Great. Thank you all for taking the time to join us for another session at the Baird Healthcare Conference. For those unfamiliar, my name is Jack Allen, and I cover the biotech space. For this session, we are joined by Oculis' CEO, Riad Sherif. Thank you so much for joining us, Riad. Thank you, Jack. Pleasure to be here. Yeah. Oculis is a story that I am getting up to speed on. I actually was transferred coverage a couple of weeks ago. But for those in the audience, if you could just give three to five minutes of an overview on Oculis, that would be a great start to the conversation- Of course. ...then we'll jump into Q&A. Yes, of course. Oculis is a biopharma company, listed in Nasdaq since March 2023. It is a portfolio company with two advanced programs, which are both actually in the phase III, in registration stage. The first one, which is Licaminlimab, is focusing on subset of dry eye, which is called TNFR1 dry eye patient, with the precision medicine type of approach, where we are genotyping patient before treating them. We expect the readout in end of the year, December or January 2027. It is really coming a matter of weeks or months now. The second asset is called Privosegtor. Privosegtor is a neuroprotective agent. It was tested in an indication which is called acute optic neuritis. The benefit of acute optic neuritis, it really offers two shot on goal. One, it is an unmet medical need. We don't have anything in optic neuritis, which is an orphan indication. The second benefit is a very solid proof of concept for neuroprotection. Why? Because retina is actually brain tissue. What works in the retina in terms of neuroprotection should work in the brain. We had amazing results, I have to say, from the phase II. We are now in phase III. We got a breakthrough from FDA, prime from EMA, and the product is in registration trial and randomizing, basically. Great. Maybe we'll start with Licaminlimab- Yes. ...because it's more proximal to the readout. Yes. Just could you level set for investors the expected study results, the design of that trial, and how you've started to select patients- Yeah. ...that could be predisposed to respond to this drug, for this drug? Yeah. Licaminlimab went into three clinical trials: DED-1, DED-2, DED-3. Two in symptoms, one in sign, all positive. But what we did in DED-2 in an exploratory manner, we explored how we can identify patient who will respond better to TNF inhibition. And we saw actually on the exploratory manner that this patient had sevenfold better symptoms improvement versus all comers. Then we, in a pre-specified manner in Dry Eye 3, we took the same biomarker, we tested it in signs, and in fact, a patient with this genotype showed five times better in signs improvement. Therefore, it just consistent between signs and symptoms. What we are doing now in the first phase III, and totally aligned with FDA, is we are actually testing patient, selecting the patient based on this genotype. 2/3 of the patient will have this genotype, and the primary endpoint will be improvement of VAS, which is a symptom score in TNFR1 DED patient, and the secondary endpoint will be improvement of VAS in all comers. Okay. If we compare in symptoms in a phase II, we had a 4-point different in VAS score in all comers. We had 28-point difference in TNFR1 patient. So 4 point is typical to any dry eye product available today. Therefore, in a phase III, if we deliver just the double, just 8 point- Yeah. ...it will be the double of anything we see in the market. Yeah. Wow. Are the patients that are genotype selected here, are they more severe patients, or how should we think about the ability to respond on standard of care for that- Yeah. ...specific patient population? Yeah, so they are not more severe or less severe. But in the study we're running, we are going into severe patient. Okay. So if we see in the VAS score, is a score on 100 point, we are going to patient who are above 60, so therefore it's pretty severe patient. Got it. I would say in terms of precision medicine with the biologic, Licaminlimab is a TNF inhibitor. Our aim is really to go to severe TNFR1 DED patient. Got it. As you think about the market landscape here, is there an existing standard of care that you're comparing to, or is it physician's choice? What do these patients get right now in clinical practice? As you may know, dry eye is a big market. Okay. At the same time, it's super unsatisfied. You see, for example, the treatment adherence. The treatment adherence after six months is 10%. Wow. It means that 90% of patients are stopping their drug. Why? Because they're not happy, not because the drug are bad or good. It's just because variability in patient is so high. Okay. In the last ARVO and in the last AAO, they ran a survey and they ask ophthalmologists, "What do you need in dry eye?" Really, consistently in both congresses, the first response was, "We need to customize our treatment. Patients are frustrated, we are frustrated." The typical patient in dry eye, they come with a bag with 10, 12 drugs, open the bag and they say, "Doctor, I tried all of them, and they don't work. What should I do? Yeah. For the first time, we have something where we can test the patient, and it's a very easy test. It's qPCR test, so it's like a COVID test. Okay. It's saliva swab. In 24 hours, we have a result, and if the patient qualifies, then the patient will get something which will work. Yeah. We see, for example, the typical response rate in our studies and in any other studies is between 15%-20%. Is around 18%, actually. Is 18% of the patient respond. This is why a typical phase III, we have like 400 patients, 500 patients, 600 patients. Yeah. In the TNFR1 positive patients, 75% of patients responded, highly responded. Wow. It's huge. It's really transformed the way we are going to treat dry eye. Our focus is really on the TNFR1-DE D only. This is what we want to do. We want really to develop a product which will truly enhance and treat patient with precision medicine. Got it. Is this a monoclonal antibody that's infused or- This is a- Yeah. How do you administer this product to patients? Yeah. This is an antibody. Okay. This is a fragment of the antibody, which allows us to have high concentration and good tissue penetration. Yeah. It's a topical actually antibody. So it's the first time- Oh, wow. ...we have topical anti-inflammatory for the eye. In fact, the product is in development in the TNFR1-DED patient. It is in the development in uveitis as well. We did the phase II uveitis, which was a positive uveitis, so it will be also developed later as a steroid sparing for uveitis. Great platform, unique biologic topical for inflammation in the eye, which can be super innovative and super transformative for this patient. Just to clarify, it is an eye drop or an eye cream that you put It is an eye drop. It is an eye drop. Is it the same kind of frequency as other dry eye disease drugs or is there anything about this? In the phase III, it is three times per day. Okay. And how does that compare for someone that is less familiar with the dry eye market to other therapies? Dry eye, you have between two to four- Okay. ...times a day, three times a day. The uniqueness of dry eye is because by definition it is a dry eye. Yeah. They tend to be actually like it to have more applications than just two times a day, because it's basically, it not only treat, but it lubricate the cornea. They like to put like in artificial tears, for example, they put like eight times a day. Yeah. It just like 10 times a day, they are every hour they say, "Oh, I will take a drop." It helps them. Therefore, like multiple applications in dry eye- It's beneficial. ...is better for patients. Yeah. How do you think about the branded dry eye market? You mentioned there are a lot of patients out there, but how many of those patients are on prescription biologics or prescription drugs in general as compared to over the counter- Yeah. ...medications in dry eye? Basically in the U.S. we have around 35 million patients. In the 35 million patients, 25 million patients will take artificial tears. Fine. Yeah. 10 million will need a drug, one type of drug. If we go to the TNFR1, we are talking about 18% of the 10 million. So we are talking about 1.8 million patients. Okay. This 1.8 million patient will be really responding much better than any other drug with Licaminlimab. Okay. This is our focus. Is there a specific external comp as it relates to branded drugs that are already available in dry eye that you look to as it relates to the commercial potential of Licaminlimab? If you take the last product which was launched, which is MIEBO, which was launched by B&L, the product is sold $11,000 per year. Okay. This is an all-comer. Therefore, if you have a precision medicine, is realistic to believe that we can be at a higher price with a much better result. Yeah. This is the first phase III study in dry eye. Yes, yes. Can you just walk us through big picture? We're going to have to get this data in, I think you said late 2026, January timeframe, somewhere around the change of the year. But then when do the rest of the studies read out and how do you think about the potential application here in getting this drug to market in the long term? Basically our aim is to deliver this first phase III to meet with FDA and discuss what FDA would like to have. Our base scenario is to have two studies in signs, two studies in symptom. We wanted by design to separate them because we know that sign and symptoms are discorrelated. Separating them is much better. And in fact, these are small trials. Okay. Like the first phase III is 160 patients, and it's more than enough because the drug effect is very strong. Therefore, we prefer to run small trials and very dedicated where we have one question, we randomize for the question, and we show the benefit. Yeah. Now we will see result of PREDICT-1. It's called PREDICT-1. Okay. We will see result. We meet with FDA, and we see if we need two and two or just another one in signs. Anyway, we need at least another one in signs. Okay. This one is symptoms, the one we are doing now. Got you. I guess this is also a subset or biomarker specific diagnosed patients, but there is an all-comer cohort in this PREDICT-1 study. Yes. Is that true? In the future, do you plan to just go into the biomarker genotyped patients or will you continue to pursue this dual path where you could have all-comer as well? Yeah. Most probably we will continue with the same scheme. Okay. A combination of both genotype patients and- Enriched with the genotype 2/3. Okay. The rest is all comers. Great. Anything else you would like to touch on in the dry eye program? No. I am excited to see the result. Yeah. No, that should be a very exciting readout. Maybe we can talk about Privosegtor in- Yes optic neuritis. I know that's a very interesting program that you've licensed into the company. Could you talk about the history of the bringing in of this asset? Yeah, of course. This asset was first licensed in from a translational neuro company, which was focusing on MS, and then we just acquired it actually. We just signed an agreement to acquire this product recently. It has a benefit. It gives us more flexibility, and we will avoid milestones and the double digit royalty. So it's a good deal for us. When we got this product, the product was just finishing phase I, starting phase II, in clinical hold with FDA because they didn't do all. It was a small company, a Spanish company, actually. Therefore, we took this product as very good conditions. We met with FDA. We responded to all their question. We completely lifted the clinical hold, completely unconditional. We delivered the phase II result. Phase II result were amazing, and I will go through them. Then we got breakthrough from FDA Prime, from Europeans and the SPA with FDA. So we have been able in three years to actually completely de-risk the product and take it from a phase I to a phase III in a red carpet type of approach with breakthrough and prime and so on. That's great. Yeah. Before you get into the clinical data, can you just level set as it relates to the mechanism of action here? You mentioned it's a neuroprotective- Yeah. ...mechanism here. Yeah. Can you talk about how the drug works in man and to protect the neurons- Yeah. ...from degeneration? Thank you. Basically, the neuroprotection is a multifactorial process. It's not like one target. No target is known related to the neuroprotection. Therefore, it's really multifactorial. Therefore, the best way to develop drug when you have a multifactorial process is to do it phenotypically. Therefore, the way we developed this product, it was by high throughput screening. We were screening for a biology which promote neuronal and oligodendrocyte survival. We tested this in apoptosis model, in inflammation model, and oxidation model, in vitro, and then in vivo, we went to glaucoma model, acute optic neuritis, and MS. Consistently what we showed, we showed that we can preserve retinal ganglion cells in the retina from dying. We preserved axons and preserved myelin. In one experiment, which was really important for us in terms of acquiring this product, is they did functional improvement in animals in MS, and animals receiving Privosegtor in an EAE model of MS were able to have a better mobility or ambulation versus animal not receiving Privosegtor. It's really for the first time in animals, because in many studies in animals, you see the pictures and so on, but you don't know really if functionally it's doing something. Yeah. Here, functionally, it did something. Therefore, based on this, we moved to optic neuritis, which is the first indication. O ptic neuritis, as I shared with you, really it has these two benefits. One is an indication without a solution, and the second is superb proof of concept for neuroprotection. Yeah. What is the existing standard of care in acute optic neuritis right now? You mentioned that there's very limited therapies, but what do- Today- ...patients get in practice? Yeah. In practice, we give them steroid because it's inflammation. Yeah. We showed actually that steroid does not change the prognosis of the patient. So with or without steroid is the same for the patient. Yeah. But steroid tend to reduce the pain, basically. Great. What has Privosegtor shown in the phase II study that has you so excited? In the phase II, the primary endpoint was safety because it is first in patient. The secondary endpoint were three, function, structure, and neurofilament. Yeah. Safety was really good safety. We did not see any signal. Now is a new molecule. We will continue to do our work in terms of the characterization. But the safety was good in ACUITY trial. In efficacy, functionally, we showed that we could improve LCVA by 18 letters. So 18 letters is more than the double. 15 letters is the double. So 18 letters is more than the double at month three, and it was sustained 15 letters at month six. Second, in terms of structure, we measure two layers in the retina. One is called GCIPL, where we see the thickness of the retinal ganglion cell. And here the most important is to keep the thickness, because if we keep the thickness, it means we do not have atrophy. Okay. The second is RNFL, which is the axonal layer. So in both, in GCIPL, we have been able to have 43% less atrophy, and in RNFL, we had more than 30% less atrophy. Therefore, we show that functionally, we have a better function. Structurally, we were able to preserve or protect the retina. And third, in terms of neurofilament, which is really a very important surrogate biomarker for axonal damage. It is an endpoint used by FDA in the last ALS study, by Biogen actually. Yeah. It was the endpoint, so it is very solid endpoint. In neurofilament, we see that we have much less neurofilament in the active versus steroid-alone, which means we had much less axonal damage. So it is really everything came together very nicely showing neuroprotective effect in the structure, neuroprotective effect in the axons, which are basically the axons are the optic nerve, is the cable between the eye and the brain. Yeah. Structurally in the retina. Can you look at retinal nerve thickness as well, or is that not impacted by acute optic neuritis to the same way that the cells directly in the retina are? You see atrophy in the MRI, but you don't see it in the OCT. In the OCT, you see only the retina. Yeah. But in the MRI, if you do the orbit, you really see the inflammation. You see it. Yeah. Yeah. Is that something you'll look at in future studies as well, or are you going to focus more on the retinal context? It is not requested by FDA at all. We do it for more research, but not for the regulatory. In fact, for the regulatory, the only thing which is needed is LCVA, is the only endpoint which is needed for FDA, and for EMA is the same. But in terms of knowing our drug, we do OCT, we do MRI. Yeah. We do neurofilament. Got it. You are now in a pivotal study, the PIONEER-1 trial, which forgive me, it was either this week or the prior week that you announced you dosed the first patient. How do you think about the footprint needed to execute this study and the number of patients that are out there with acute optic neuritis- Yeah. ...neurop- Oh. Yeah. This question is really important because it is not a disease which is like, I would not say simple or diseases are complicated, but there are diseases which are like, you have chronic disease, you have a pool of patient, and they are managed by one doctor. Here is an event-driven, so it is acute. When they have pain and they lose vision, they might go to the ophthalmologist or to the ER. In fact, the patient journey is they go to the ER or to the neuro-ophthalmologist, they do the OCT, they do the visual exam, they go to the neurologist, they do the MRI, they do the neurological exam, and the treatment is really decided by a multidisciplinary team, and it is delivered in the infusion center. Today is the case with the steroid. Therefore, to activate a center, you really need to build up this ecosystem of three doctors or three PIs almost with the ER, the neuro-ophthalmologist, and the neurologist to work together. Yeah. This is basically what we have been doing and we are doing now. In terms of footprint, this trial, PIONEER-1, will be done in U.S., Canada, Australia, Europe because we want to keep the same population, MS population. This is why we are doing this. We assume that we will need around 60 centers in the end of the period to be activated, and our system is ongoing. Yeah. How do you think about the cadence of activation of sites for this trial? Where do you sit as it relates to active sites, and when might we expect to have the full study up and running? Then as it relates- Yeah. ...to enrollment, once you have the full study up and running, do you expect it will take a long time to enroll this trial, or would it be fairly abbreviated given- Basically- ...the frame? Yeah. The study will be starting at the critical mass in terms of centers and so on in Q4. Okay. This is the plan. It's aligned, I would say, and it fit well with the seasonality of the disease. I don't know if you know, but the relapses, it's seasonal. Yeah. It goes up in November, December, and it goes down in May. Therefore, our aim, if you ask me now my goal, my goal is to have at least 50% of the centers activated by December. You can get this first season. Yeah. Exactly. To be ready to have enough open centers to capture this patient. Great. Do you have a sense for how many seasons you have to go through to capture a sufficient number of patients or The aim based on how many centers we have and so on, the aim is to finish the randomization by the end of next year, and you have readout around year-end next year. As a company policy, we give guidance when we have 50% of the patient enrolled, so we should give it next year. Based on what we know from ACUITY, based on what we know with the centers we are already working with, I think it's realistic. Got it. I'm not worried. It's just work. How do you think about the commercial opportunity in optic neuritis? Do you have a sense for the number of acute cases, and what do you think, I know it's early days, but how could you price this therapy? Yeah. Being that it's given in an acute setting? In the U.S., we have around, and Europe is the same number, we have around 30,000- 35,000 patients every year in acute optic neuritis. We have a similar number in NAION, which is the second optic neuropathy we are going to later. The pricing in orphan indications today in the U.S. is between $100,000- $400,000. Yeah. So even if we price it at the lower price, which is $100,000, we have a market of $3.5 billion just with optic neuritis in the U.S. only. Okay. And we do not have any competition. So it is huge. The unmet medical need is huge. We are talking about young patient, like the typical patient in acute optic neuritis is a young mother of 32 years. So it is crucial to treat because if you do not treat, then if this patient have another relapse, then they will become blind completely. Therefore, it is so important to treat not only for the acute phase but also to protect, to keep your pool of neurons for the future. Yeah. And in fact, when we ask the doctors, we say, "Who are you going to treat? Do you have a threshold in terms of BCVA or LCVA or age or something?" And they say, "No." Consistently, and we did this survey in our investigator meetings, and they all say, "You know what? It is simple. Any patient who use iPhone need to be treated because you lose color, and you lose contrast, and you cannot work with it. You cannot work with the screen. Wow. Therefore, it is almost all patient, actually. Yeah. With the new foldable iPhone, I'm sure that's going to expand the market opportunity too. I didn't think about it. Great. Well, then you're also looking at testing in MS relapses as well. Yes. I think you have a plan to submit an IND in the relative near term there. Yes. Where do things sit as it relates to that IND and when we could get initial data from that relapsed MS population as well? So basically, our plan, as you said, is to submit an IND, and hopefully to get it in Q4. The good news from our interactions with the neuro division is that they consider that the product is advanced, and we don't need to provide any new, or to do any new preclinical data. Okay. They agreed on the dose, the regimen for acute MS relapse, the dose, the regimen, the timing. So for the first time, we're not going to do an MS trial in two years, endpoint is three months, so it's the same as acute optic neuritis. The concept is really the following. In MS, we have three types of relapses. We have acute optic neuritis, we have ambulatory, and we have sensorial. All relapses which need treatment, it's around 170,000 relapses per year in the U.S. So it's really like, not double, but multiplied by 6x the market. Got it. It's huge. Yeah. What we are going to do, we are going to do another trial in ambulatory MS relapses. We are planning for R&D day. We will talk more about it, upcoming in Q4. This is our plan. Basically, the plan is first label, first indication, acute optic neuritis. Yeah. Second indication, any acute MS relapse. The third indication, NAION. As you think about the expertise you have at the company, we started off by talking about dry eye, then we went to an acute optic neuritis indication, and now we are into relapsing MS, which is more of a Central Nervous System, but it does relate to the eye in that all of it is implicated in the CNS. How do you think about the expertise as you go into MS, and could you potentially look to partner with someone who has specific MS expertise there, or is that an area where you want to pursue development as a standalone business? Yeah. So by chance, I worked in MS in the past. Okay. So in fact, I launched GILENYA, which was the first oral MS. Yeah. Therefore, I kept a very solid network of KOLs and experts and so on in the U.S. and Europe. In fact, we have already, and it is almost. We did not communicate about it yet, but we have already a very strong SAB, like the top of the top. Seriously, the top of the top of MS experts. We have them. We did not say it, but I can say it. We just hired the neurologists who will be Franchise Head for the MS development and clinical development. He is from The Mount Sinai. George joined us. Therefore, we are building a dedicated franchise for neurology. The indications we are talking about are orphan. We really believe we can do them ourself, and we can capture the whole value. Now, you never know in the future what could happen. We are always open, but at the same time, we are well-financed. We are financed till the second half of 2029. We can deliver all these clinical trials, as Oculis. We have the team, we have dedicated off that team. We have now a dedicated neuro team with a head who is neurologist, and we have more coming. I can tell you, it's amazing to be in a company where neurologists in other big companies call you and they say to you, "Riad, we want to work for Oculis." And you ask them, "Well, why?" I'm like, "We are a small company. You want to come to us, and you are there? Yeah. And they say, "Yes, because we want to be part of Privosegtor. That's great. Well, we covered a lot of ground today. I don't know if you had any closing remarks, but my last question is typically the cash runway and how that encompasses the upcoming catalyst. But you did just touch on it with your last response. Any other points you wanted to emphasize for investors today? No, listen, conclusion, super excited about [pindacimod] coming. I know Privosegtor is great, and I agree. Yeah. [P indacimod] will be transformative if the trial is positive, and we did everything to make it positive, let's see. Yeah. Very excited about it. We'll have to keep an eye out for that data in the coming months here. Yes. Coming. Riad, thank you so much. Thank you. For taking the time to join us. Thank you. Thank you. Thank you very much. Thank you. Thank you.