Thank you for joining us for our next session. I'm Marc Goodman, one of the Biopharma Analysts at Leerink, and we are lucky enough to have Riad Sherif from Oculis Holding AG, the CEO, one of my favorite stories. You know what's funny is I told this story, but I'll just say it one more time. You know, when I first met you a couple of years ago, I met the company, I viewed it as like there's two really interesting products, and then there's this third program that they're doing that probably has no chance of working because nothing ever works in neurodegeneration. Here we are today where that third, you know, kind of extra product that you were working on is probably the most exciting thing in the company and probably has the biggest potential peak sales. The other two products are still just as interesting. The whole story's just completely changed and become more interesting. You know, kudos to the team for making that happen and stuff. Let's kinda walk through the programs. I think we'll start with the DME program. That is the one where we're gonna have data the soonest, right? Coming up very soon. I think that's probably on the minds of everybody. Set the stage for what we're talking about here with DME. What's special about the product? What data do we have? What data are we gonna see in the pivotal program? Yeah. Thank you. Thank you, Marc, for inviting us and for being monitoring us and following up for all these years. As you said, we have three clinical stage asset. The three clinical stage asset are in phase III. The first asset is OCS-01 is in DME. Really the first and only topical product for retina. Readout for both phase IIIs, DIAMOND-1 and DIAMOND-2, is now anticipated into the second half of Q2. We will have both studies at the same time. The profile is, I would say, materially different from all what we have in the market, but also upcoming because it's really the only one which is topical. Therefore, it allows us to address patients who are unaddressed today. On one hand, address early intervention or naïve patient who are literally waiting to be worse to accept the needle into the eye. This patient will not need to wait. This patient will be treated in the future as soon as the diagnosis is made, which will be a paradigm shift in this disease. This is the first part, and this represent the same pool of patient who are treated. Huge transformation. The second segment of patients who are unaddressed today, who are patients who are not responding appropriately to anti-VEGF, and this represent 40%, more than 40% of patients who are not responding. These patients, why they are not responding actually to anti-VEGF, while anti-VEGF are very good treatment. They are not responding because DME is a combination between VEGF, between neovascularization and inflammation. Therefore, the best for this patient will be to give them actually potentially combination to address VEGF and to address inflammation. This and our product is able to be combined with the anti-VEGF. Therefore, the TPP of this product is materially different from any other product. It address a market which is unaddressed, naive patient, but also combination. When you put everything together, it represent a pool of patient which is bigger than the current market, actually. Talk about the data that we've seen so far, the previous study that gives you the confidence that the phase III is gonna work. Yeah. Yeah. Yeah. This product went into four clinical trials consistently showing benefit in terms of vision improvement or BCVA and improvement in terms of CMT or reduction of the inflammation into the retina. This positive data were seen in both groups, naive and previously treated with anti-VEGF and then switched to OCS-01. I mean, we are confident on a multiple reason. One, the biology is approved as an implant. API is approved as an implant. The second, clinically, OCS-01 was consistently positive. The third, we really tested in stage one, phase III, we tested our regimen, which is induction and then maintenance. Consistently, we show that we can drive the efficacy up and we can maintain the efficacy. Therefore, we are confident. Of course, we don't know what we don't know. At the same time, we are pretty confident about it. In the phase II study, talk about what the endpoints showed. Yeah. The endpoint in phase II were the primary endpoint was mean change BCVA at week 6 and mean change BCVA at week 12, and we achieved 7.8 letters mean change, BCVA, which is similar to what we see with anti-VEGF at the same time point. The secondary endpoint was responders, and it was higher than 27%, which is also similar to what we see with anti-VEGF. Very efficacious profile, actually. Just to be clear, we're in the ZIP code of what you get from an injection, and this is an eye drop that you would just do multiple times a day. Exactly. Exactly. Okay. Now we've got the two phase III studies. Yes. Just talk about the design of those studies. The endpoints are the same? The endpoint are the same. Primary endpoint will be mean change BCVA. The secondary endpoint will be responders. How many patients gain more than 15 letters? Is exactly the same. The difference between stage 1 and stage 2, stage 1 was 12 weeks, trial and stage 2 is 52-week trial as any other phase III in DME, okay? In our mind, we have 2 scenarios. 1 is a base scenario, which is this is the same API as Ozurdex, so therefore if we have the same safety and the same efficacy, we will still address 8x-10x more patients than Ozurdex just because we can go early and we can combine. With the same profile, and this is actually amazing when you speak with the medical community, their expectations are so low for the following reason, because they want an eye drop and they don't have any eye drop. They say, "If your product shows something, we need it. We will use it because we do not have anything." Therefore, when you think about it, you say, okay, base case scenario would be similar to Ozurdex in terms of efficacy and safety. We will still address 8x-10x more patients because we go to early and we go to combination. The great scenario will be same safety, a higher efficacy as shown in the previous trial. It would be still 8x-10x more patient. At the same time, most probably more penetration. When the data comes in late 2Q, as you said, it's two studies. They're both gonna be reported together. Yes. You'll report them, I guess, separately, you know? It will be separate and pooled. It will be separate. So, 7.8 letters is what we saw in the first one. Yes. Is that kind of what you're hoping for here again? Or is that a really good scenario and, you know, even if it's, e ven if it's six, it'll be a great scenario. This would be a great scenario. Yeah In our mind. Yeah. Because if you see the data of Ozurdex at week 52, which was lower than that. Mm-hmm. Therefore, this is why we are saying it's the same API. Base scenario should be similar. Great scenario should be better on efficacy, the same on safety. Okay. This is six weeks and 12 weeks. Well, it's 12 weeks. This will be. Stage 1 is 12 weeks. Stage 1 was 12 weeks. Yeah, yeah. Six weeks and six weeks. Stage 2 is six weeks induction and 46 weeks maintenance. Right. Yeah, I got it. Okay. Very exciting. That's coming up very soon. Both studies are positive. We work to file as fast as possible, basically. We file immediately after, yeah t his year. Is it even possible that one study would work and one doesn't? I mean, I know possible is a silly way to ask. Depending on the development we see. I'm just meaning like it should both be either it's gonna work or it's not gonna work, right? I mean, in both studies. Yeah. It should work, but. I'm just wondering like what could go wrong in one study that didn't go wrong in another? I would say we are doing the studies in a parallel manner. When you compare in terms of execution and KPIs, it's very similar, so I don't expect it different. Okay. Let's just assume positive data. We file a year later, the product's on the market. How do we handle the commercialization of this kind of product? This product is very differentiated vis-a-vis any other product in the field. Yeah. Therefore, commercially it's pretty straightforward actually. Our aim, if you take the whole retina universe and the universe of general ophthalmologists who are doing retina, which means they have OCT, basically, we are talking about the field force of between 50-60 FTEs fully loaded for field force, MSLs and the regional- All in, 50-60. All in. Yeah. Including MSLs and regionals. Yes. Oh, wow. Yeah. Okay. It's actually an efficient launch because the product is differentiated. As you know, the two hurdles for launches is if you need to educate. Market is not aware about DME and you need to tell them we have DME. Right. In our case, they know we have DME. Everyone knows DME. Patients actually are diagnosed. This is the first point. The second point which makes this harder is when you need to displace somebody else. We are not displacing anybody. We are not saying stop on the DME and take on OCS-01. We are saying if you have a diagnosis, so start to treat with it. Why wait? Like, why leave your patients sick and worsening because we know that when the patient worsens. We cannot get back the letters. Therefore, the market is educated. We are not displacing anybody. We are really addressing the white space early and for patients who are not responding, where doctors do not have today any other alternative. They will use our product actually. How are you thinking about pricing the product? How is Ozurdex priced? The pricing of the product, as you know, depending on how many injections, of course, is really between around $8,000-$16,000 per year per patient, depending on how many injections. Our strategy is to be priced around $10,000 price tag for a year. This allows us to be able to enter rapidly and have a very fast penetration into early intervention, but also be able to sustain a combination treatment. Our price tag is $10,000. The one you were just quoting, the 8-16, that's Ozurdex? 8-16 is anti-VEGF, Ozurdex is around $8,000. That's what I was wondering. Yeah. Okay. $8,000 for Ozurdex. Yeah, yeah. You're gonna come in. Yeah, yeah. Ozurdex is around. You're gonna come in above Ozurdex. Anti-VEGF, depending on how many injections it's between the patients. Yeah. That's Yeah. That's what I was wondering when you said that. Correct. Yeah. Yeah, absolutely. Okay. Excellent. Let's move to the second program for dry eye. Talk about the study that was run last year, I think it was, or whatever. What you learned from it and how you came to the conclusion of, you know, what we're doing for our pivotal study. Yeah. Our learning about dry eye is the following. First, inflammation is a core component of dry eye. The second, variability between patient is huge, and this leads to very expensive, inefficient development plans, and it's lead also to not great commercial success. Therefore, we ask ourself, "Okay, how we can reverse engineer this?" Therefore, we went into this biomarker which allows us to identify patient who are responding. We were able to identify this biomarker in the DED 2, which was the second dry eye trial, and we validated again in the DED 3, which is the third trial. Now we are in the situation where we can know who will respond ahead of time. We met with FDA and we said, "We want to drive precision medicine and to go to patient who are responsive to our drug." FDA was supportive, and they said, "Okay, you can have as a primary endpoint the patient positive to the TNFR1 patient." Therefore, our aim is really to develop product. We call it the genotype development because it's based on this biomarker, which is genetic biomarker, which allows us to lead the precision medicine after. Therefore, the aim is to go to 20% of dry eye population, which is huge. We are talking about 2 million patient who are positive to our biomarker. These 2 million patient, we know they respond to our drug. Therefore, this allows us three wins. First, to have a very efficient, with high probability of success, phase III program. I mean, any dry eye program, we are talking about 600 patients. In our program, we are talking about 160 patients, and is enough. Is super powered. This is the first point. Therefore, less risky, high probability of success. The second win commercially is a doctor will stop this trial and error, which is a real issue. Like the typical patient come to you, open the bag, they have like 10 drugs and they say, "Doctor, I tried this, didn't work. This didn't work." We will stop this craziness. We do the test. If it works for you take this product. The third, which is absolutely welcomed by the payers because we talked to them, is the payer will pay what works for the patient. In terms of forecast, when you do the forecast, it's much better to go to 20% of the patient. Actually, we deliver higher revenues. Why? For two reasons. One, the price is better, but the second, which is materially important, is the compliance is better. Therefore, because patients are compliant, they take longer our drug. I mean the compliance rate in dry eye is between 10%-15%. Our compliance will be 70%, which means 5x more. The patient will generate 5x more value. This is really the difference, like from where the difference is coming. Just to be clear, this is an eye drop. This is an eye drop. This is an anti-TNF eye drop. Correct. This, the data that we've seen, it worked in the dry eye patients in the broad population. Correct It worked even better in a certain group of patients who have a specific genetic mutation. Correct. Are these patients being, you know, checked for this genetic mutation today? Will they be? How will they be checked? How is this gonna be factored in? Yeah. Yes, completely right. The patient responded they had between 5 x- 7 x better response when they were TNFR1 positive. This patient today are not checked, and tomorrow they will be checked by a very simple qPCR test. It's very simple, rapid, and actually cheap test, and it is done in 80% of the labs in the U.S. today actually. Patient comes to the ophthalmologist's office. The ophthalmologist says, "You have dry eye. Yes. It's clear. Yes. You have dry eye. They'll immediately say, "Aha, we have a new product," because we're fast-forwarding the drugs approved. We're just gonna fast-forward. Let's test you to see if you have this because if you do, you know. Exactly. They just do a quick, what, swab or whatever? Swab and saliva. Right. Saliva swab. Yeah A couple of days later they find out. They send it to the lab. It's 24 hours. Right. They find out, "Okay. Yes you are. You're perfect for this product. If you are, you take this drug. Yes. How are you thinking about pricing that product? If you take the pricing like MIEBO, which is actually the most recent dry eye product, the yearly treatment is $11,000. Really? Yeah. For MIEBO? Yes. Wow. If you price it at this price. That's a prescription product. This is prescription. If you price it at this price for precision medicine, you have 20% of the 2 million. You have pretty good. You're thinking pricing it at what? Parity. At that price? Yeah. Interesting. Yeah. It's actually a huge market. Again, the difference at the same price, we are not even going to higher price. We'll be very competitive. Extremely well competitive. But what will make a difference is the compliance. Yeah. Patient will generate 5x with our product versus other products. Okay. The phase III program has begun? The phase III PREDICT-1 was initiated last year. We are activating centers now, and we will have first patient, first visit really in the upcoming weeks now. Readout is in Q4 this year. That's so fast. How come you do it so It's fast because it's symptoms. Symptoms is 28 days. Like, really the difference in symptoms is we need to show rapid improvement. Like, I mean, as you may know, the critique vis-à-vis the previous standard of care is it took time to show improvement in symptoms. Today, really, the expectation from the patient is if it hurt me, if it is irritating, I need to see the pain going down rapidly. This is why it's 28 days. Okay. We get the study results in the fourth quarter, it's positive. What do we do next for the program? We design study. This study is a symptoms study. We design study after and then submission. You only need one of each? Normally, we are assuming, at least our assumption, is we need two and two. This is our assumption. I know FDA is changing. Let's see how things evolve, but our assumption is two and two. Well, the reason I asked the question is if you thought it was two and two, why wouldn't you go, "Okay, we have one positive symptom. Okay, now we have the money." Let's just presume. We'd do the parallel. Why wouldn't you do both a sign and a symptom together? We do them in parallel after. You might do that? Yeah. Right. Well, you'd have to do two signs and one symptoms, right? I guess. Let's see how things evolve. Yeah. Our assumption really, we'd never change it. We say it first. We don't want to combine because they are uncorrelated, signs and symptoms. We said we preferred to do small studies, but separated between signs and symptoms. This is the first point. The second, we always said, and our assumption, unless things change, we need to do two and two. Okay. Fair enough. Privosegtor. Yes. Let's talk about this product. Where did it come from? How did you know, kind of think that this was a good idea to make this bet? What data did we see that's gotten everybody so excited? Yeah, this product came from CNS company, translational CNS company. Why we believed that it made sense. First, we really looked for neuroprotection for many, many years. Really, neuroprotection from our side was driven by the need of glaucoma. Glaucoma, we have good IOP lowering drugs, but still with IOP lowering drugs, we still are not able to address glaucoma as a disease, basically. Therefore, we have been looking, and we screened, I don't know how many drugs, like more than 90 drugs. This product gave us the confidence that potentially might have something different for multiple reasons. First, the preclinical data. Preclinical data were very strong in multiple models and in vitro and in vivo. In vitro showing that the product protect or preserve neuron from dying in a multiple injury model, inflammation, apoptosis, and oxidation, and so on. It was tested in vivo in glaucoma, in optic neuritis, and in MS, consistently showing actually that animal receiving this product were able to protect their neurons. This is from the biology point of view. The second, on a tox point of view, we knew that this product crosses the brain barrier and the retina barrier, and this is important. Many times we have product w hich have a benefit, but actually they are not able to cross the barrier, and therefore they will not reach the target. The third, experts supporting this biology were very well known. I mean, one is the head of neurology in UCSF, Stephen Hauser, another professor in Stanford. We had very solid, I would say, expert around this product. The last one, it was actually good price for us and made sense. You bring the product in, talk about the phase II data in acute optic neuritis. What did we see? Basically, optic neuritis was really used as a proof of concept for neuroprotection. Why optic neuritis is a good proof of concept? It's a good proof of concept because you can measure the function, you can measure the structure, and you can measure it precisely. Like we don't have OCT for the brain. We do MRI, but MRI is not as precise as OCT. Yeah. Therefore, optic neuritis really offers this. This product showed that we improved the function. We doubled the function. The difference between steroid alone or placebo versus Privosegtor plus steroid was 18 letters. We doubled. Function meaning vision? Vision. We doubled the vision. We preserved the retinal ganglion cells and axons from dying by showing less atrophy, basically because we have an atrophy. We have much less atrophy into the retina. The last point, which is really important, is we measured neurofilament. Neurofilament are the skeleton of the axons. When the axon get damaged, neurofilament are released into the CSF into the blood. We can measure them. Neurofilament is an important endpoint. It is a regulatory endpoint in ALS, and it is now used in MS because it's directly correlated with the progression of the disease. Yes. The good news here on neurofilament, we showed that we can maintain them very low, which means we protected axons from being damaged. Actually, we will, in the future, release more data around the biomarkers. Consistently, this product is showing that Privosegtor protects neurons from dying and axons from dying. Therefore, it opens the door for multiple clinical application. The first is we can advance on optic neuritis, and we are in PIONEER-1, which is the first phase III in optic neuritis. The good news is this benefit can be applied into multiple other clinical applications. What we said, we said any neuroaxonal disease. When you think about neuroaxonal disease, we are talking about multiple diseases where we have neurodegeneration, and this product can play a key role. Yep. The benefits that we're getting from a protection of the neurons, talk about that data. Talk about those markers that we're seeing, 'cause I think they're new to people. In terms of neurons, we disclose one, which is important which is Neurofilament. Yeah. Neurofilament, as I said, the axon is like a cylinder, and the signal is transmitted when the cylinder is open. Cylinder cannot collapse. If the cylinder collapses, signal is not anymore transmitted. What maintains this cylinder open is Neurofilament, which is really a chain of proteins which play a role like skeleton of the cylinder. When the axon get damaged in the multiple diseases, in MS, in ALS, in multiple diseases. Right. The Neurofilament is released into the blood. It really tells you, okay, there is axonal damage happening in the body. That's not an endpoint. NFL won't be an endpoint, or would that be a secondary endpoint? It will be an endpoint. But the other- Which will help us to bridge with other neurological diseases. Yeah. For PIONEER, which is the optic neuritis trial. Right. Okay The endpoint will be LCVA. It will be the function. Okay. The secondary will be what else? The primary endpoint will be mean LCVA. Okay. The secondary endpoint will be responders. These are the two endpoints for approval. We don't need the rest. FDA, for example, does not ask for structure. We will do it. That's what I was gonna ask you. Yeah. The structural biomarkers that you had in the phase II. It will be GCIPL, yes. It will be GCIPL. Yeah. We will do it, yes. Right. We will do GCIPL, we will do Neurofilament. Got it. How can we price this product? It's a good question. As you know, orphan indications in ophthalmology are really between $100,000-$400,000. Yeah. The price most probably is in between. $100,000-$400,000. $100,000-$400,000. I think, retina always drives a premium. We are talking really about the retina here. Yeah. Therefore, most probably around $150-$200 will be at least the price for this for a cycle of treatment. Right. Wow. I mean, it's really important when you think about it, and back to the biomarkers to the GCIPL. GCIPL is the layer of the retinal ganglion cell in the retina. GCIPL thickness is around 100 microns. When this thickness goes down to 60, we lose vision. When you see the arm without Privosegtor, patient lost in average 23 microns. This patient, if they have another relapse, they will lose vision. They'll lose vision. Therefore, it's really important to treat this patient to keep the thickness actually and to avoid atrophy. Yeah. Thank you. Thanks for joining us. Great. You're welcome. Thank you. A lot going on. Big year. Thank you. Thank you very much.