All right, good afternoon, everyone, and welcome to the Oculis session. We've got our wonderful CEO here, Riad Sherif, and I know that Sylvia Cheung, the CFO, is hiding in the background taking pictures of us right now. Anyway, Oculis is an ophthalmology company that has three late-stage programs right now in early to non-responsive DME, let's call it, dry eye disease, and even most interestingly, a neuro-ophthalmology protectant Privosegtor, and I said that very well, I would say. Why don't I hand the floor over to you, and you can give a quick overview, and we'll go into Q&A.
Thank you. Thank you, Annabel, for inviting us. Yeah, so Oculis used to be an ophthalmology company till the beginning of this year.
Oh, now you're neuro.
Now we are a company with two franchises: neuro-ophthalmology and ophthalmology. In neuro-ophthalmology, we have Privosegtor which showed an extremely positive result, first time, and actually first time very positive in acute optic neuritis, which is in two-thirds of the cases relapse of MS. I will go through it. In the ophthalmology franchise, we have, as you said, two candidates in a phase III, one with the readout planned in Q2 2026 in DME, which is the first eye drop for DME and the first eye drop for retina, targeting two segments, one segment which represents actually 60% of the diagnosed population of DME, at least in the U.S., which is early, first line, but also a second segment which is around 40% or slightly more, 40% of the patients who are treated with VEGF and not responding appropriately to VEGF.
Really two very well-defined groups where there is an unmet medical need, and our product can truly transform the life of this patient.
Excellent. I want to start with the most recent program that has caught a lot of attention. That's Privosegtor, and that's rapidly moving into late-stage pivotal studies. It's accelerated. You've recently capitalized to help move the program forward. Can you talk about the specific indications? Two of them are relatively rare, but is there potential to broaden that out? I'm not going to ask you to broaden it out too much yet, but at least focus on the two indications now and where you might see it going.
Yes, absolutely. Perhaps before going into the two indications, or in fact three indications we are starting, I would like to go to what really this product does. This product promotes survival of the neurons and oligodendrocyte during an injury phase. In preclinical data, in vivo data, we tested multiple models of injuries. One is apoptosis, the second one is inflammation, and the third one is oxidation. In these three models, the product is able to show and to promote survival of the neurons and oligodendrocyte. Based on this data, we went into acute optic neuritis, which is an inflammation in the optic nerve. Inflammation, demyelinization, then the soma of the cell is in distress, and then it dies, and the cell is retinal ganglion cells.
Therefore, we started with this indication, which, as you know, was tried multiple times, and really never something worked. We were extremely pleased with the data we got in the beginning of this year, where we showed improvement in function, which is LCVA in this case, where we showed the difference in Privosegtor plus steroid versus placebo plus steroid of 18 letters difference at month three and sustained at month six with 15 letters difference. We showed an improvement or protection of the structure of the retina by preserving retinal ganglion cells, which is a layer called GCIPL, and we preserved this layer 42% more than steroid alone. The third surrogate biomarker, which is a biomarker for neuroaxonal damage, is neurofilament, which is in fact a regulatory endpoint.
It was used in ALS, and we saw also here significant and material protection of the neurons vis-à-vis steroid alone. In each parameter, functional, structural, and biologic, the product showed efficacy. Therefore, we met with FDA, and the aim now is we are moving to phase III in acute optic neuritis with almost, I would say, 99% the same protocol as we did with ACUITY, which was a phase II, and the program is called PIONEER -1 and PIONEER-2 . Now, when you step back and you see optic neuropathies, we have mainly two, I mean, if we want to summarize, we have mainly two main optic neuropathies. One, which is acute optic neuritis, we have in the U.S. around 30,000-35,000 patients. The second optic neuropathy is called NAION, and we have also around 30,000-35,000 patients in the U.S.
The PIONEER-3 will be a phase II, III in NAION as well. Our aim is really to bring a product which will be able to treat optic neuropathies and to preserve the function, basically. This is the first plan with the program, an umbrella program called PIONEER with three clinical trials, PIONEER-1 , PIONEER-2 , and PIONEER-3 . I would like to highlight also that these are two different programs. PIONEER-1 and PIONEER-2 is one study in one disease, which is acute optic neuritis, and PIONEER-3 is a second study, different study, very similar, but slightly different for NAION. The third indication we are preparing for the next year is relapse of MS. Acute optic neuritis is a relapse of MS.
We believe, based on the data we have preclinical and clinical now, that we can treat relapse of MS, the acute treatment of relapse of MS. This is not a replacement of immunomodulators who are able to reduce the frequency of a relapse, but rather, if you have a relapse, to treat a relapse, and this is what we are preparing. Three indications. Let me now focus on the two first just in terms of giving what this really can represent for the patient and for the company. Today, these patients do not have treatment. AON, they use steroids to reduce inflammation, but they do not have anything for neuroprotection, and they lose contrast, they lose colors, and so on. For NAION, we do not have anything, like zero. Therefore, it is a huge transformation for this patient.
In terms of business point of view, this is a huge business opportunity for the company. If you take the total population of optic neuropathies in the U.S., we are talking about between 60,000-70,000 patients per year. If you take the orphan indication type of pricing, it's between $100,000 for the NK for oxalate, to $400,000 per year or per cycle for TEPEZZA. If you take the lowest price and you take the number of patients, we are talking about the business or a market of $7 billion with zero competition. The only product which really showed something which is super meaningful is Privosegtor. Extremely excited about this opportunity for the patient and for the business.
Okay. Just one question before I forget this question. When you have an acute relapse of MS, to what extent is AON the signal of that acute relapse of MS? How tight are these two indications?
In our trial, 2/3 of patients were MS patients already, so it was a relapse of their MS. We know that in the last third, at least half of the patients will convert into MS, and AON was just the first onset of MS. Therefore, it's extremely correlated to MS.
Okay. So it is.
It's not only MS, but MS extremely correlated.
It is extremely correlated.
Or 90%.
I see. I see. Okay. Just to go back to how AON is treated today, the steroids, I think some investors were looking at, they say that the steroids were able to treat 70% of these patients, right? Now, the component that they're missing is they're not getting the neuroprotection. Do these patients who just get treated with steroids still have damage to their optic nerve?
Yeah. I mean, it's simple. With Privosegtor, we were able to double the vision for patients. So we are doubling the vision for, I mean, 15 letters is doubling the vision. We achieved 18 letters. It happened actually three or four weeks ago. I was with the investors meeting, and they had exactly the same question, and I was lucky in a sense because in.
Are you going to ask yourself this question?
No, no, no. I was really very lucky in a sense because in the room, I mean, I'm very serious. This was in Geneva, actually. I mean, I was in the room, in the room, and a lady stand-up, and she said, "No, I can tell you." She said, "I have MS." And they had AON. And since AON, I received steroid. I recovered 80% of my BCVA. I didn't recover colors. I didn't recover contrast. I cannot read newspaper. I cannot drive. She got one crisis. If I had the product which allows me to have a normal life where I can drive, play, read the newspaper, and protect my neurons for the future, absolutely, I will take it.
Okay. All right. At what stage of disease do you capture this patient to treat them?
Is an acute treatment. In the study, the first dose was delivered before day 12. Therefore, it's really an acute treatment. In fact, steroids are used also in an acute manner.
Okay. Is it hard to capture them within those 12 days? Do patients know when they're having an acute phase of AON? Do they go see someone? How easy is it for them to go in?
That's a very important question, as you are saying. Like, for example, if I compare with other trials in DME and so on, where you have a pool of patients who is available, and you will screen them and randomize, here you need to wait for patients because it is a crisis when they have. Now, when they have their crisis, it's not very difficult to get them because two-thirds, they know already that they have MS, so they have a relapse of MS, and they go to their neurologist who will refer them to the neuro OFTA. For the one-third who didn't know, you randomize them in the
They come in and.
They come. Yeah, in terms of symptoms, we are really talking about the typical profile of AON is a lady. 2/3 are ladies. 2/3 because it's a.
They're predisposed to MS, yes.
Exactly. 2/3 is a lady, 32 years old, so young lady, no issue in her vision, and she comes in because of pain and loss of vision, which is brutal. Therefore, it's not difficult. Like this patient, I'm not losing one letter every month, where it's progressive and you don't know when to. This, like they know, they really know there is a problem because it's painful also.
Right. Okay.
Therefore, it's not difficult.
Okay. I guess one of the questions that we've also gotten is, obviously, the phase II-A trial took some time to enroll and get enough acute patients to complete the trial. How long do you think this is going to take to enroll? Is the community now aware of this given the data that's come out, and is there an increased awareness of AON patients, and are they kind of like primed to be able to enroll these patients?
No, you are totally right in terms of the time it took for ACUITY. I mean, it was not crazy time. It was like three years, but within the three years, a sponsor changed. So we acquired this product. Therefore, when the sponsor changed, you have, it just takes time. It takes time to change the contract with the centers and so on. This is the first point. The second point in phase II, we did not know if this product worked. Therefore, the way you convince a patient who is, I mean, imagine back to the typical patient. You have a young woman, young mother. You are telling her potentially it might be MS, and by the way, would you like to test the product? And she asks you, "Does it work?" You say, "I do not know." Therefore, it is difficult.
Yeah.
In this case, we have a product which works. It works extremely well. In fact, the investigators ask us if we can have two to one because they want to have more patients on Privosegtor. There is huge support from the medical community. Just if I can share with you a data point which is really telling. We are working with the CRO, of course, a big CRO, one of the top three CROs in the world. The way they screen centers, they send a questionnaire, and they ask if the centers are interested or not to participate in a trial. The typical response rate for this type of questionnaire is 10% response after week six. This is the typical. For us, we had more than 20% response first week.
Therefore, the excitement about this biology, the will to participate and to be part of it is huge. They see it really from the medical community. I see it also from patients. I mean, you cannot imagine how many emails we received from patients saying, "I want to participate.
These are mostly MS patients.
Yes.
Knowing very well that they are.
Yes. I want to participate. Can I participate?
I see.
The medical community and the patient extremely, I mean, amazing, actually. The third, we saw it in the support we got from FDA. FDA is extremely supportive on this program. They understand that this biology, really back to your very first question, they understand that this biology could have a huge impact in much more indications. Like we are really talking about the tip of the iceberg. I mean, in this case, the tip of the iceberg is a market of $7 billion with zero competition.
That's just AON and NAION.
This is AON and NAION. That's it.
Not MS.
No. That's it.
Not MS. Let me just ask you one more question related to the MS patients. This is an all-comers trial. You're going to include non-MS patients as well as MS patients. Realistically, given what you just said, non-MS patients are probably potentially MS patients, and this is their first acute episode. Are you seeing any difference between those two types of patients, and should you essentially be treating them the same almost?
Yeah. So we analyze MS versus MS in terms of response. The response was significant in both groups. We analyzed also mild versus moderate to severe, and the response was positive in both groups.
Okay.
We did not see the difference. It is really when you understand how the product works, it is not about MS or non-MS. It is really about promoting the survival of the cell during an injury.
It's just the biology.
It's just the biology. Exactly. Therefore, if it is an inflammation due to MS or inflammation due to something else, the cell is protected.
Okay. And then just another question, I know that you have a whole other host of programs, so I want to get to those. When you talk about the registrational design, you've got various readouts. Can you lay those out? I think you have one month, three months, six months. Why are the different time points, and what are you measuring at each time point?
Basically, why three months? Because in the natural history of AON, the three-month data point is predictable. It predicts how the patient will evolve. The gains or the loss are made the first three months, and it remains stable after. Therefore, it's predictable. This is what FDA asked us. What we agreed with FDA, we have a readout at month three in terms of mean difference and in terms of responders. Then we have safety at month six and safety at month 12.
Okay. So there's nothing in one month.
In one month, no.
Okay.
What we have in one month is we have NfLs.
Okay.
Not LCVA.
Got it.
Not GCIPL. LCVA and GCIPL will be done at month three.
Okay. And then moving into MS, if you see the results for the MS population in AON, is that enough proof of concept to move straight into MS as a pivotal, or do you have to do another proof of concept in MS patients?
Yeah. We are planning to meet with FDA. Once we meet with FDA, I will be able to respond.
Okay.
Yeah.
I guess one other question on the NAION. We're pretty impressed that the FDA allowed you to jump from a proof of concept straight to a pivotal phase two, phase three, but counting as a pivotal for NAION. How did they get comfortable with that?
I think they got comfortable because it's really the only product so far which showed that we were able to show a very concrete neuroprotective effect in the neuron, which is the same process which is ongoing in NAION.
Okay.
We do not need to do more talks. The dose is defined, so therefore, it is pretty straightforward.
Yeah. So it's advancing very rapidly. Okay. I know that we have other products, so let's talk about that because you have an endpoint coming up or a readout coming up in the second quarter. That's for OCS-01 in DME. And now you've completed enrollment of DIAMOND-1 and DIAMOND-2 . How much confidence do you have in the ability to replicate what you saw already in the first DIAMOND trial? And given broadening out to a larger, possibly more variable or homogeneous, or sorry, heterogeneous population, how predictable is that letter improvement that you're going to see in that first couple of weeks? And do you think you could replicate the same result?
Yeah. So I'm very confident for two reasons. One, because we tested OCS-01 four times in consistently all-comers in the U.S. and in Europe and in Asia, in Japan, and consistently in these three regions, the same disease, the same population, the product works in CMT and BCVA. We are still doing it with North America, Europe, and Asia. Therefore, I don't see why it would not work the fifth time. This is the first point. The second point also, which gives me the confidence, is the API, which is dexamethasone. API is approved in DME. Here, really, the innovation is we are bringing something which is approved in DME today in an implant in a solution which is much more versatile, which allows us to go with the product which is efficacious and safe to early intervention, which is early first line.
Solution being topical for a neurodegenerative patient.
Exactly. To treat patients faster and earlier, or to treat patients who are not responding with anti-VEGF potentially as a standalone or combination. Why it is important really to treat patients early? Because we know it's really interesting when you see, for example, the phase III of LUCENTIS. Phase III of LUCENTIS was a three-year trial. Okay? We did the crossover at month 24. When you see the benefit of patients who gained vision, who were treated early at month 12, and patients who were crossed over two years after, so they were treated two years later, the patients who were treated two years later gained between two to three letters. Patients who were treated early gained 10 letters. This is really what this product can bring. This product can truly change completely the prognosis of patients by delivering better outcomes for patients.
I mean, when you speak with retina, they all tell you, "Yes, anti-VEGF are good," which is true. I mean, I launched LUCENTIS. They are really good, actually. After five years, they're all back to baseline for multiple reasons. One, they are starting late. Second, they are not complying for injections, and the outcomes are not good. I think by having something which is topical, which is efficacious and safe, where you can start to treat early, when you can help anti-VEGF in terms of efficacy when they are not responding well, or for durability, if they are not compliant, will change completely the picture.
This trial that you've, the DIAMOND program that you've enrolled, let me reverse a little bit. The initial DIAMOND trial, the one where you.
Stage one.
Since the beginning, stage one. Exactly. You gained seven letters pretty rapidly.
7.6 letters.
That was all-comers. So that included patients who were newly diagnosed as well as patients who were not responding to their standard therapy.
Correct.
Have you ever bifurcated the response in the early patients versus the later patients?
Yes. Yeah. We did a subgroup where we have naive or previously treated. Naive responded slightly better. There was one letter difference between better for naive versus previously treated.
Okay. It was still on average 7 letters.
It was different. It was different, and the benefits were concrete in both BCVA and CMT in both groups. The product works in both groups, but naive responded slightly better.
Just to be clear, seven letters is about what LUCENTIS does.
At the same time.
At the same time without injections.
Without injections, yes.
Yeah. Okay. So as you designed DIAMOND, is there any, what proportion is naive versus refractory?
Yeah. We do not stratify. Therefore, it's really all-comers. We didn't disclose the demographic. I would say it's more or less the same range, so I'm not worried about the change of population.
Okay. And then how do you think about broadening the prescriber base here for DME? Right now, it's just retinal specialists who are injecting this, but are you envisioning that this could potentially go to ophthalmologists, to optometrists? How do you capture that full population of DME patients? There are a lot of them.
Yeah. First, about retina. We had many questions before, and many people told us, "Yeah, you will not be able to randomize retina. The surgeons are just, they just want to inject. They do not want eye drops." First good news is retina were extremely supportive. Our randomization rate was twice as fast as what was planned by the CRO, which was the benchmark based on all injectables. Therefore, in the U.S., in fact, we have 75% of our patients in the U.S. Out of the 800, 600 are in the U.S. We have 119 centers. 75% are in the U.S. Therefore, we have a huge footprint in terms of phase III in the U.S. It is amazing how fast and how well randomization took place in the U.S. Therefore, retina are super supportive. Now, yes, you are right.
This product might be used by ophthalmologists. They will really focus on ophthalmologists. In terms of population, we have around 2,000 retina specialists in the U.S., 2,400, and we have 20,000 ophthalmologists. In the 20,000 ophthalmologists, not all of them do retina. It is actually a small group. It is around 30%, which is 6,000, between 6,000-8,000 who have an OCT and are interested with retina. For this ophthalmologist, most probably, they will be using it. In fact, for this population, they will use it as a first line. They will refer. You cannot imagine how many ophthalmologists we met and we speak with, and they tell us, "You know what? I see DME. I need to refer it to the retina. I cannot treat him or her.
The referral takes time, and they are not treated during three to six months. If I have this product, I will start with it. I mean, think about it. This is the only disease where we lose vision. We become blind. Imagine heart disease, and we say to patients, "You know what? The day it will become worse, come back." No.
The day before going blind, come back.
Yeah. If we are sick, we should treat. OCS-01 will allow this, which is not possible today.
All right. That's good to know. Okay. We've got two minutes, so I've got one more product to go over. OCS-02, that's the first topical anti-TNF, obviously, for dry eye disease. And you're designing it as a personalized medicine. So right now, the trial is designed. There is an all-comers component to it, but really, just remind us how you've designed it so that you can establish the personalized part of it.
Yeah. I would say if you come back to really why the personalized medicine, like, do we need the personalized medicine in dry eye?
Yeah.
The reason is yes. Yes because first, it's a huge market, multifactorial market, the disease, highly unsatisfied. In fact, when basically you see the data at month six, 90% of the patients are not anymore taking their drug because they are not happy with the response. This is the first point. Commercially, unsatisfied market, big market, unsatisfied market. The second challenge in dry eye is a very high risk in phase three. It's because it's really trials and errors. We do it commercially, but we do it in phase three. We end up with this huge phase III, 600 patients showing something, and everybody's happy because the phase III is positive. Is it meaningful for patients? We don't know. We end up after commercially saying, "Oh, actually, it is not delivering enough sales." It was expected, actually, based on the phase III data.
Therefore, we completely changed the paradigm and said, "Okay. When we do our responder analysis, we saw in the beginning, without knowing about this biomarker, we saw that there are patients who are responding much better, much more than the rest." The question was, "Okay. Can we identify them?" Really, the aha moment was, "Yes, we can." We could. We did it. We did it the first time. It was first exploratory. We did it. It was positive. Then we validated again in the previous trial where the same patients who were identified responded much better. In fact.
Nothing like five times, right?
Between five to seven times better. Five times in signs, seven times in symptoms. This really defined what we call a genotype-based development where genetically we know who will respond, who will not respond. We made a proposal to FDA. We said, "Listen, this is a big market, but we want to go only to patients who respond to our drug. This makes sense for the patient, for the doctor, and for the payer." The primary endpoint is TNF-R1 positive, who are patients who are responsive to our drug. This allows us to have a study which is 160 patients instead of 600.
Much more efficient cash use, much higher probability of success for the phase three, meaningful result because basically we are, so if you take our TNF-R1 patient, at day 15, we have five times more response than Xiidra, for example, at day 42. Much more meaningful. This will allow us also to have a much easier access, pricing, and launch.
Yeah. Excellent. We're out of time, but maybe the next catalyst is 2Q. And then for dry eye.
DME, genotype, the precision in dry eye, and then acute optic neuritis, NAION, MS. We will say the rest after.
Okay. There's a lot going on.
Thank you.
Thank you.
Thank you. Thank you very much, Annabel. Thank you.
Okay. You have too much happening.