differentiated response, predictive and profound, of Licaminlimab with subjects who were positive to TNFR1 genetic biomarker in signs. We saw it in symptoms, we wanted to see it in signs as well. And the third, of course, with this learning from objective one and objective two, to select the primary sign efficacy endpoint for phase three and inform the overall development plan. This is the study protocol. It was a 10-week trial, two-week run-in. Patients received artificial tears. Patients who responded to artificial tears were not randomized. Then six weeks of licaminlimab, and then two weeks of follow-up, safety follow-up. Nothing to report here, here. Sorry, it's a typical phase II-B to select the sign. The primary objective, as we discussed, was to evaluate efficacy and safety in subjects with signs of dry eye, with a focus on corneal, conjunctival staining, redness, and Schirmer. The patient population was moderate to severe corneal staining and, with corneal damage on the inferior region under stress conditions. In terms of patients, as you may know, the frequency of the TNFR1 in the U.S. is between 18%-20% of the population. It's slightly more in Europe. We ended up with a population randomized with the TNFR1 equal to 19% or 23 patients, 12 in the active and 11 in vehicle. Just a rapid snapshot about the test we are performing. This test is based on a qPCR technology. It is a very simple, straightforward, binary yes or no test, which was, of course, done in the clinical trial in a centralized lab. In clinical practice, this test can be done at point of care with a response which can be as fast as 20 minutes after the start of the test. So very simple, affordable, actually, and rapid, and specific binary result are yes or no. As you know, as well, FDA published recommendations for dry eye disease on December 2020, where basically the expectation is to show safety and efficacy should be demonstrated in at least two adequate and well-controlled multicenter independent trials. Efficacy for a sign and efficacy for a symptom do not have to be demonstrated in the same trial, but it should be demonstrated in more than one trial. This is the strategy we are applying. In symptoms, we selected already ocular discomfort or signs. These are the signs which we tested, and we will see the result immediately out. This is the subject disposition. 122 patients randomized, 62 with licaminlimab, 60 with vehicle. 58 finished the trial with licaminlimab and 57. The study was well executed with all TNFR positive, finished, completed with 12 on the active and 11 on the vehicle. These are the subject demographics. I would say nothing to highlight here, a typical dry eye study performed in the U.S. In terms of baseline, baseline were balanced with the full population, but importantly as well, with the TNFR1 genotype group, they were well-balanced, and therefore, we could make conclusions with this baseline, which are well-balanced, regardless of which group we consider. Just a reminder for us, because we will be focusing on staining and just to put a context for the group here, connected Xiidra, which is I would say, a successful lifitegrast, which is a successful product in dry eye, was approved on staining, on inferior corneal staining. These are the three signs study Xiidra did. The difference at day 42, we'll be speaking at the day 42. Our trial was six weeks, so we'll be speaking at day 42, and this is more to put context in place. We don't have a head-to-head. If we go into what was approved, Xiidra basically delivered an improvement between -0.003 to -0.10 at day 42. This is what we, what Xiidra delivered into their three phase III clinical trials. So what Licaminlimab does? If we take exactly the same endpoint, these are the results with Licaminlimab with full population, which is -0.12, which is actually higher than the best result we saw with the previous slide, even if it is not head-to-head, and I want to be clear here, I'm just putting the context to allow interpretation. In the same time, when we see the result into the TNFR1 genotype result are fivefold higher, so much stronger, much profound response with the TNFR1, which is extremely encouraging. Why corneal staining is important? Corneal staining actually is reflective of inflammation and apoptosis, which play a crucial role in dry eye. The corneal staining, and mainly the inferior part, given its exposure, is also the most commonly assessed sign in clinical practice, as it can affect quality of vision. We have an expert with us here who can help us to understand the clinical relevance of this endpoint, which is an FDA-approvable endpoint, and why this endpoint is important, and why this endpoint in clinical practice is important, and why this endpoint in clinical care and evolution of the disease for patient is important. Here, it's extremely encouraging to see that within the full population, the product is efficacious, and within the TNFR1 genotype, the product is extremely efficacious and very rapid. We can see here in the next slide, response already at day 14 is -0.38, at day 42 is -0.59. So extremely rapid onset and extremely efficacious. If we go to the rest of the endpoints which were measured, we see that the full population, Licaminlimab showed a positive effect in many signs. At the same time, in the TNFR1 group, we see this response much more predictable and much more profound. And this is what we saw in symptoms, and this is what we see here in signs. So in terms of efficacy and based on the goals we had for the clinical trial, first, the treatment is in favor of Licaminlimab, observed in multiple signs with rapid onset, which continued to increase over time, consistently which sign you take. On the second objective, the TNFR1 genetic biomarker had more pronounced and predictive treatment response on multiple signs, consistent with the previous symptom trial. The third, corneal staining is an approvable endpoint by FDA and the commonly assessed sign in clinical practice, as it can affect quality of vision. Licaminlimab has the potential to be disease-modifying, with its dual mode of action as inflammation and apoptosis. It's helping the cornea to reduce inflammation and to heal, basically, and it's directly linked to the pathogenesis of dry eye. So for the first time, precision medicine could be applied to dry eye in the clinical trial, which will make the clinical trial de-risked and more efficient in terms of capital, but also potentially we can truly offer a transformative product profile to the doctors and to the patient. Let's go now to the safety. The safety was, I would say, excellent, similar to what we see with vehicle. Nothing to report. The salient patients are here, basically, is mainly instillation site irritation. When we see how we characterize them, this is really the summary. So low incidence of adverse events reported with Licaminlimab, similar to vehicle. The most frequently reported ocular PAEs are mild and transient, related to instillation site irritation and slight pruritus. What is important here, because in this disease, patients have symptoms, and they have irritation, and they have burning, and they don't want this type of safety concerns, which we can see with others. We didn't see any burning or blurred vision reported by investigators. This product has been extremely well-tolerated, and the comfort is excellent with this product. This is basically the drop comfort scale and attribute, and you can see it here, drop attribute, any positive response. So it's comfortable, it's cool, it's refreshing, it's smooth. So the comfort was on the very high end. So in conclusion, Licaminlimab can truly offer a highly differentiated product profile. It has the potential to address key unmet medical need in a market where nine out of ten patients are not happy with the treatment they have, and can transform the treatment paradigm of dry eye to allow the doctors to identify the patient who will respond to this product in a predictive and profound way. In terms of unmet medical need, Licaminlimab offer a meaningful treatment effect in both signs and symptoms, with the potential disease-modifying TNF inhibitor acting on inflammation and apoptosis, which are a key pillars of dry eye disease, but also key pillars of the inflammation of the ocular surface and the cornea. Product showed rapid onset of action in both symptoms and signs. But symptoms, of course, are very important for the patient because this is the reason why the patient goes to see his or her doctor. Product showed a very solid safety profile, with mild and transient adverse events reported with drop comfort, consistent with artificial tears. And I would say the very differentiated approach is the diagnostic. The TNFR1 response was fivefold higher in signs and sevenfold higher in symptoms, which could offer a product which is extremely differentiated in a market where nine out of ten patients are not happy with what they are receiving. So in conclusion, RELIEF trial showed a positive result on signs in full population, with five times improvement in TNFR1 genotype group. Phase II RELIEF study in signs, along with the previous completed phase II study in symptoms, provide consistent and meaningful results from two randomized controlled studies, the ED2 and the ED3, with fast, fast-acting, meaningful treatment effect on ocular discomfort and corneal staining, and well tolerated. We identified now the signs and symptoms primary endpoint for a phase III, inferior corneal staining and ocular discomfort, which will be our endpoint for the phase III trials. We confirmed also the novel precision medicine approach, targeting patient population with the TNFR1-related genotype, which allows us to identify high responders to the licaminlimab with, as shared with you, they respond 5- to 7-fold improvement in treatment effect for signs and symptoms. It significantly and materially de-risk the phase III development, with, achieving in terms of, smaller, faster, most cost-efficient, and more predictable phase III program now, with the TNFR1, and potentially transforming completely the commercial product profile for a, a potential disease-modifying precision medicine in dry eye. The next step for us now is to conduct an end-of-phase-II meeting with FDA to finalize the phase III development plan. Thank you very much, and happy to respond to your questions. Great. Thank you, Riad. So at this time, we'll be conducting a question and answer session with our speakers. Please hold for a brief moment while we poll for questions. So our first question comes from Madhu Yennawar at Leerink. Please go ahead, Madhu. Hi, this is Madhu for Mark Goodman. Congrats on the data. I just have a couple questions. So can we expect additional data from this trial, either on symptoms like ocular discomfort or any measures of apoptosis that could demonstrate that second prong of the MOA of licaminlimab? And then can you also tell us about how you plan to approach the end-of-phase 2 meeting with the FDA? Do you have a population in mind that you're going in to discuss with them, or are you going to let the FDA kind of look at the data and let the discussion kind of dictate where you think the phase III will go? Thank you. Okay, thank you. So, two questions. I will address the first, and I will ask my colleagues, Snehal Shah, to address the second one on the FDA interaction. For the first question, this trial was a sign trial. We didn't randomize for symptoms at all, actually. So therefore, we have the, I would say, a very consistent approach to randomize for symptoms, to show improvement in symptoms, and randomize for signs, and to show improvement in signs. And therefore, we do not expect this trial to show something in symptoms because it was not the goal, and we didn't randomize for symptoms. For the regulatory, I will ask Snehal, please, if you can address the regulatory question. Yeah, thank you for your question. So we'll discuss the full data set with FDA at the end of phase II meeting. And that will also include, you know, further development in the full population and biomarker-specific population, so we don't wanna rule anything out at this time. Got it. Thank you. Thank you. Thanks for the questions, Madhu. Our next question comes from Colleen Kusy at Baird. Please go ahead, Colleen. Great. Thanks. Good morning, and thanks for taking our questions. Sorry if I missed this, but can you clarify, of the signs that you laid out on the slide that had the green check mark, does the green check imply a statistically significant improvement, or... And if not, can you specify which of the endpoints you saw a statistically significant improvement in the overall group and the biomarker group? And then I have a follow-up, please. Okay. So first, the protocol and the statistical model didn't have any hypothesis in terms of p-value. Our... If we come back to the goals, the goals were really to select the sign which will be the most relevant for the phase III. This is on the statistical model. Now, in the same time, and if I come back to the slide you were referring to, I think, Colleen, let me see. In the same time, the sign in the genotype was statistical significant, and you can see here that it's always below zero actually, in terms of yeah. So therefore, this is on the statistical. Snehal, would you like to add further, please? Yeah, no, that was a great question. So as Riad said, the confidence interval here does not cross zero, so it is statistically significant. And then you could see on the forest plot, the directional p-value is less than 0.05. So these were very significant findings in the biomarker population. Got it. Thank you- Just to- Oh. Thank you, Snehal. Just to add actually on what Snehal is saying also, and I didn't say it, like, we are speaking about 23 patients showing this type of drug effect and showing this type of statistical difference. So it means that the effect is so pronounced that in this population specifically, we need very small phase III to show significance. Understood. That's helpful, thank you. And maybe for Dr. Perez, if he could put into context, you know, the importance of this inferior corneal staining versus some of the other signs, endpoints, and how he kind of thinks about the comparison. Yeah, Colleen- Dr. Perez, would you like to... Yeah, thank you. Yeah, for sure. Thank you, Colleen. That's a very good question. And, you know, so if you think of the inflammatory milieu of the tears, and they kind of pull inferiorly, and then in addition to that, you kind of, like, add the friction of blinking, this is the way that we actually have been thinking about inferior corneal staining. That you have, more of a inflammatory stress, if you will. So that makes sense, actually. So if you're able to change that milieu with a, you know, an anti-inflammatory medication and prevent the corneal epithelial damage, because that's what the staining is, right? Is breaking of the, of the tight junctions, and inflammation certainly is involved with that. That's kind of the way we think about the inferior corneal staining. We've been thinking about this a lot. Then, you know, you can also add, right, that, you know, meibomian glands are also in that area, so they're in direct contact with the corneal epithelium. Even though we also think about central corneal staining, because it's more exposed, they feature in a staining, and it's kind of like a very interesting area to look at from that point of view. That's helpful, thank you. Thanks for taking our questions. Thank you. Of course. Thanks for the questions, Colleen. Our next question comes from Annabel Samimy at Stifel. Please go ahead, Annabelle. Hi, thanks for taking my question. Congratulations on the data. So I just want to understand, for the phase III trial, I guess, first, obviously, there's a pretty remarkable impact on the biomarker-positive patients, and it doesn't look to me that there was statistical significance on the overall population. So as you approach, the phase III trial, are you going to request for it to be primarily a biomarker positive patient study, given that pronounced effect? And on a separate. On the signs and symptoms endpoints, I'm curious if in DD1, DD2, I believe, that you showed benefit as early as 15 days. So maybe you can help us understand what is the more meaningful endpoint to show rapid effect. You know, is that something that you're gonna see on the signs? Is that something that takes a little bit longer, given that you're affecting the biological mechanism? Is it really the symptoms that most people from a, I guess, commercial perspective want to see more rapid effect? So maybe you can sort of put that into context for us. Yeah. Okay. So, I will respond to your question, Annabel, and I will ask also Dr. Victor Perez to give his opinion about the importance of signs and symptoms. In terms of the rapid onset, really what is important, and prescribers repeatedly say it, what is important is to treat symptoms rapidly, because this is the reason why patients go and consult and ask for help. So therefore, showing rapid symptom onset is important, and this is what we showed in the previous trial. Now on your second question, I would perhaps ask Dr. Victor Perez to address this question first, and then I will go to your second question, Annabel. Yeah. Victor, would you like to give your opinion about the importance of symptoms and? Oh, yeah. Thank you, Riad. And another great question. You know, this is a disease of symptoms, and of course, we continue to understand it. And from the inflammatory point of view, I think this makes sense. You know, TNF is a very potent inflammatory pathway. So, our patients come to us based on symptoms. I can look in the slit-lamp and see all the corneal staining. That's just gonna drive me to decide how I'm gonna treat these patients. But at the end of the day, it's how patients feel. So, it's... This is very significant, that you have a rapid onset on the relief of symptoms. And, you know, it's like, actually, if you think about it, in radiology, it's the same thing. You know, when you look at a chest X-ray on a lesion or a pneumonia, usually symptoms, you know, when you do the right treatment, start acting first, and then the X-ray eventually gets to baseline. It's the same thing in the eye. And so yeah, this is a disease of symptoms, so it's very, very important that you can act fast in the symptoms because, you know, it'll do two things. You know, the patient will be compliant for the therapy. If he feel better, he'll continue to do it, he believe in what you prescribe. And, you know, as Riad mentioned in his presentation, you know, the three big bad boys if you will, or girls, in an eye drop is if they irritate, cause blurry vision, and redness. So the fact that, you know, you don't have any of those confounding factors into a patient that already has an irritated ocular surface, where they'll be more sensitive to any type of irritation, and you're relieving symptoms that fast, that's a very good quality to have for a drug that's gonna treat ocular surface disease. And just quickly on that point, does it take longer to show an impact on signs than it does for symptoms usually? Yes. You know, and we have, you know, experience with that using other type of, you know, protective ocular surface drugs. So yes, patients will definitely have more relief of symptoms, and you still will see some corneal staining, and eventually, that will catch up. It's a very interesting concept, you know? We still have a lot to learn from the ocular surface. Sometimes you have a lot of symptoms and no signs, by the way. Mm-hmm. So as you know, the fact that you know this molecule or this protein, small protein or fragment, it's hitting symptoms, it's very interesting and very important. Okay. And maybe on the- Thank you ... path forward. The second, so on your question, Annabel, about the statistical model, again, we didn't have, and we didn't want to have, actually, hypothesis, because we went to select the right sign, and therefore, it was just not the expectation. Now, again, we are extremely happy with this result, which are, I would say, outstanding, with 23 patients. But if we want the significance in full population, we need to do what all dry eye studies do, which is, as you know, we are speaking about... I mean, if I come back here, I don't remember exactly the numbers, but we are speaking about 500 patient or 600 patient or 700 patient to show significance. Now, the great news in our model with this molecule and with this TNFR1 genotype is potentially we would show significance with much less patients. And this is really also the advantage in what I was saying about a much more efficient and the risk phase III. Is that- I would perhaps... Yeah, sorry, Annabel. Is that much- Go ahead ... much less patients, because you're gonna be focusing primarily on the biomarker patients, or? Potent- potentially. Yeah. Yeah, no, potentially. I mean, as Neha said, this, this will be a discussion with the, with FDA. But there is a path which is, extremely exciting in terms of science, in terms of patient, and in terms of access and pricing, is to potentially focus on 20% of the population, which represent 2 million patients in the U.S. only.... where we have something which works, and works extremely well, with a perfect safety profile. So therefore, the, the case is extremely compelling, actually. I would perhaps ask, just to, add his context and experience, George Ousler perhaps did 90% of the dry eye studies in the U.S., which means 90% of the dry eye studies in the world. So if he can share with us his opinion about what he sees here, vis-à-vis what he knows about dry eye studies in general. Please, George, share your opinion with us. And if there is any question, happy to take it. Absolutely, Riad. I would say it's critical that we find what we call the right patient in a dry eye program. A patient that's going to responding to that therapy and also have that response be reproducible. So in this context, where we've identified patients that have, you know, five to sevenfold higher response, that's unheard of, and very good for Oculis. And then, as we know, we want to have this predictability in Phase III and reproducibility of data. When we look at these patient populations, they will be more homogeneous, and this is what Oculis is going after, the symptom population specifically, and then the sign population specifically, with this additional layer of the genotype. So again, that helps with a homogeneous patient population, more predictable and efficient phase conversion. And Riad, if I may add, you know, from a clinician point of view, I want something that works, even if it's 20% of my patients, and I know it's going to work. Because if I give a medication to most of my patients, it doesn't work, which is 80%, they're going to come back, and they're going to be not friendly user to me, not friendly user to the drug, and we don't change their life. So this is precision medicine, and this is the way that ocular surface should move forward. So I congratulate you, Riad, for moving forward. Victor, thank you for saying it. I didn't ask you, but thank you because it's really... I mean, it's exactly what you're saying. Let's think about this disease, and you know it more than all of us, this disease is very heterogeneous. Only one patient out of 10 is happy. 13%. Mm-hmm. 90% of the treatment is discontinued after six months. So if you have something... And we have millions of patients, so if you have something which allows you, as exactly Dr. Perez is saying, if you have something which allows you to select the population which will respond, it makes sense for the doctor, it makes sense for the patient, and it makes sense for the payer. Yes. Thank you. Thank you. Thank you, Annabelle. Any other question? More than happy we have, I think we have- Yes ... minutes also. Yep. So our next question comes from Pavan Patel at Bank of America. Please go ahead, Pavan. Mm-hmm. Hey, Riad, this is Pavan- Hey, Pavan. I'm from Bank of America. Thanks for the presentation this morning. Two questions from us. No questions. On corneal inflammation endpoint, that was shown to be statistically significant, within the subgroup of genetically selected patients, can you confirm that you saw at least some benefit in all 12 active treatment arm subjects? And how did the 11 patients on placebo perform on symptoms? And then my second question is more of a high-level question, which is, even with the subgroup, is the benefit with OCS-02 any better than the current broad-based treatments on the market? And I appreciate that it's not a head-to-head trial, but I'm wondering how you would frame a response. Okay. So on your first question, we do not have this data yet. This is really top line data, so we don't have individual data. What I can share with you is when we take the response rate in symptoms in all comers, it was 18% were highly responding in symptoms with 20 point in OSDI. In full population with the TNFR1 genotype, they were 75%. So much more profound, but also much more predictable. But this is what we know and what we have on the symptoms. For the signs, we didn't do this analysis yet. On your second question about the effect, I think I agree with you. It's not a head-to-head. We are putting data side by side without comparing, because it's very difficult to compare. But when you put side by side the data, with the product which is very successful, actually, we are comparing this benefit at day 42 versus this benefit for full population, which is already higher than the best study, with much less patients. And when we compare this drug effect, I mean, as George Ousler said, "Unheard of." So therefore, the drug effect is very high if you compare with the... if you put side by side with a product which is a successful product. Now, why staining is important is because really this is we learned from the clinician, this is what they use to control their patient. If I give an illustration, and please, Victor L. Perez, please correct me if I am wrong, but if I give an illustration, retina, the doctors control BCVA, which is a functional improvement, the symptom, and they control the CMT, which gives them the thickness of the retina. The dry eye doctors control, of course, the symptoms, and they control the staining because it gives them the status of the health of the cornea. And the very nice, and I would say extremely encouraging thing here, is we have a product which is acting on the dry eye disease itself, and therefore truly bringing potentially disease-modifying treatment to dry eye. And this is, this is extremely encouraging, because we understand the science, and the science is working on the issue of the disease, and it is fixing a surrogate, which is the stain. I mean, Dr. Perez, please give your opinion about the importance of staining in the dry eye, and is it clinically relevant for you, and is it something you monitor, basically? Yeah, I mean, for sure. I mean, that was a great analogy, Riad. For us, the cornea, by the way, imagine the cornea is the windshield of your car, and the surface is not scratched. You're not gonna see anything, and so it affects vision, it affects discomfort because the corneal nerves are right there. So, you know, for us, corneal staining, you know, I remember way back when we started working on this, right? Riad, you know, yeah, symptoms are great, I want to see some signs. You know, corneal staining is what we looked at. You know, at the end of the day, the cornea pays the price for all the inflammatory milieu that is in the ocular surface. So corneal staining is the best thing we have to understand damage to the surface of the eye, and most of the time it's inflammation. So this is kind of like a indirect biomarker of an inflammatory response. You know, the, those cells, they get stressed, and they break up, and they stain more, and, you know, that's what we see in the slit lamp. So when you're talking to general ophthalmologists, optometrists, what they look is at the surface of the eye on corneal staining. And the fact that you can reverse that or affect that is what we're looking for, so it's very important. And Riad, you mentioned something important, it's disease-modifying. That's very important. You know, TNF is an upstream cytokine that we know causes damage in other parts of the body, in the joints, in the lungs, in the GI tract. I mean, we learn from Humira and Remicade. I mean, these would be the most successful biological therapies that we ever had. You know, thinking from an immunologist point of view, an autoimmune disease doctor, this is, you know, this has been the most significant drug that has changed how we manage patients with inflammation. So the fact that we can bring it to the surface of the eye, deal with it, and, you know, the fact that you're putting it in as an eye drop, you know, you're not gonna have off-target effects systemically. So, that's what we're doing. We're taking care of inflammation very upstream, and the corneal epithelial cells and the staining is showing us that. Thank you, Victor. Thank you. Thanks, Riad- Yes. Congrats to the team. Thank you, Pavan. Thank you. Thank you very much. Thank- Any other question? Yes. So our next question comes from Daniil Gataulin at Chardan. Please go ahead. Hey, good morning, guys. Thank you for taking the question. Just a quick one from me. To clarify on your current plan for the phase three program, do you anticipate running two trials to look at both the signs and the symptoms, or do you plan on breaking it down into more trials, and have some trials look at the signs and then others symptoms, basically separately? Thank you. Yeah. So as already actually it was our strategy since the beginning, our focus is really to do two trials in signs and two trials in symptoms. The very good news here is that if we go with TNFR1 genotype, we will be able to do small trials, predictive in terms of response and efficient in terms of capital, because we will not need hundreds of patients, typical dry eye studies. But still, our aim is to do two in signs and two in symptoms. Okay. Thank you for clarifying. You're welcome. Any other question? Yes. Our next question comes from Yi Chen at H.C. Wainwright. Please go ahead, Yi. Mm-hmm. Yi, we can't hear you. Hello, Yi. Questions. Hello. Good morning, Yi. Just a very quick one. Just want to clarify, were symptom endpoints measured in the RELIEF trial? Yes. Symptoms were measured. The baseline was almost normal patient- Mm-hmm ... so therefore, it trended towards better, but they were already normal. Like, it's... Think about it like this: if you have a painkiller and you want to measure the effect of your painkiller and your patient do not have pain, then it's very hard to show reduction of the pain. It's really the same. This is why I say we didn't randomize for symptoms at all.... but yes, it was measured, and it shows actually in patients who didn't have symptoms, it showed slightly improvement of symptoms, but we didn't expect anything. It was just, let's do something complete. But, the symptom improvement for TNFR1 genotype patients, were they more significant than the, Yeah - broad population? Absolutely, and this is basically what we showed in the previous trial. So in the previous trial, we showed that in terms of symptoms, TNFR1 patient showed sevenfold better symptoms relief versus all comers. Sevenfold. So therefore, yes, absolutely. And within the same patient who showed this type of improvement, it's actually sevenfold improvement in symptoms. And within the same patient who showed this type of improvement, which is very profound, like signs, and very predictive, because 75% showed high improvement, more than 20 points. This patient, when we measured the mRNA expression of the TNF in their tear film, the same patient showed a reduction of the TNF. So it's really what the Dr. Perez was saying, is we are acting on symptoms, but also we are acting on the disease, improving the corneal health. So therefore, yes, and we know it, so we know it works on symptoms. It works on all comers, and it works extremely well or much better on the TNFR1. This is why, back to the previous question, I was saying our plan is to randomize for signs and to show signs improvement, and to do two trials in phase III, and then two trials for symptoms and to randomize for symptoms. And as a painkiller, we need patients who have more symptoms to be able to show that we can reduce the symptoms. I might perhaps ask George, anything I missed? I mean, you are our advisor in terms of clinical design. You know this field so well. Anything I missed, please? Riad, you did an excellent job reviewing that, but what I would add is that this RELIEF trial, again, to highlight the fact that it was designed specifically to investigate signs, and in fact, there were no inclusion criteria around symptoms. And the symptom that Riad mentioned, you know, we measured just one, just for some reference, and, and as he indicated, there is a trend in favor of the active, but the baseline scores were quite low. And this, again, was by design, and in fact, in some ways, it validates the approach that Oculis is taking, where you have to go to the enriched symptom patient population in a symptom trial versus enriched patient population for a sign in a sign population. So it actually helps to validate the whole concept that they're moving forward with, and what we saw with Xiidra as well. Thank you. Thank you. Lastly- Any- Lastly- Any other- The, uh- Uh, uh, uh- The percentage of TNFR1 genotype patients in the trial, do you think that represent the percentage of those genotype in the real world practice? It's pretty aligned with what is published, yeah. Yeah, it's pretty aligned with what is published. I mean, what we know is, they say in the U.S., it's around 18%, 18. We ended up at 19. Mm-hmm. It's pretty aligned. Yeah. Okay. Yeah. Thank you very much. Yeah. Thank you. Any other question? I just would like to have one minute to conclude, but if there is a question, more than happy to take it. Yes, we have one more question, Riad, if that's all right. Yeah. Okay. Our final question comes from Chen- Sun Li at Pareto. Please go ahead. Mm-hmm. Hi, congrats on the data. Yeah, I just have a quick question. Thank you. Yeah, just trying to address one of the main concerns among our investor base. Regarding the commercial perspective, so considering there's some reimbursement challenge for Xiidra, do you expect a different behavior from payers, if you're targeting this, TNF-α? Mm-hmm ... groups? And, or do you expect to argue for a potentially higher price? Yeah. Thank you. Yeah. Thank you. Thank you for the question, and it's a really important question, and it might also guide us in terms of strategy, because as you may know, payers are not against paying. They are against paying for nothing. They are against paying for something which does not work. They are against paying for something which might work in 10% of the population. This is what they don't like for obvious reasons. So therefore, for the payer point of view, having a genotype, allowing them to pay for something which will work in their patient, it just, for them, is fantastic. For them, is the best return on investment, is when they pay for something which work. So therefore, for the payer point of view, we will be their best friend with our TNFR1 genotype, if we go with it. So therefore, now in terms of pricing, we are, of course, doing our work, but most probably, the genotype will allow for a better pricing because the return on investment is better. It's really about return on investment more than pricing itself, which is just one item within the formula. But the formula is a return on investment from the payer point of view, and with the diagnostic tool, the return of investment is most probably 5-7 times. It's really taking this between 5-7 times better. ... Okay, perfect. So therefore- Thank you very much. You're welcome. So, just for conclusion, I would like just to highlight a few things. So with this, DED-3, it's really complete the full data set in terms of clinic. We have a complete data set. This product works. It works in symptoms, it works in signs, and it works fast, and it has a safety profile and tolerance profile and comfort profile, which is equivalent to vehicle or tear film, artificial tears, so really excellent profile. Furthermore, it is true that the TNFR1 related genotype brings something very unique to the product, which could allow us to really transform the way we develop, Licaminlimab in dry eye by potentially doing... I mean, the typical phase 3s, and please have a look. Typical phase III are around 2,000 patients in total. We might end up with 10%, and it might be enough for us because of the predictive and the profound response within this population. Overall, we believe that this makes sense. It makes sense for the doctors, their patients would be happy. It makes sense for the patient, but also it makes sense for the payer. And the last point, with this modification, which is perfectly fit with the disease itself, it truly can be a disease-modifying. So we can, for the first time ever, we can really treat and the disease itself into the cornea, which is, in the end of the day, the part which is suffering in the eye. Thank you so much. I would like to thank you all. I would like to thank also our speakers, Dr. Perez and Dr. Ousler. I would like also to take to thank my colleagues, Sylvia Cheung, our CFO, and Snehal Shah, our R&D president, for your help. And thank you, our partners at LifeSci, and thank you all of you for your help and for following us. It's a pleasure to work and collaborate with you all. Thank you.