Good morning and welcome to the Oculis Holding AG Conference Call. All participants are now in a listen-only mode. There will be a question-and-answer session at the end of this call. If you would like to ask a question via the webcast, please submit your questions through the Q&A function at the bottom of the webcast player. If you are in full-screen mode, you will need to exit full screen in order to see the questions in the portal. To our analysts in the Zoom queue, please raise your hand to indicate you have a question. Please be advised that this call is being recorded at the company's request, and a replay will be available on the company's website. I would now like to turn the call over to Sylvia Cheung, CFO of Oculis Holding AG. Please go ahead, Sylvia.
Thanks, Tara, and thank you all for joining today's call. The slide deck that accompanies today's presentation can be viewed using the webcast link provided on the Investors and Media page of the Oculis website. Also posted on our website is the press release issued earlier today announcing the positive results of OCS-05 ACUITY phase II trial. It is in acute optic neuritis, as well as the IND clearance received from the U.S. FDA.
Before we begin today's presentation, I would first note that during this conference call, we may make forward-looking statements within the meaning of the U.S. federal securities law regarding future events or performance of the company. We refer you to the documents that the company has filed from time to time with the SEC. The company's filings contain and identify important factors that could cause actual results to differ materially from those contained in any forward-looking statements.
Please note that the forward-looking statements made during this call speak only as of today's date, and we undertake no obligation to update them to reflect subsequent events or circumstances, except to the extent required by law. The words anticipate, continue, estimate, expect, intend, will, and similar expressions are intended to identify forward-looking statements. Now, moving on to the next slide. Joining us today are Oculis CEO Dr. Riad Sherif and four key opinion leaders, Doctors Mark Kupersmith, Len Levin, Pablo Villoslada, and Sebastian Wolf. It is our absolute honor and privilege to have the esteemed experts on this call. Dr. Kupersmith is a professor of neurology, ophthalmology, and neurosurgery at Mount Sinai.
He has over 40 years of experience in neuro-ophthalmology patient care, consulting and assisting neurologists, ophthalmologists, optometrists, neurosurgeons, and others. Dr. Kupersmith currently oversees the clinical trial unit for New York Eye and Ear Infirmary and Mount Sinai Health System. He is the chair of the planning committee for NORDIC, which stands for Neuro-Ophthalmology Research Disease Investigator Consortium, and he has directed NORDIC since 2009. Dr. Levin is a professor in the Department of Ophthalmology and Visual Sciences, as well as Neurology and Neurosurgery of McGill University. His research is focused on optic nerve diseases and related disorders, which resulted to date in over 200 peer-reviewed papers, reviews, and book chapters, and a number of related patents.
He currently serves on the steering committee of the National Eye Institute Audacious Goals Initiative and the scientific advisory board of the Vision Restoration Program of the Gilbert Family Foundation. Dr. Villoslada is the Chair of the Department of Neurology at Hospital del Mar, Pompeu Fabra University in Barcelona, Spain, and an adjunct professor at Stanford University.
He has over 25 years of experience studying neurological diseases and developing new therapies and biomarkers for MS and neuro-ophthalmological diseases, as well as new neuroimaging techniques for monitoring retina and brain diseases. He also serves on Oculis Scientific Advisory Board. Dr. Wolf is a professor of ophthalmology and Managing Director of Bern Photographic Reading Center in Switzerland. He has authored over 400 publications in peer-reviewed journals and serves on the editorial board of various scientific journals. He serves as the Editor-in-Chief of Ophthalmologica. Currently, he has been appointed as the ARVO Gold Fellow and is the past general secretary and past president of EURETINA. Thank you, doctors, very much for joining us today.
Let's move on to slide four, which contains our agenda for today. After my opening remarks, Riad will review the data from our phase II ACUITY trial, which evaluated OCS-05 safety and efficacy for the treatment of acute optic neuritis. Following the presentation of the data, Doctors Kupersmith, Levin, Villoslada, and Wolf will provide their interpretation of the positive results and the potential of OCS-05 in acute optic neuritis and beyond. We will then open the call to Q&A with management and our thought leaders, and we will conclude today's call with a brief closing remarks from Riad. Thanks again for joining us, and I will now pass the call off to Riad.
Thank you very much, Sylvia, and thank you very much for the key opinion leaders who are joining us into this call. I am very pleased today to announce the result of the EQUATE trial, which is a phase II study in acute optic neuritis with our third candidate, OCS-05. The primary endpoint in the EQUATE trial was safety. This is the first trial in patients in combination with steroids. Very pleased to say that for the safety, we do not see any difference in patients shifted from normal baseline to abnormal post-baseline ECG event, which was the topic for safety for this trial, and I will go into more details after. In terms of efficacy, very happy to say that the product has been able to show benefit in terms of anatomy of the retina as measured by OCT, but also benefit in terms of vision.
We see statistical significance difference in GCIPL, which gives us the biomarker for retinal ganglion cell health. Retinal ganglion cells, as you may know, are the neurons we have in the retina, and they play a role as a bridge between the photoreceptors and the brain. Here, we see that more than 43% in the active OCS-05 of retinal ganglion cells were preserved, as seen by the GCIPL layer in OCT at month three, and this was sustained at month six. The second endpoint was RNFL, and here RNFL is a biomarker for axon preservation, and here also we see a material benefit in OCS-05 arm versus steroid alone in three months and sustained at six months with more than 28% better result in the OCS-05 arm.
And last but not least, very importantly, we have been able to show that functionally we have been able to preserve function and give back function to the patient by having an improvement in LCVA, low contrast visual ACUITY with 18 letters difference in OCS-05 arm at month three, and this result, this difference, this benefit had been sustained over time at month six versus steroid alone. In terms of adverse event, no drug-related serious adverse event, SAEs, or adverse event leading to drug withdrawal or study discontinuation. And we see, which was extremely interesting and really goes into the same direction, we see a lower relapse episode in the OCS-05 arm versus steroid alone. And that will go into the details why this is important information as well. So before going into the clinical trial, let's see rapidly have a snapshot of OCS-05.
OCS-05 is a novel peptidomimetic small molecule with trophic factor impacting neuroprotective activities. OCS-05 targets IGF-1 signaling, including SGK, and acts on three targets. The first is SGK promote neuronal survival and differentiation through FOXO3 and GSK3-beta. By this action, OCS-05 is able to reduce apoptosis and promote survival. OCS-05 as well activated by SGK-induced oligodendrocyte differentiation, and we know that oligodendrocyte are vital for the myelin, which is the substance around the axon, which protects the axon. The third, the OCS-05 induces the cell-protective phenotype of microglia by avoiding oxidation. OCS-05 could be a disease-modifying drug, and we will see the data in acute optic neuritis, and could have multiple potential clinical applications. Of course, first in acute optic neuritis, which we are going to see together, but also in other diseases which are related to retina, but also to neuroscience.
So in terms of preclinical data, the product has been tested multiple times in seven clinical animal trials, consistently showing benefit in terms of anatomy and benefit in terms of function. The three models which were used were glaucoma, acute optic neuritis, and an autoimmune model for multiple sclerosis. The product has been able to show consistently that in terms of anatomy, and here in the picture in the middle of the slide, we see that animals receiving in a glaucoma model, animal receiving an acute optic neuritis model, it was the same result. Animal receiving OCS-05 were able to prevent their retinal ganglion cells from dying. In an autoimmune model, which is similar to MS, animals receiving OCS-05 were able to show that they had better mobility score versus animal not receiving OCS-05. And this is just supporting that not only anatomically, but functionally, the product is bringing benefit.
In other animal models, the product has been also able to show that it can promote axonal sparing and reduce demyelination in the model of acute optic neuritis. In conclusion, in terms of development status, the product had very solid preclinical data showing neuroprotection by preventing retinal ganglion cell death, promoting axonal sparing, reducing demyelination, and improving function in multiple sclerosis model. The product also went into phase I, randomized, double-masked, placebo-controlled, single- and multiple-ascending-dose studies of safety, tolerability, and PK with 48 healthy volunteers. Very happy also to say that the product received its IND clearance from the FDA, which opens a door for OCS-01 to be developed in the U.S. as well in acute optic neuritis. Now we are going to see the phase II efficacy trial, which is a first-in-patient trial in acute optic neuritis.
But before going into the trial, I would like to speak about acute optic neuritis as a disease. And we will have a chance, and you will have a chance to ask questions to the experts who are with us in the call today. So what is acute optic neuritis? Acute optic neuritis is an inflammation of the optic nerve that can lead to permanent visual impairment. This is an illustration of the retinal ganglion cell, where the retinal ganglion cell is in the retina while its axon constitutes the optic nerve, and the terminations of the cell are in the brain. In acute optic neuritis, we have inflammation in the axon, and this inflammation will create a stress for the whole cell, and the cell will die. It happens here in the optic nerve, and then the cell is here in the retina. What are the symptoms?
It is a type of neuropathy which comes with the symptoms of vision loss, contrast visual loss, and colors, and it could be combined with pain. It is an inflammation which affects the optic nerve here, and therefore no transmission of the signal from the photoreceptors to the brain. It's frequently associated with multiple sclerosis, and it could be the first onset of multiple sclerosis, and therefore, because it is acute, the timely treatment might help prevent more severe long-term effects. There are three measurements which help to measure the status of the patient and understand the prognosis of the disease. There are two measurements which are objective measurements which we do via OCT. One is the GCIPL thickness. The GCIPL thickness gives us a biomarker for the health of the retinal ganglion cells, which are here, here in the retina. The second measurement we do is RNFL thickness.
It gives us, it is a biomarker for the health of axons. We know that GCIPL are very well correlated with LCVA. Is acute optic neuritis a medical need? Yes, absolutely. First, it is an orphan indication, as you saw in my slide before, 65,000 patients between Europe and the U.S.. It is an orphan indication, and in fact, OCS-05 has an orphan designation in the U.S. and in Europe. Do we have a product which is approved? No, we do not have a product approved for acute optic neuritis. And in fact, what is used is high-dose steroid, very high-dose steroid between five to 10 times what is approved systemically, which is given in an IV infusion the first five days of the crisis.
However, the steroid will work very well on inflammation, as we know steroids, but at the same time, they are not neuroprotective, and therefore we need something to protect retinal ganglion cells from dying and avoid the situation which is frequently the end of six months after the disease, where the patient could see on a high contrast visual ACUITY, could see almost 20/20 or 20/25. However, the same patient will tell you, "I cannot read the newspaper, I cannot drive in the end of the day," and so on. So it comes with a very material impairment in terms of visual function. So let's go now to the phase II trial.
The two goals of the phase II trial were first to evaluate the safety and tolerability of OCS-05 plus steroid, which is today the standard of care, IV infusion, both OCS-05 and steroid compared with steroid IV alone. The second objective was to explore the potential neuroprotective effect of OCS-05 by focusing on retinal structure, so the anatomy, to tell us what is the health of the retinal ganglion cell, which is the neuron in the retina, the health of RNFL, which is the axon, and then the visual function measured by LCVA. This is the snapshot of the study design. It was a randomized double-mask placebo-controlled study, multicenter six-month trial with 36 patients. Among the 36 patients, 33 received OCS-05, and therefore all the analysis will be made on 33 patients, which is called a modified ITT.
All patients received a once-daily IV infusion of OCS-05 plus steroid or placebo plus steroid for five consecutive days. Patients were followed during six months. Primary endpoint, as you see them here, one is the cardiac safety, which we will see in details, and the secondary endpoint were three. First, the health of the retinal ganglion cell measured by GCIPL layer. The second, the change of RNFL, which gives us the health of the axon, and then the change in visual function by LCVA. In the beginning, the study had three arms: a low dose, a high dose two milligram, a high dose three milligram, and placebo. Oculis became the sponsor of this product two years and a half ago. When we became the sponsor, we decided to stop the low dose and to keep the high dose, which was actually the dose recommended by the previous PK trial.
However, we ended up with five patients in the low dose, which will be analyzed in this result: 15 patients in the high dose and 16 patients in placebo. The MITT will have four patients with the low dose, 15 patients with high dose, and 14 patients with placebo plus steroid. All these patients will be analyzed. In the safety analysis, we will pool the active. We will show you both, but we will pool the active. While on the efficacy assessment, we will be analyzing mainly the three milligram, which will be the dose we will go with for the future. However, for completeness, you will see the data for the two milligrams. This is the patient demographic and baseline characteristics. Perhaps a few things to highlight.
As I shared, this disease is in many cases related to MS, so we see the same demographic, more young age, mainly female. The time to treat is important. These patients were treated around 10 days after symptoms, and multiple sclerosis is frequent. 60% of patients had multiple sclerosis as well already in the baseline. The only thing perhaps to highlight in the group of the two milligram, where we had only four patients, we had an imbalance of RNFL. It has an effect I will show you, but the rest, the good news is between the three milligram and the steroid alone, we have a very nice balance, which allows us to have a good analysis. This is the first primary endpoint, safety, which was the primary endpoint. Cardiac ECG showed no difference in percentage of patients that shifted to abnormal electrocardiogram.
This safety item was guided by the tox. Of course, as you know, in the tox, we give much higher dose, up to 50 times what we are giving here. As soon as you see the signal, you start to characterize the drug. This is a new molecular entity, so therefore it is important to characterize the drug. But extremely pleased to say that with the dose being used, and I am speaking about the high dose, the three milligrams, with the dose being used in acute optic neuritis in intravenous daily injection, we do not see any concern here on cardiac. And the two events were both mild and transient and qualified by central reading center and as not clinically meaningful or significant. So I would say this is very good for the drug and for the patient.
We continue with the safety because it was the primary endpoint. No adverse event leading to drug withdrawal or study discontinuation and no drug-related serious adverse events. If I continue with the safety, we do not see anything which is specific or which is abnormal. So therefore, the safety of the product at this dose, IV injected in acute optic neuritis, shows a very good safety profile. Last slide on safety, which actually we captured during the six months, how many relapses we had for MS. Remember, this product is a neuroprotective drug, and therefore the question was, are we going to reduce the relapses? Now, of course, these numbers are small, but extremely encouraging to see that regardless of how you analyze it, the number of relapses due to MS are lower in the OCS-05 plus steroid versus steroid alone.
Of course, this trial was not done to respond to this question, so I would say this is good to see, opens the door for the future and extremely encouraging for patients and for the future of this drug, where we had 10% of patients who had relapse versus 35%. Let's start with the efficacy. This is GCIPL. If you recall, GCIPL gives us the health of the retinal ganglion cell. And here, the goal is to maintain the thickness of GCIPL. If we maintain the thickness of GCIPL, it means that we are maintaining the health of retinal ganglion cells, and here, you can see that the active patients receiving OCS-05 were able to have 43% more thickness or prevention of the thickness of their GCIPL. This is the same GCIPL with three milligram and two milligram.
The numbers are small, of course, but we see a nice dose response, so very encouraging, and the three milligram continues to be very consistent with what we saw before. But also, we see here that the result at one month is predictive to what we have at six months. And you will see the function is extremely encouraging what we see in the function. So in terms of GCIPL, which is the health of the retinal ganglion cell, the product is showing material benefit and material preservation of retinal ganglion cells, which are the neurons in the retina. Now, the question, and we will see it after, do we have a translation in the function or no? But before going to the function, let's see the health of the axon. Are we protecting the axons as well? And the response is yes, we are protecting the axons.
We are protecting the axons. We see the benefit already on month one, and actually, it continues, so the product OCS-05, three milligram, is able to protect the retinal ganglion cells in the retina and is able to protect the axons in the retina. This is the first time ever, and I really would like our experts to share their experience, which is by far bigger than my experience in this disease. This is the very first time where we see this kind of benefit and everything going into the same direction, everything. If we go to the next, as I shared with you in the beginning, in the two milligram with the four patients, it was completely imbalanced. They had more swelling and edema, so you see that the two milligram is lower here than the steroid alone and OCS-01.
It's known, and I would like our expert to respond. Perhaps I know that actually, if I may, Dr. Kupersmith, I know that you spent in your 40 years, 39 years in reading OCTs with RNFL and GCIPL. Anything you would like to say about this? Because we had the conversation and you shared with me your view. So anything you would like to say about this?
Yeah, just one quick comment, not to interrupt. That is the measurement of the retinal nerve fiber layer change in any acute optic nerve injury is always a little bit problematic because the baseline, if you look at the beginning, could be very variable. It's not normal because in that measurement of the retinal nerve fiber layer includes the number of axons, whether the axons are swollen, and whether there is edema outside of the axons, interstitial edema. The OCT can't differentiate that.
So some of the dramatic change in the retinal nerve fiber layer in the two milligram group was because they were significantly swollen. So when the swelling goes away, the nerve fiber layer measurement becomes thinner regardless of whether axons are preserved or not. So we're just looking at a change here. This is not an absolute measurement of the preserved retinal nerve fiber layer. So that's how I explain that. And that's why the GCL measurement is a much more accurate measurement for looking at acute retrobulbar optic nerve problems like optic neuritis.
Yeah, thank you. Now, let's go to the function. So we saw that concretely, OCS-05 is being able to materially in the anatomy prevent retinal ganglion cells from dying, protect axons. Do we see a better function then? And the response is yes. We see concretely a better function.
We see concretely a better function already at day 15 here. It's V3 at one month, three months, and six months. So we are saying we are speaking about a mean change of almost four lines or more than three lines, 18 letters here in LCVA versus steroid alone. And this benefit is maintained over time till month six. So extremely encouraging data here where we see a very nice correlation between GCIPL showing the retinal ganglion cell health, which are the neurons we have in the retina, RNFL showing the axon, and then the function. How about the two and three and the steroid alone? This is the two, this is the three, and this is a steroid alone. So really building on what Dr. Kupersmith said, we see that the two milligram is actually bringing benefit as well in terms of function. The three is better.
As I say, the three is the dose we will go with in the future. So here we have been able to show that with OCS-05, we achieved a primary endpoint, which is the safety. And importantly as well, we have been able to show dramatic improvement in the anatomy of the retina and in the function by more than three lines, which is the double of the vision basically in LCVA. So in conclusion, OCS-05 achieved the primary safety endpoint and key secondary endpoint showing neuroprotective anatomical benefit and vision improvement. Primary endpoint in terms of safety, we see that with the three milligram injected IV in acute optic neuritis, the product is safe. The secondary endpoint in terms of efficacy, we have been able to show that we preserve retinal ganglion cells, which are the neuron in the retina, to die.
We have been able to preserve the optic nerve and the axon of the retinal ganglion cell. And we have been able, importantly, to improve vision with 18 letters difference at month three. And with no drug-related serious adverse event and with a very encouraging data point in terms of less relapse of MS in the active arm with OCS-05 plus steroid versus steroid alone. So in conclusion, what this really means for OCS-05? So first, FDA IND clearance and the successful, very solid and successful ACUITY trial will drive acute optic neuritis development program now. And the aim is to go full steam to bring this product to the market.
And this mode of action and the neuroprotective benefit we are showing in acute optic neuritis, which is important for acute optic neuritis, but also a very solid proof of concept for neuroprotection for retina and for neuroscience, will open a door for multiple clinical applications. So first, we are speaking about acute optic neuritis, which is an orphan indication. This is the first indication we will go with. We are developing a topical formulation for neurotrophic keratitis, which is a second orphan indication we are preparing. And we will go through a whole portfolio review for OCS-05 to see what next for this neuroprotective drug, which is for the first time ever. And I really spent time to look at what was shown in the past.
For the first time ever, we have something which is able to show anatomical benefit, functional benefit in a disease where we do not have anything and we never show any neuroprotective benefit from any other candidate. So concretely, in terms of next step, is to interact with FDA to advance OCS-05 development program in acute optic neuritis. And the aim is to meet with FDA to discuss a registration program now with OCS-05. And the second, as I said, is explore additional indications to maximize OCS-05 neuroprotective pathway in neuro-ophthalmology. And there are a few indications here listed. We are really speaking about a biology which is not only big for acute optic neuritis. This is pretty transformational for Oculis, but also for patient, for patient in ophthalmology, for patient in neuro-ophthalmology, and for patient in neurology. This is big.
This is for the first time where we have neuroprotection for patients. Our aim now is to make sure that this will change the life of patients. Thank you very much. That will open for questions now. I have a few questions. I would like to start the discussion. I have a few questions for our expert, and then we will open the questions from our analysts. Perhaps I will continue with Mark, actually. Dr. Kupersmith, how today, just to have an idea about a medical need and so on, how do you treat patients right now using steroid alone? What is the expected response both in vision and on OCT scans? What makes you most excited about the potential benefit of OCS-05?
So currently, patients in the United States are treated if they have significant visual impairment with optic neuritis with intravenous corticosteroids, Solu-Medrol being the one, and/or very, very high-dose oral steroids to get the same effect. But if patients have very minor vision loss and no MS-looking lesions on the MRI scan, there are a lot of ophthalmologists and neuro-ophthalmologists who might not treat them, and those are very few. Most patients have profound visual loss, and they're treated with steroids because even though we know at the end of the day, it will not change the eventual outcome at six months or a year, patients don't want to not see, so it helps speed up their improvement, but there has been no proven neuroprotective benefit.
We and others have done studies to show that the nerve fiber layer thinning and the ganglion cell thinning occurs regardless of giving steroids or not. There is no structural treatment benefit for this. I just want to take, and I'm going to get close for what might make a very important point here is that people say, "Well, what's low contrast vision?" People go to their eye doctors. They understand looking at the black letters on the white chart. That's high contrast vision. But in this disorder, many patients will recover their visual ACUITY. 90% will recover their visual ACUITY to 6/6 , or almost 100 letters with the high contrast vision. But more than 60% will not recover their contrast vision to a reasonable stage.
That is why the patients are left with this deficit about looking at things as if it's always a cloudy day or reading the paper. There's a significant unmet need here in this cohort of patients. I think that for me, this is the first of all the drugs that I've seen with different studies on optic nerve injury from different causes where the clinical data in a study actually match the preclinical data. This is, to me, a very interesting drug to consider to do further studies with.
Thank you. Thank you very much. Because you spoke about the animal studies, I would like the person who led the animal studies, Pablo, to tell us, Pablo, what gave you the confidence to move into human trial after your preclinical work and why acute optic neuritis?
I mean, you are a neuroscientist. So why did you go to ophthalmology?
Okay. First, we decided to do a combination of different animal models reflecting different mechanisms of damage. We use, because my topic is multiple sclerosis, I use first the model of multiple sclerosis, experimental autoimmune encephalomyelitis. And there we show very good efficacy at the clinical level, meaning these are animal models in which you are able to assess the paralysis and motor score. This is quite objective, and second, the pathology was very consistent, then we move to a model of optic neuritis in which, by injecting directly in the optic nerve a chemical, we induce demyelination, inflammation, and again, we were able to see the pathology at the pathological level, neuroprotection, and finally, we move to a model of glaucoma. Why do a model of glaucoma? Okay.
Same neurons are being damaged, the retinal ganglion cells. And then there is no inflammation because potentially a small chemical might interfere with the activity of the immune system. But in glaucoma, inflammation has a minor role. Then we observe in different animal models, mice, rats, different mechanisms of damage, always a consistent effect, efficacy at the clinical level, pathological level. And then we move to optic neuritis. Why? Okay. My grant was in MS, and I was concerned about all aspects of MS. But for the last decade, the neuro-ophthalmology community, Mark and Leonard is one of the samples here, we have done a lot of efforts in order to characterize optic neuritis.
We have wonderful technologies like OCT, visual fields, visual evoked potentials, and also the clinical studies that are led by Laura Balcer in New York that help validate low contrast visual ACUITY as an excellent point that is relevant for quality of life. Altogether, [they] make optic neuritis as an excellent model, also because it's acute. Acute means shorter period of time in order to do the testing. Overall, we have an excellent clinical model. And many times, in addition to having a good science and a good drug, having a good clinical model is a path to success. Even in the glaucoma community, they are proposing optic neuritis as a testing model, clinical model to validate drugs before moving to a chronic condition, meaning that altogether is the rationale that we have used in order to move this drug to clinical testing in optic neuritis.
Thank you.
Thank you, Dr. Villoslada . So I would like to go to Dr. Levin. So Dr. Levin, how do you, I mean, share with us your interpretation of this result and have you seen drug that showed a positive preclinical data and translation in human? Did you see this type of result? And what is your interpretation of this result?
Well, this is the first time that I personally have seen such an excellent translation to a phase II study. There have been several preclinical studies of neuroprotective drugs, many actually, that I've been involved with, where even a phase I might show something, a phase IA .
This is the first time where I've seen not just a phase II showing the primary and a key secondary outcome measure as being positive, but also that there's a combination of really three different supportive measures of each other because one can always have small n, small numbers. One can have statistically significant, but yet maybe not as believable results. But in this case, we saw three pretty independent results, all of supportive, which is the first being the GCIPL, the structural measure of the preservation of the ganglion cell and its synaptic connections within the retina. The second being the low contrast visual ACUITY, so a functional measure, which is highly relevant to optic neuritis because that's a measure that people actually notice, especially when it's dim, when the contrast is already poor because of lighting conditions and so on.
And the third being one which was listed under the adverse effects, which is that there was a lower incidence of a second relapse or a worsening of a relapse in patients who already had multiple sclerosis. And so these are three pretty independent measures. I mean, they correlate with each other, but the fact that they all showed the same direction and showed significant results makes it very unlikely that this is a statistical aberration and much more likely that this is a true drug effect. And so this is something that is unique in my own experience, seeing many of these programs and working with companies usually that they're developing programs like this. So I think this is superb. And I'm glad that your company is planning on going ahead and presumably to a registration level trial or trials with FDA.
Thank you. Thank you very much.
The last question before opening to Dr. Wolf, I know that you have been involved in acute optic neuritis trial in the past. So you have, I would say, a very solid experience here as a clinician and as a researcher. What is your interpretation of this result and what is your takeaway?
So I can only echo my previous speaker. It's fantastic that we do see in all three categories the same effect. Low contrast visual ACUITY improvement, less loss of ganglion cells in the retina and retinal nerve fiber layer. We have to see this with a little bit of caution because of the baseline issue elucidated by Mark before. But it's all going in the same direction, onset to relapse of MS. So I haven't seen it in any previous study, and especially the ganglion cell IPL layer thickness. It's a very sensitive measurement.
And that we see with relatively small numbers such a significant effect. This shows that there has to be something for this drug. And I can congratulate you only and encourage you to go forward with development.
Thank you. We will listen to you all. Thank you. We cannot just interject one other thing I wanted to say, and that is, again, for the audience, is that there is a tremendous amount of research that has been done. And Pablo Villoslada stated this that shows that measuring the macular ganglion cell layer like they measured it correlates with low contrast visual ACUITY changes. That is an important thing because there is no other optic nerve disease where this has been shown before. In glaucoma, they are looking at retinal nerve fiber layer, but the correlations are very mild between structure and function.
So here, they have a model that shows a strong correlation between the structure and function, and the drug hit them both. Yeah. No, thank you. Thank you very much. So perhaps we will open the floor for questions from our analysts. So who would like to go first?
Great. Thanks, Riad. So our first question comes from Marc Goodman at Leerink. Please go ahead, Marc.
Yeah. Can you just talk about what you think?
Marc, we don't hear you very well. If you can—
Is that better?
Yes. Thank you.
Thank you. Sorry about that.
No worries.
Can you talk about what you think a phase III program is going to look like? And then are these the endpoints that are critical endpoints to kind of— that the FDA is going to need to see?
And then just for the physicians, I'm not sure who the right person is, but what are some of these other indications that make the most sense for this asset to kind of pursue after optic neuritis? Thank you.
Okay. Okay. Yes. So of course, so perhaps I will just address the first part of the question, and I will ask our expert to develop on the second part. On the regulatory point of view, of course, we need to meet with FDA, but I would say we have a dose, and the three endpoints will be most probably the endpoint we have in the trial. So therefore, it will be really about speaking about the design and speaking about how to implement. But I would say a priori, it needs to be discussed with FDA again. But a priori, we have the endpoint we need to measure.
They are pretty well characterized. The correlations are very strong, and we were able to have, like in other retinal diseases such as what AMD or DME, the endpoint related to the anatomy with GCIPL mainly, which is correlated to the function. So I would say the aim will be to go with something as close as what we have here on the regulatory, and we will be informing the market as soon as we have the feedback from FDA. On the clinical applications beyond acute optic neuritis, perhaps I can ask Mark first, and I mean, I will ask them all if you can just be all brief, but please, if you can give your opinion about how this biology could be leveraged or maximized in other indications. Mark,
So I'm Mark as well. I'm like a kid in a candy shop here.
I really don't know which is the one to go to first after, let's say, repeating a phase III, doing a phase III trial with optic neuritis because all of the potentials are there. It's just been a question of how big are the resources to do the studies. So I can't tell you which one I would personally do first, but there's no wrong choice, it seems to me, from what I can see. So I would say. Oh, sorry. Yeah.
Yeah. Go ahead, please, Dr. Levin.
Yeah. I would say that if a registration trial of acute optic neuritis leads to a label, I think there's really, to me, the two big options are multiple sclerosis, clearly, because most of the mechanism of action that we know about from the preclinical data that Pablo has generated point to effects that would be highly relevant to MS.
And in fact, there's a signal in the AE rates between the groups compared to placebo in MS. But the second one that I would consider strongly is glaucoma. And this would first require a deep dive into some of the data from this phase II study and hopefully positive phase III study to understand a little bit better because we know that there's at least three arms of neuroprotective effect of ganglion cells, an effect on microglia, an effect on demyelination. And it's really the first of them. It's most relevant to glaucoma. But glaucoma is the most common cause of irreversible blindness in the entire world, second most in the U.S. and Canada, and for which many people continue to go blind despite treatment.
And so I think glaucoma is definitely up there as well, but it requires some more analysis of the data, which I'm sure will be coming up in the near and distant future.
Thank you. Thank you. Pablo and Sebastian, if you would like to, yeah.
Yeah, at least you're endorsing what I've said. And of course, you know I truly focus on MS. But I would like to add on top of that, diabetic retinopathy. And this is because the mechanism of action and the pathway we are targeting, I have a personal belief that this is a very good niche in which we can have a strong impact and at the same time is a huge unmet need in ophthalmology.
Dr. Villoslada , if I may disagree, the only one point is diabetic retinopathy is not a niche, but all the rest, you are much more competent than me. Dr. Wolf, yeah,
so I would probably first go with some multiple sclerosis, but see enormous potential for glaucoma. But this needs to be a more dive in probably after more patients with acute neuritis because glaucoma is a multifactorial disease. And for some patients, it may work very well for others. And I do see not only for diabetic retinopathy, but for diabetic neuritis. So these patients have problems with peripheral neuritis, and there may be potential. So I wouldn't forget diabetics.
Thank you. Any other question?
All right, so I guess we'll go to the next question. So our next question is from Annabel Samimy at Stifel. Please go ahead, Annabel.
Hi, good morning.
Hello, Annabel.
Congratulations on this data.
So just in terms of future development, do you intend to maintain the IV formulation of this drug? And do you envision this as a one-time treatment or an intermittent treatment? Would it be administered every three months or six months? How do you foresee this moving forward? And for practical purposes, if you're looking at larger indications like glaucoma and diabetic retinopathy, I don't think IV is necessarily the ideal formulation for that. So maybe you could talk about how you see this moving forward into broader indications.
Yeah. Thank you, Annabel. And then good morning. So for acute optic neuritis, the formulation we have, which is IV, will continue into acute optic neuritis for now. This is what we have today. Of course, we are working on multiple other formulations.
As I said, for neurotrophic keratitis, we have a topical formulation which is going to IND enabling this year. And we are thinking seriously about other, I would say, more friendly formulations for chronic diseases, such as it could be IVT, it could be subcutaneous formulations. And we are working on that. And we will be informing the market as soon as we have something meaningful. But I agree with you. Yeah. And perhaps just, yeah? Go ahead, Annabel.
Sorry. Just in terms of whether it's an intermittent treatment and how do you envision the actual administration to be?
Yeah. So today, in the clinical trial and in the clinical practice with OCS-05, it will be an IV infusion daily for five days. It was the protocol, and this is what is expected in the clinical practice. It is not a chronic treatment because this is not an inhibitor.
This is an activator, and Pablo can speak better than me about it, so I will ask him to add. And this is really the acute treatment for acute episode. If there is a relapse, of course, we will need to treat again. But Pablo, would you like, please, Dr. Villoslada, would you like to give your opinion about the treatment regimen?
Yes. As Riad has said, the idea here is activating the trophic factor signaling. And by this way, you protect the neurons, meaning once you activate, these effects stay for several days and weeks, and you receive a benefit. For acute indication, a short period of time is just enough.
At the time of moving to a chronic indication, like the one that we are mentioning here, we need to find the right therapeutic regimen, most likely going to be every, let's say, one week, several weeks with one of these new formulations. This is something that we need to explore, but it's most likely the kind of regimen that we are envisioning.
Okay. Great. Thank you.
Thank you.
Thanks for the questions, Annabel. Our next question comes from Jason Gerberry of Bank of America. Please go ahead, Jason.
Hey, Jason. Good morning.
Good morning. Thanks for taking my question. Can either the company or the doctors speak to how commonly patients relapse annually? And based on these data, if there's an expectation that I'm trying to get a sense of how common the relapse rate will be and potentially be lessened based on these data?
My second question is just sort of what underpins the confidence that three milligrams is the right dose? It didn't seem like you ran into any kind of limiting toxicity. So any plans to push dose in the future? Thanks.
Yeah. I will perhaps start with the second part, and I will ask one of the experts to take the first part related to the relapses of acute optic neuritis and so on. For the first part, the three milligrams was really not a low dose. It was actually guided by the PK studies before. It is actually the right dose. Therefore, based on this data, of course, again, I always add a condition because everything is done in collaboration with FDA. But this is the dose we do not have at least intention today.
We don't have a reason to go higher than three milligram. Three milligram seems extremely efficacious and safe. Extremely efficacious even if I come back, for example, to the LCVA. We have highly significant with the three milligram and a very safe profile. So therefore, I think this is really the right dose. For the relapse of acute optic neuritis, who would like to take the question?
I will.
Yeah, please, Mark.
So patients who have acute optic neuritis that develop MS will go into disease-modifying drugs for MS, and they'll have much fewer relapses. So I don't think you can think of this population as a potential for recurrence and supporting a market for this once they go into MS-related drugs. Now, if the drug is effective for MS exacerbations, many patients still have relapses despite having no further optic neuritis while they're on disease-modifying drugs.
So that will be there. And of course, as Pablo knows better than me, is that there are those people who also have either primary or secondary progressive MS, and those are very niche groups that have no treatment for them. And if this is really neuroprotective, that'll be another market for that particular group. In terms of other inflammations of the optic nerve, because we don't know when the patients come in the door, whether they have one of these other autoimmune disorders, they will have recurrences often despite therapy. But you remember, you're talking about young patients who will have at a rate 30,000 or 40,000 cases per year in the United States and another 30,000, 40,000 per year in Europe as a constant flow of patients for this drug if that indication gets approved.
Yeah. Let me add on top of that.
MS has changed a lot in the last five to 10 years because the new drugs are highly efficacious in order to prevent relapses. Although they don't change, they are not so efficacious in progressive disease. This means that most of the relapses are new patients, meaning patients are starting MS with optic neuritis or maybe other relapses, meaning this happened in the trial, and this is going to happen in clinical practice, and as Mark has saying, even patients being treated with disease-modifying therapies, some of them will suffer relapses, meaning that, okay, we attempt to reduce the disability related with these relapses, optic neuritis or in the future, other type of relapses.
Of course, if we move this drug with a new formulation, a new therapeutic regimen for chronic MS, of course, the big target is progressive MS because with the current therapies, we are not so efficacious in reducing disease progression.
Thank you. Any other question?
Great. So our next question comes from Sushila Hernandez from Kempen . Please go ahead, Sushila.
Hello, Sushila.
Hi, Riad. Yes, thank you for taking my questions. Could you walk us through the steps that led to the IND clearance by the FDA? And with this clearance, what else needs to be discussed with the FDA before starting clinical development? And just to clarify, are you able to initiate a global phase III study, including in the U.S. with this data? And what timelines are you looking at? Thank you.
Okay.
For the first question related to the IND clearance, as we, I think, disclosed a while ago, the FDA wanted a second tox, which is a normal process, actually. It was not specific to this program. It was just not done as the FDA wanted the tox to be done. We sat with the FDA, and we did exactly what the FDA asked us to do in terms of tox study, which responded exactly to the question to the FDA, and we submitted this data, and the FDA was, I would say, pleased with the data in terms of process and in terms of a very clear definition of the NOAEL. Therefore, this led us to lift the clinical hold. In terms of next step, as I said, it will be really a result of the FDA discussion.
I would say our intention is to meet with FDA, to meet also with other regulatory bodies in the world. Our aim is to have a global program. We are extremely happy now that we have the clearance in the U.S. We will be working with EMEA. We already worked in Europe, in the U.K., and in France. So we will be working also with EMEA to have a global program. But this is our aim, and we will be able to inform the market specifically on the outcomes of the discussion with FDA as soon as we meet with them. But our aim is to discuss a global registration program.
Okay. Thank you.
You're welcome.
Thank you for the question, Sushila . So our next question comes from Dan Akschuti at Pareto . Please go ahead, Dan.
Yes. Hey, Dan.
Hi, everyone, and a great presentation. Thank you for your time.
Just one more question, I think more to the key opinion leaders regarding MS. It was mentioned that you see a signal, and I think that's from Slide 23. But the numbers there are quite small, so I wonder how to interpret that difference between one patient having that in the OCS-05 group and quite more in the placebo. Is that something that is very insignificant, or would you say that this difference is quite telling?
Who would like to address this question? I mean, I don't have the results of a chi-square here or a Fisher's exact test, but it's just encouraging that it's basically, if you compare the rightmost placebo plus steroid, which is 35.7%, and so five out of 14 with the three milligram, which is, to me, the key point here, which is 13.3% out of 15 or the two out of 19.
It's approximately three times. You've decreased by a third, roughly, the rate. And so if that holds up in numbers that are large enough to achieve significance, then that's relevant.
And you would say that this is unlikely that these events are unlikely randomly occurring more or less during that time. Is that something that is more stable or?
Well, this gets to what we mean by statistical significance. So because the numbers are small, and again, as I said, I don't have access to the appropriate test would be some kind of a variation of a Chi-square. But so could this have occurred by chance? My guess is it could have occurred by chance, but it's encouraging because it's a fairly large effect. But yet, again, I'm sure that the confidence intervals may include zero or in this case, one. And so it's hard to say.
It's just that this is a fairly big change, but is it significant or not? That's going to require some deeper diving into the data.
One comment on that, and that is, Dan, what we don't know is we haven't looked at the brain MRIs that were done, which just would like to show that if you could correlate, if they had equal amounts of brain lesions indicating that they had a propensity to develop MS, that would be more important, but don't forget that the majority of the patients, if I remember at the beginning, were diagnosed as having MS when they came into the study, right, Pablo? So there were 60%. 60%. So it's likely that the groups were matched for MRI, but a deeper dive into the data would be correlating it with the MRI and seeing that they were fairly matched.
I would say just from the company point of view, I mean, this was not a hypothesis. So therefore, it's good to see, as the experts say, this is very encouraging, and it needs further analysis, but extremely encouraging because everything is going toward the same direction. I think really the hypothesis here is first the safety. The good news is the product is safe. And the second is really GCIPL and the function, and it's working extremely well. And I would say this is really the question from the study. The rest is very encouraging to say, very happy as a company to say that, but we will need to further do our work. This is just a top-line result. We will continue to analyze the data, and this data will inform the next steps of the development of this program.
Yeah, I would highlight everything pointing in the same direction. And this is small numbers, very unlikely that this is just a chance.
Thank you, Dr. Wolf.
Yeah.
Thank you for the questions, Dan. So this concludes our Q&A session for today. I'll turn it back over to Riad for closing remarks.
Thank you. Thank you very much, Tara. I would like to thank all our KOLs for their contribution. I would like to congratulate also, Pablo, for 10 years of work. I think this is the first step and extremely happy with what we have here. I would like really to conclude the call by saying this is a big day today. This is a big day for OCS-05, a big day for Oculis, but really a big day for neuroprotection.
This is the very first time ever, as shared with the experts we have here, where we have a product which is showing benefit in the retina, benefit in the function, and really opens the door for multiple clinical applications. The first one is acute optic neuritis. We will go immediately to it, but we will be analyzing and we will be maximizing the value of this product in other diseases to make sure that if there is a benefit, this will be brought to patients, and this is our goal, and this is why we are here. Thank you all for your support, and very happy to continue our collaboration in 2025, and happy New Year to all.