All right. Good afternoon, everyone, and welcome to the Oculis presentation. We are pleased to have Riad Sherif with us today, Chief Executive Officer of Oculis, and we have Sylvia Cheung taking pictures in the back, CFO. Thank you for joining us today. Oculis is a diversified ophthalmology company that is transitioning to neuro-ophthalmology, depending on how things come out with licaminlimab, which I said very well. Thank you.
Yes.
Riad, maybe you can just give us an overview first, and then we can go into questions.
Yeah. Thank you, Annabel, and thank you, Stifel, for a well-organized meeting. As you said, Oculis is a neuro-ophthalmology company.
Yeah, that is it.
Or neuroprotection company. In fact, the first neuroprotection company with clinical data. At the same time, we have an upcoming readout in ophthalmology with the product which is called licaminlimab in a subset of population of dry eye. As you know, dry eye is a very, I would say, heterogeneous disease, and we are focusing on a subset of population which is called TNFR1, and this result is coming in upcoming weeks.
In neuro-ophthalmology and neuro, we have a candidate which is called privosegtor. Privosegtor was tested in acute optic neuritis or optic neuritis, which is an inflammation of the optic nerve. In more than 60% of the cases, it's an exacerbation of multiple sclerosis, and it comes with pain and loss of vision. We are really talking about young population, young patient. The average age is 32 years. I really speak about it because I saw it. It's really like the typical patient is a young mother who lose her vision. It's devastating for the person. In general, two-thirds of these patients recover BCVA, but not LCVA. Therefore, you end up at 32 years not being able to use a screen, not being able to drive or do multiple things in life. This is after first exacerbation. If you have more, of course, it's worse.
Therefore, in our trial, which is called ACUITY, which was a phase II, we showed that with privosegtor, that we were able to improve vision by 18 letters, which was LCVA. We preserved the structure of the retina, and we preserved really the neuronal structure of the retina, which is called retinal ganglion cells, or GCIPL. We reduced the axonal damage, and it was measured with the neurofilament, and we reduced astrocyte activation or neuroinflammation by reducing the GFAP. An amazing data set, because everything going into the same direction. Our product was granted Breakthrough Therapy designation in the U.S., PRIME in Europe, and now privosegtor is in phase III.
Great. Let's continue with privosegtor.
Okay.
Or do you want to start with licaminlimab?
You decide.
Okay. Let's get licaminlimab out of the way, because that's going to be the next data point you see. That's going to be the first of possibly four, maybe up to four trials for dry eye disease. So, what does success look like to you in this trial?
The first layer of success is the positive study.
Okay.
The second layer is doing better than the competition. I would say the question is really why we are going with the TNF in dry eye, and then after, why precision medicine? Why not doing a product for everyone? There are millions of patients. The first why TNF is because inflammation is the core component of dry. Inflammation sustain the pain and the irritation and the redness and the disease itself. Therefore, tackling inflammation makes this product potentially one of the first really disease-modifying drug in dry eye. Therefore, it is very relevant. Now, why going to precision medicine? Dry eye, as you know, there is huge variability in patients, and we end up in situations where phase IIIs are complicated because of variability of patients.
We end up also commercially having a very unsatisfied population, where in general, when you do surveys, typically 87% of patients are not happy with their drug. In fact, when you see the renewal of prescription at month six, 85%-90% of patients stop their drug because they are not happy. Therefore, what we did, based on our phase II, we really asked ourself, "Okay, if we go to the high responders, can we identify these high responders ahead of time?" We were lucky to identify a biomarker which really allows us actually to, in pre-specified manner, to identify this biomarker and know who will respond and who will not respond.
We tested this hypothesis in a previous trial, which was called RELIEF, and the product in between the two last trials showed that in TNFR1 population, we were able to deliver five times better improvement in signs and seven times better improvement in symptoms. Therefore, we met with FDA, we shared our data, and FDA agreed for us to go to TNFR1 population. In fact, we are enriching the phase III with the TNFR1. Two-thirds of the patients are TNFR1 in PREDICT-1, which is the first symptom trial. Primary endpoint will be mean improvement in TNFR1 patient. Secondary endpoint will be mean improvement in all-comers. The last secondary endpoint, which is really important, will be responders. How many patients gain more than 20 points, or how many patients improve more than 20 points? This endpoint is really important because many times we focus on mean.
Mean is very important. It tells you, in average, this product is efficacious by this. But in the end of the day, the patient who will stay with your drug are patients who respond well to your drug. If we gain on a scale of 100, one point, yes, it is one point, but is it meaningful? Am I going to keep the drug because I gain one point out of 100? Most probably not, because I will see you not, doctor, is the same. If I gain 20, then I will keep it because I feel that it is meaningful for me. Therefore, this is really important, and typically in all trials, it is between 15%-18%. In our trial, in all-comers, it was 18%.
And really for us, I would be very happy if we go beyond this number, because it means that we are keeping patients in drug. And what it means? It means that when we think about forecast, when we think about revenues, the two parameters or the three parameters which are important is, one, how many patients you have on drug. Penetration, the market penetration. Second, what is your price? But the third, which many times we don't think about it, but it's so important, is how long you keep the patient, and therefore the revenue per patient, because it's really defined. It's actually at the same price, if you keep patient two times, you sell twice. Therefore, the most important point in our view is, of course, the mean. And I really hope, of course, the mean will be higher than what we saw in all-comers.
The second important will be the responders, because it will tell us about adherence to the treatment, and therefore how long the patient will stay and what is the value per patient.
Just to be clear, this is a symptoms trial.
This is a symptom trial.
Right.
Now, overall, really what we are aiming to do in dry eye, and I really like to say it because this is really the paradigm shift. We are moving from a disease which is driven by trials and error. The typical patient, I saw it multiple times. A typical patient, they go to the ophthalmologist, they open the bag, and they say, "Doctor, I tried this eight, nine, 10 drugs. No one worked. What should I do?" It is pure trials and error. Everyone is frustrated in this disease. And to something which is you test and you treat. It is whole change from trials and error to test and treat. And our aim is to focus on the population, which is around 1.5 million patients who are TNFR1 positive, moderate to severe, who need a drug, and this is our core segment.
We are not trying. I don't want to go to all-comers. I want us to be very selective to go to 1.5 million patients who we should deliver better result, who should deliver high adherence because they will have positive experience with our drug. This is what we are looking for.
Right. Just to be clear, in this TNFR1 positive patient, if you do, as you showed in the PREDICT trial, I'm sorry, in the RELIEF trial
In the RELIEF trial
five times higher than the standard, which I think you compare to XIIDRA, would that be sufficient to clearly establish the symptoms? Then you maybe only have to do one other signs trial and you're done? Or do you feel like you're still going to have to do two symptoms and two signs?
Yeah, so the base scenario is really two signs and two symptoms.
This is the base scenario.
What would be the scenario where you only do one sign and one symptom? Because that's kind of the standard design for most trials.
The standard design actually is to do two trials, but together signs and symptoms. You end up missing, and you end up doing at least four. RESTASIS did seven trials.
Okay, you are just starting with four.
Just like RESTASIS did seven trials, seven phase IIIs.
Oh, because it does not really work.
They did seven.
Just to be clear.
It was more than a billion-dollar product for many, many years.
RESTASIS did four trials because the same, they tried to do signs and symptoms together, and they ended up having a program with more than 2,000 patients. Our program, base case scenario, is four trials with separate signs and symptoms. They are discorrelated, does not make biological sense to combine them, actually. Our program is planned to be 650 patients, three times or four times smaller than any other program, because we are very specific. We go to signs and we deliver sign. We go to symptom, we deliver symptoms, and we are enriching with the TNFR1.
With the specific population that is TNFR1 positive.
Exactly. Now, potentially, but I really do not know now, potentially FDA will ask only for another sign and not more. This we know. Once we deliver PREDICT-1, we will meet with FDA, and we will see what FDA want. But in simple, this is unique precision medicine in a disease which really needs precision medicine. In fact, just to finish on licaminlimab, in the last two congresses, AAO and ARVO, survey done with all of the community, the first to the question, "What do we need in dry eye?" The first response in both congresses is, "We need customization." This product will allow customization.
It should allow very good experience in the TNFR1. This is our focus. The test is very easy. It is a qPCR, it is a saliva swab, it is very rapid, not invasive, not expensive. Now let us see the data. Now we need to see the data.
Okay. Coming December, maybe January.
Coming December or January, yeah. I don't know yet.
All right. Let's shift over to privosegtor because that's really been the focus of everyone's attention, and your strategic focus. Your data was obviously very good. You showed positive results on anatomical, on functional, and structural, all three. How has the medical community responded to this, and what are they hoping for with this upcoming trial, in terms of what you can potentially bring out?
Yeah. So, the privosegtor has been for us an amazing surprise because, to be totally frank, we were hoping, of course, the product works, but not at this level and not with this clarity. The product showed amazing functional improvement, 18 letters at month three, which is more than three lines. In LCVA, showed protection of the brain tissue we have all in the retina, which is called retinal ganglion cells, and we measure it with OCT. Showed, as we said, improvement in neurofilament, which is a direct biomarker for axonal damage. And we showed improvement in GFAP, which is a direct biomarker for astrocyte
Inflammation
inflammation. And the safety was good. Therefore, I would say extremely compelling data. And based on this data and based on the totality of the data, we got a Breakthrough Therapy designation with FDA and PRIME with EMA. Therefore, this is excellent. This opened the door for us for registration trial with privosegtor in optic neuritis. Optic neuritis really has two short-term goal, or three even. The first short-term goal, it is a disease, an orphan indication. We have around 35,000 patients in the U.S. We don't have a treatment, zero treatment for these patients. So, this is potentially the first treatment for optic neuritis. This is the first short-term goal. The second short-term goal is optic neuritis is a type of relapse of MS, and it opens the door for us to go to more relapses.
Therefore, the optic neuritis study, which will support the labeling optic neuritis, will be supporting as well a label which will be the half of the studies supporting the label in acute MS relapse. What it means for us, it means broadening the reach of this product from 30,000 to 35,000 patients to 170,000 or 180,000 patients. So, huge. The third short-term goal is really what you can show in the retina on the brain tissue level. There is a translation into the brain later on. Therefore, this is our third wave of development. Today, we are really focusing on the acute diseases. But you can imagine, if we have a neuroprotective drug which works, the potential of the drug is just endless. It's crazy.
Or any condition that has optic nerve degeneration or any-
Yeah
Or degeneration in general. I guess one of the questions I have, first to roll back a little bit, you went from a proof of concept study in AON, I can see the direct line to MS since AON is a form of relapse in MS. How did the FDA get comfortable going from proof of concept in MS to NAION, which is a-
Yeah. No, you are-
different pathology completely.
You are totally right. Optic neuritis and NAION are different diseases.
Yeah.
You are totally right. In fact, the insult or the injury is different. In optic neuritis, it's inflammation. In NAION, it's ischemia. Therefore, they are different, absolutely. Now, on downstream effect, it's the same. It's retinal ganglion cell dying, actually. In our preclinical work, in animal works and so on, we show that the product promotes survival of neurons, retinal ganglion cells and neurons, and oligodendrocyte in three injury model, oxidation, apoptosis, and inflammation. Therefore, based on our preclinical work, we can make a hypothesis, it is a hypothesis, that it should work in NAION. Now, you are totally right. We don't have yet human data in NAION, and we need to run a phase II/III. From where we would learn and potentially extend, adapt, continue, but let's see. But you are totally right. Yeah, these are two different diseases.
Based on really the way this product works, the hypothesis is solid, but it needs to be validated.
With AON. Sorry, go ahead.
Sorry, just to continue. AON is really a disease which is rare as well. It is a devastating disease. It is a disease where you lose vision, you do not recover at all, and no solution exists. I do not know if you saw it, but recently, last Monday or Tuesday, FDA asked all the GLP-1 companies to actually add a warning.
Yeah, we saw that.
Therefore, it is really a disease which might go up because GLP-1 penetration is very high, and hopefully we have a solution, but we need to validate it.
So, let's go back to AON for a minute. How is it designed right now? It has AON patients, and you also have a component of patients that are also MS patients.
Yeah. So basically, in PIONEER-1, all optic neuritis are included. All. The only optic neuritis which would not be in the mITT, and this is aligned with FDA, AQP4 or NMO. NMO, AQP4, this type of optic neuritis would not be in mITT. MOGAD will be in mITT. We had, in fact, MOGAD patient in ACUITY, and the product worked very well, actually, in MOGAD, but not AQP4. So, we will have all comers. Most probably, we are not changing the regions in terms of MS incidents. We did it in Europe. We are doing it only in Europe and the U.S. So, it has more or less the same incidence of MS, therefore, we should end up with two-thirds MS and one-third non-MS.
Should the MS component of the AON trial be sufficient to provide enough proof of concept for PIONEER-4, which is going to be the full MS trial?
Yeah. So the plan is to do PIONEER-1.
You have to wait for PIONEER-1 before you start PIONEER-4.
Yeah. PIONEER-1 is all optic neuritis, okay? PIONEER-2 is optic neuritis only in MS patient. It can be inaugural, like it can be first onset in MS, or it can be MS with optic neuritis. This is PIONEER-2. PIONEER-3, in alignment with FDA, and we are waiting now IND. As you may recall, we had the pre-IND meeting in summer. We submITTed IND. We are expecting IND to come in Q4, and this IND will allow us to go to acute MS relapse. Our aim for acute MS relapse is to do only one type of relapse, which will be combined with optic neuritis, and then it will support an acute MS relapse. NAION is a different program, yeah.
All right. Can we move to-
Yeah.
Sorry, go ahead.
We have an R&D day, as you may recall, on December 8th. We will really give much more details because hopefully by then we have the IND, so we can talk concretely, like we have IND, we are moving now, and this is the plan. We will be giving in details an update on the execution of PIONEER-1, but also clarity in terms of protocol design for PIONEER-2, for PIONEER-3, and so on.
Okay. Let's just stick with PIONEER-1 for a minute. You have all the sites up and running already, or are you waiting for the sites to fully get on board? Because I think the complication with this trial is that you have to wait for an acute incident of AON before you can enroll the patient.
Yeah. This is what we said, and really typical to this disease. This is an event-driven disease, as you know. To build up a site, we need a multidisciplinary team. We need the neurologists, we need ER, we need ophthalmology. To build the site, we need to create this ecosystem. The ecosystem is being created. We have a plan to activate 60 sites in total in the end of the process. Our goal is to activate half of them by the end of this year.
We are tracking well. In the R&D day, we will be giving more details about where we are and so on, but it's tracking well. We are also screening and randomizing already in the U.S., and it's starting now in Europe.
Okay. You've dosed your first patient already?
Yeah, yeah. It was dosed in the end of August, yeah.
Okay. Once these sites are up and running, how often do these patients come in with events?
It depends really on the site. There are sites who recruit more than others. I would say, we didn't give this data. We might give it in the end of the process. Let's wait to have at least this 50% of the site in the end of the year, then we can-
Okay
have a good assumption. But vis-a-vis our historical data, our historical data in ACUITY and so on is going pretty well, actually.
Okay.
It's going well.
The primary endpoint for this trial is LCVA?
Yes.
Other endpoints that you're looking for specifically, or what?
The endpoint we are looking for are LCVA, GCIPL. The key endpoint, primary and the key secondary, are LCVA, GCIPL, neurofilament. And exploratory, we are doing GFAP as well.
That's the inflammation-
Yes
biomarker. Okay. All right, the AON trial is, this first AON trial is not going to have any MS patients. The second one will have MS patients.
We will have MS patients.
They will. You will have MS patients.
Yeah.
Okay. It wasn't clear. I thought maybe you said the second one. From these two trials, will you have everything that you need to start the PIONEER? Is it possible that you start PIONEER-4 before you even go to PIONEER-3 and do NAION? Are you trying to sort of capitalize more on the
I would say, yeah.
the MS angle of it?
The strategy, as exactly you are saying, actually, we will capitalize on the MS. I would say these three indications in two clusters. One is inflammation.
Inflammation is optic neuritis and acute MS relapse. And one is ischemic, is NAION. We will capitalize first on inflammation, and we go to ischemic.
Okay. Maybe you can talk about other areas of neurodegeneration. I know that you've got your hands full with AON, NAION, MS, but this is presumably applicable to a number of optic nerve degeneration conditions. So what are the options you have for other conditions right now, like glaucoma or-
Yeah.
you know, AMD?
We hired a neurologist. We hired actually two the last six weeks, neurologists. One of them is coming from a big MS company.
Number one MS company. He is a professor of neurology. He is passionate, actually, about what this product can do, which is great. I am very happy when I hear him excited about what we have. He will be attending the R&D Day, and I asked him to make a-
You are going to-- I have to wait till December 8 then.
Yeah, I am sorry.
Okay, I see.
I am sorry.
All right. Well, I mean, theoretically, how about theoretically, where could this product-
Yeah, so
presumably go?
Björn Tackenberg will be presenting this.
Okay. You working on any other formulations?
Yes, we are.
Okay.
Yeah, we are working on other formulations.
Because this is IV administered.
This is IV infusion.
for everyone to know.
Exactly.
Acute administered.
This is IV infusion, and we are working on oral formulation, yes.
Oral formulations. Is that sufficient to get to? Is that oral for the brain or oral for the eyes?
It's always for the brain.
Okay.
Eye is the balcony of the brain.
Right. Okay. Any intravitreal options or drop options?
We are working, I would say it's in early stage drop, early stage IVT. What is more advanced is the oral.
Okay. I know you are not going to answer this question, but when do you think we can see the first data point coming from this?
Data point from?
From the AON trial.
So, what we said, I will really-
Should we go back to licaminlimab in the back?
No, no. It is fine. It is fine. No, no. Based on our current tracking, and we will give more precision when we have 50% of the patients, which is really our common practice. We have three data points where we inform the market, where we have the first patient, first visit.
Where we have 50% of the patient, and where we close the randomization. When we have 50% of the patient, we will give precision in terms of top line result and so on. Based on what we said already in the past, it is really tracking well. We should be able to finalize the randomization in 2027, and potentially around year end have the top line result. I would prefer to be more precise once we have the 50% patients. I think really, I know the timing is important. We grow all in the school system where the timing is important. We need to be on time in the classroom and so on. The timing is really important for all of us. Really, we really need to think, this product can be transformative for all of us.
If we all age, which I hope, we will need somehow.
something which helps our neurons, actually. It is really, like, we are on the verge of something which can be huge. As a company and as a CEO also, I am really currently focusing on quality of the study.
I just want to make sure that the execution of what we are doing, the activation, like the centers are right, the equipment is controlled, the LCVA, everyone is certified. This is really the focus of what we are doing now, is so important. The good news in this trial, activation takes time, and this is what we always said from the beginning, so we are on track. But once you activate, the randomization is really easy.
It is easy because even if it is an event-driven, it is acute, it is painful, they come, you see them immediately, it is five days treatment, and then after, it is just follow-up. So it is simple. Product works, at least in the phase II.
How long are you following them for? So it is five-day treatment, and then you follow them for-
Five days treatment. The readout is at month three.
It is identical to the phase II. For the safety database, we need to have 100 patients followed. It is FDA request. We need to have 100 patients followed till month 12. We will follow them till month 12. In fact, for PIONEER-1, patients who are having a relapse between month three and the end of the follow-up, they will receive all of them, not only the active arm, but all of them privosegtor, which is really good because it will give us experience on repeat.
I mean, seriously, we are, and I am so excited about what we are doing. It is really amazing. It can be so transformative for the patient. Precision medicine, transformative for millions of patients who are not happy. This one can transform the life of patient, like of 32 years, a young mother who will change her life. It is big. This is the excitement. It should be on time. We will inform the market. I am not worried.
Okay. That is fantastic. What is your cash position to do all these trials?
The cash position, we just announced our third quarter. We had CHF 252 million.
This covers us till the second half of 2029. And what is included, this does not take into account our loan facility with BlackRock.
This takes into account PIONEER-1, 2, 3, and PREDICT-1, of course.
Any chance for monetization of PIONEER-1? I am sorry, not PIONEER-1, PREDICT-1?
Future will tell.
Okay. All right. Well, until December 8th then.
Thank you. Thank you.
You're welcome.
Thank you very much.