ProQR Therapeutics N.V. (PRQR) Earnings Call Transcript & Summary

Good afternoon, and welcome to the ProQR Expert Perspectives Call. [Operator Instructions] Today's call is being recorded, and a replay will be made available on the ProQR website following the event. At this time, I would like to turn the call over to Daniel de Boer, Founder and Chief Executive Officer of ProQR for some introductory remarks. Please go ahead, Daniel.

Thank you, Sarah, and good afternoon, and good morning, everyone, wherever you are. Welcome to today's expert perspective call. At ProQR, we work every day to create transformative RNA therapies for severe genetic and rare indications. For those on the call today that may be just learning about us, we are a biotechnology company that is headquartered in Leiden in the Netherlands, and we have a U.S. site in Cambridge, Massachusetts. While our RNA oligonucleotides platform has brought applicability, our focus is on the development of medicines for inherited retinal diseases. We have a pipeline of a few dozen programs for inherited retinal diseases, of which 3 are currently clinical stage assets. These are sepofarsen, which is in a pivotal study for LCA10. And for this program, we recently completed enrollment. The second program is QR-421a, which is currently in a Phase I/II trial for Usher syndrome and retinitis pigmentosa. And this is the program that we will be focusing on today. And QR-1123, which is in testing for autosomal dominant retinitis pigmentosa. Our fourth program is QR-504a, which is for the ophthalmic disease of Fuchs endothelial corneal dystrophy, which is scheduled to enter the clinic in the next few months. And all 4 clinical programs are expected to produce clinical data in the coming 12 to 15 months. Today, we're hosting this expert prospectives call in a whole series where we take deeper dives on interesting aspects of IRDs, such as endpoints, patient baselines and disease progression. Our goal is to provide the perspective of an expert to show where the space is moving and where we believe there is an opportunity to make a real difference. As a housekeeping item on today's call, there are maybe forward-looking statements, there are risks and uncertain uncertainties associated with an investment in ProQR, please review our SEC filings, which are available on our website for more information. So I'll now turn the call over to our Chief Medical Officer, Dr. Aniz Girach. Aniz is a board-certified ophthalmologist himself and an experienced drug developer. And Aniz will be hosting the discussion today with Dr. Paul Yang of the KCI Institute. Aniz, over to you.

Thanks, Daniel. And it's a pleasure for me to host this expert perspective series on Usher syndrome and non-syndromic RP. Just a quick introduction to myself and also our special guest today. I'm an ophthalmologist, retina trained ophthalmologist, have worked in the academic and clinical setting for some 10, 12 years and then moved into the industry. And now I've spent about 25 years in the industry, having worked for big pharma companies as well as smaller biotech and start up companies. I've had the pleasure of working on biologics as well as small molecules. And indeed, a lot of work done on gene therapies as well. So today's call is really going to focus on disease education and really think about endpoints as it relates to Usher syndrome, in particular. We'll be asking the key questions from our expert on things like what's vision made out of? How do we measure vision? What are the outcome measures that actually accurately measure vision in this disease and indeed other inherited retinal diseases as a whole? We want to also explore things like the role of the patient baselines on these outcome measures and indeed how the disease progresses and what's the best outcome measures, ultimately, and the analysis that we should be looking at when it comes to Usher syndrome data. Hopefully, we'll get a chance to have a Q&A session at the end as well, where we'll have Daniel de Boer, our CEO, joining us again as well as Smital Shah, our CFO and Chief Business Officer as well. So let me just introduce you to our special guests an expert, Dr. Paul Yang. Dr. Yang is an expert IID specialist who works at the Casey Eye Institute in Portland, Oregon. His background is that he got adopted from the Dartmouth Medical School. He completed his residency and fellowship in ophthalmology at the Moran Eye Center in Salt Lake City, he then pursued a fellowship in ophthalmic genetics and inherent retinal disease areas at the Casey Eye Institute itself, where he's currently an assistant professor of ophthalmology in ophthalmic genetics and also immunology. He has been an investigator in multiple gene therapy and neuroprotection trials in the past. And indeed, he's our current investigator on 2 of our current programs as a disclaimer, including the Stellar trial, which we'll be talking about briefly today. But of course, at this stage, we'll only be discussing only the publicly available data. So it's with a great pleasure to welcome you, Paul Yang. Thank you very much for joining us today.

Great. Thanks for having me.

So Dr. Yang, let's kick off the discussion. Give us a background on what is Usher syndrome? And how is it different from non-syndromic RP or retinitis pigmentosa?

Sure. So Usher's syndrome is defined by retinitis pigmentosa plus sensorineural hearing loss. And mutations in the USH2A gene leads to dysfunctional cochlear hair cells and photoreceptor degeneration. In other words, it causes Usher syndrome type 2 or retinitis pigmentosa by itself without hearing loss, also referred to as non-syndromic retinitis pigmentosa or RP. Prevalence, the Usher syndrome occurs about 1 in 30,000 in the population and RP is about 1 in 4,000. We know that mutations in USH2A account for about 50% to 75% of Usher type 2 and 12% to 25% of RP. So there are roughly tens of thousands of patients in the western world.

And we have the figure of 16,000 that's been published in the literature. Does that sound about right for you in the western world, at least?

I think so. And it very well may be an underestimate because genetic testing is only becoming more prevalent and available.

So Dr. Yang, how many patients with Usher syndrome or indeed, non-syndromic RP, would you see in a typical calendar week, month or year?

I see patients with RP or Usher due to USH2A mutations nearly every week. So it is quite common. In my practice, I probably have 50-plus patients just by myself, including my partners, we probably have over 100.

So of course, that also is because the Casey Eye Institute is quite a significant hub center in seeing a lot of inherited retinal disease patients. Typically, if you're a general ophthalmologist in the middle of nowhere, how many patients would you see?

If you're in the community, you may see -- you may come across maybe 1 or 2 a year. That's assuming that you know what the genotype is. Most of the patients I see are coming in either as young adults or children. The adults usually do come from specialty retina referrals. Children usually come from pediatric ophthalmology via optometrists or they actually are starting to come in from the ear, nose, throat specialist due to congenital hearing loss. So Usher type 2, these children, they're born with profound hearing loss. And the ear, nose, throat specialists are now using genetic test panels for hearing loss to test for these syndromic patients. So we're actually getting referrals for these children earlier and earlier now.

And are you seeing many referrals from genetic counselors at all, with the advent of genetic testing going on much more?

We're starting to see that. The genetic counselors do have a network. And we have a genetic counselor that's tapped into that. So we do get referrals that way as well.

The disease progress. We can see a graph here. Hopefully, the audience can see that as well of a couple of important outcome measures that we'll talk about in much more detail in a few moments. But how does the disease present itself to you? And how do these patients typically progress over a period of time?

Okay. So as I said, in Usher syndrome, the hearing loss occurs at birth. Whereas the retinal component, the RP, that's usually diagnosed in adolescents or young adulthood. It's due to a slow degeneration of the retina, starting with the rod photoreceptors and then eventually the cone photoreceptors too. Because of the way the disease progresses, the initial symptoms are night vision loss and peripheral vision loss, which then progresses to tunnel vision and legal blindness. And visual acuity, though, is usually typically pretty good at initial presentation. So this is a good schematic illustrating the general course of the disease state. So if you look at the first curve, visual field, it dies down gradually, but consistently in the early to moderate disease phase. And the patients here, they continue losing their peripheral vision until finally, they have very severe tunnel vision in advanced disease, whereas visual acuity is relatively stable in the early to moderate disease state. And then only as the approach advance disease, does it begin to decline.

And I guess how do you diagnose a condition like this?

So we -- of course, when we see these patients, we put together the entire picture, the clinical presentation, the eye exam. We also use diagnostics that include imaging, ERG, and we make a diagnosis of either Usher type 2 or retinitis pigmentosa non-syndromic. But that's not all. So after that, you have to do genetic testing to figure out among which of the genes that cause each of those conditions exists in that specific patient. So you have to do genetic testing to figure out that the patient has USH2A associated disease.

And I guess once you've diagnosed patients with this condition, is there anything that you can do for them at this stage?

Unfortunately, there is no treatment or cure for RP or Usher syndrome due to mutations in USH2A. Any slowing or halting of the disease progression would be a big win for these patients.

So just to be clear on that, Dr. Yang, people may have heard about certain gene therapies that may be approved for other inherited retinal diseases and for blindness. Can those not be used here for these patients?

No. Because gene therapy is very specific. We all know there's been one approved gene therapy for the eye due to mutations in RPE65. And so that is very specific. And if you don't have mutations in RPE65, it won't work.

Right. So then this has got no treatments available at the moment. And of course, this is why there are a lot of investigational treatments potentially going out there at this stage, right?

Exactly. There are hundreds of known genes that can cause these inherited retinal degenerations. And so for each given gene, therapy must be developed.

So Dr. Yang you speak with these patients day in, day out. You mentioned earlier that stabilization would be a win. Can you expand on that a little bit? Why is it that we need to see an improvement? Why is it just -- that even stabilization is a win for these patients?

Well, these patients, they have -- they had the disease their whole lives. They adapted to it. And their big fear is the continual loss and especially the eventual loss of visual acuity in advanced disease. But most of these patients, while they still have good visual acuity, they're still able to get on with their lives with their careers and do what they need to do. So when you talk to these patients, right? They -- if we can just stop the rate of either visual field or visual acuity decline, that would be a big win for them. That way they can stay in their careers, continue about their lives, without having to claim disability or change jobs. So for them, that's really the first thing is if they can just keep what they have, that would be a big win.

Right, right. Exactly. Well, we'll come back to that theme in just a second. So let me just switch gears here a little bit and focus more on some of the endpoints that we're going to discuss. I guess before I dive into some of these endpoints here and before we dive into this, can you maybe explain to us how patients -- how people see? What's vision comprised of? Is it a simple thing that like just gets into the eye, and that's it? Or can you maybe elaborate on that a little bit?

Well, sure. So for any of these tests that require patient participation, such as visual acuity and visual field. Good performance relies on an intact visual pathway, right? So that's -- we're talking about the entire pathway from the front of the eye to the macula, the optic nerve and the visual part of the brain as well as the patient's consciousness, right? So that's the entire pathway that we're assessing when we do visual acuity and visual field. And that's why we call it a cycle physical assessment because it relies, not only on good anatomy, but also a good performance by the patient.

And then as we think about endpoints here, maybe you can take these one at a time and just describe to us what's visual acuity as an endpoint? And I'm referring to, broadly speaking, across inherited retinal diseases. We will focus a little bit more about these endpoints in Ushers in the next section here. But just at a broader level, can you describe to us how you measure visual acuity, what it is and the historic presence of such an endpoint measure in ophthalmology trials?

Sure. So visual acuity or BCVA, best corrected visual acuity, is the most well understood. It's a universal standard of vision assessment. The patient is directed to read letters on a standard chart in a controlled environmental setting. In the research world, instead of using Snellen units such as 20/20 being perfect vision versus 20/200 being legally blind. We use logMAR. logMAR is the different unit that we use in research. It converts the typical Snellen units to a continuous numerical range that makes it easier for research purposes. So for example, a logMAR of 0 equals 20/20, perfect vision. A logMAR of 1.0 equals 20/200, which is legally blind. And then each incremental change between 0 and 1 is roughly 1 line on the eye chart.

And so can you elaborate on what the noise of the assay is here and what you would deem to be clinically significant change?

Yes. So the noise level based on various studies have been published is approximately 5 letters or 1 line on the chart. This is an FDA registrable endpoint, and a 3-line gain is considered significant by the FDA.

And I might also add that as the European representative here that in Europe, 2-line gains tend to be also favorably accepted. I think European agencies. So I just want to point out a plug for the European agencies here as well. Anything else to say on BCVA before we move on to the next endpoint?

Well, just -- this is kind of a segue. I think it's important to note that good BCVA requires only a tiny amount of intact central macular anatomy. And that may not always be observable on perimetry, which is the next topic. And so BCVA and perimetry are not exactly interchangeable, and one does not necessarily predict the other.

And so let's take the next endpoint on our list, which is the perimetry. So can you talk to us a little bit more about perimetry as a whole?

Of course. Perimetry is an assessment of the central and the peripheral areas of visual field. And it's done by flashing small dots of light in a standardized grid pattern also in a controlled environmental setting. As I said, it's a psychophysical assessment. So the patient has to be a good test taker as well, not just having an intact visual pathway. Perimetry has been established for other conditions like glaucoma. And it's been validated with an established noise level and thus, the requirement of 7 dB change in a minimum of 5 points. And so that's the FDA registrable endpoint. However, there isn't really any precedents yet for prior approval as an endpoint for RP. Static perimetry, as looking at the 3 different methods here. Static perimetry, as we talk about it in this study is an assessment of the entire visual field of the patient, right? It's the entire field. Whereas microperimetry is really the central -- the most central area, approximately the area of the macula. So the microchemistry does not assess the peripheral field. And then finally, dark adapted chromatic perimetry is still rather experimental exploratory type of microperimetry, but it has the advantage of using dark adaptation at different colors to try and isolate rod photoreceptors.

So let's take each one of these in a little bit more detail. If we move to static perimetry, and you mentioned something about the 7 decibel change at 5 locations. But could you elaborate more on static perimetry, your experience with using static perimetry historically in these kind of patients. And indeed, what kind of possibility that could be for that registrable endpoint to become a positive value, just like the BCVA has done with the 3-line gains in the future.

So it is a good endpoint, I think, that's -- can be potentially used to demonstrate stabilization as if you recall from the previous slide, the schematic demonstrating that in early to moderate disease, there is a consistent decline in the visual field. And so that can be followed using static perimetry. And so an endpoint that can show you a consistent decline in the natural history of the disease. Is the kind of endpoint that you would want in order to demonstrate that a given interventional treatment might stabilize the disease.

So Dr. Yang, can I maybe ask you, why do you think the FDA is keen on this 5-point analysis? Typically, you'd expect a mean analysis to be the one to be overriding this. Is it because in many of these patients, you have so many non-seeing points, and therefore, the mean is not going to be that helpful and not change much over a bit of time.

Yes, that's true. Depending on the course of the disease state in the patient -- in a given patient, there can be large areas of the visual field that are already dysfunctional. And those areas basically have no data. The patient just doesn't respond. So it doesn't really make sense to average those areas that have no data with the areas that do. So when looking for a change, looking for a relative change in those specific -- in specific locations can be more meaningful. The problem with the areas with no data at all, that's basically a floor effect, right? So you don't -- you may not know whether or not any changes exceed the threshold for which you can detect a visual field.

But if I was to maybe move you on at this stage to microperimetry. And so maybe you can just speak to a little bit about microperimetry and what value that could bring here, given that, of course, a lot of these patients may be actually a lot earlier in the disease process. And whether this could still be helpful across the board or not?

Yes. So as I said, microperimetry is focused only on the macular sensitivity or the patient's central vision. But there's no information on the peripheral visual field. It's suited to studies where in the treatment is focused in the macular area, such as subretinal injections that are typically done for gene therapy. As far as for demonstrating stabilization or improvement, it is suited to studies that are in more advanced RP where macular sensitivity is beginning to decline. And/or the macular sensitivity is already sufficiently reduced and Snellen effect is not a problem. Because in earlier phase disease, microperimetry as a measure of macular sensitivity can still be quite good. Yes.

And what sort of noise levels can we expect to see typically with microperimetry readings? And how does that also compare with best created visual acuity for very advanced patients?

I'm sorry, you're going to have repeat that one more time. I have a Sabator on my side here.

Well, luckily, we're getting 2 for the price of 1 here. So we're going to take advantage of that. But I was just going to say that microperimetry is, of course, useful for, like I say, the very advanced stages of the disease, and that's why gene therapy tends to look at microperimetry. But what sort of noise levels can you expect typically with microperimetry and how does that compare with maybe the BCVA responses that you might see?

Okay. So I think that's a good question. I think, first of all, I'll kind of repeat as well that BCVA and microperimetry are not necessarily comparable. Sometimes the grid that's used for microperimetry doesn't necessarily have a data point right in the fovea, the foveola, which is the most central area of the macula. And that's the part that the patient uses for recording BCVA. The noise level is different. And as we mentioned, for BCVA, it's about 1 line, whereas per perimetry, and that includes microperimetry, there's a minimum change required 7 dB in 5 locations that's required to be considered meaningful. So they are very different tests. BCVA, the patient, as I said, it's being directed to read the letters on the chart. For microperimetry, it's a much lengthier test. It's about 20, 30 minutes. And there are multiple points where the patient has to trigger a button when they see a light or don't see it like. And so with all those multiple points and also considering the patients on disease state, and how easy it is for them to keep their eyes still and see -- have good enough vision to be able to recognize those small dots of light. All of that can add up to increased noise levels.

Well, let's look forward into DAC perimetry, the dark-adapted chromatic perimetry. Can you tell us more about this particular endpoint?

Sure. As I said, it's still an exploratory endpoint, it's not been used as a primary endpoint in registration studies before, but one published study on USH2A suggest that it might be beneficial in early to moderate disease for tracking the degeneration of rod photoreceptors. As I said in the beginning, rod photoreceptors they degenerate primarily in the early to moderate phase of the disease. And so if you're able to utilize dark-adapted chromatic perimetry. And this gets verified and validated in additional studies. You should be able to follow the degeneration of rod photoreceptors earlier on in the disease, which will give you the ability to detect stabilization earlier. So there's a good potential there for the utility of DAC perimetry, but it's still in experimental and exploratory stage.

Right. Right. So we've talked about the BCVA. We've talked about the perimeter set of endpoints. The last one would be talking about the structural or anatomical endpoints. Can you comment on the role of OCT and anything that's very important here for us to look for as an input?

Sure. So one of the most specific imaging tools that we have in assessing the macula as it pertains to RP is optical coherence tomography or OCT. So in OCT, we get pictures of the macula in cross-section as shown here. It allows for the quantification of retinal structure, specifically the photoreceptor layer. And there's a specific structure within the photoreceptor layer that we call it an easy layer. The easy layer is roughly correlated with the area of good vision that the patient has. And so when the macula degenerates in RP, you can see that the residual eye line of good anatomy in the macula, it also recedes. So there's a correlation there, and you can use OCT and the easy layer to follow degeneration in RP.

Very helpful. If we then take a step back a little bit now and think about these endpoints in the context of Usher syndrome, and the kind of patients that we could see. You showed us a nice graph there of the early to moderate patients having relatively stable digital acuities, central visual acuity and yet having a progressive visual field loss and then the advanced stage of the patients where actually, they have very little visual field left now. And then subsequently now, the BCVA is deteriorating. If we think about the BCVA in the context of Usher syndrome, what kind of patients would be best served at looking at BCVA? Would they be the early to mid-stage patients or the advanced stage visions?

BCVA is best used as an endpoint in advanced disease for demonstrating stabilization. Because that's really when visual acuity is expected to be declining. In addition, the baseline BCVA is still quite good and rather high. In early to moderate RP. So ceiling effect is an issue even if you're using BCVA to look for improvements.

That's very helpful to put this in context now. So -- and then as we think about static perimetry, where do you think static perimetry could be of use in the progression of Usher syndrome from early to mid to late stage. Where is the best place for us to think about that as an endpoint?

Great. Yes. So as opposed to BCVA, static perimetry is a good endpoint for demonstrating stabilization in early to moderate disease because that's when the greatest changes in the visual field is occurring. So deficits are seen on visual field in nearly all patients with RP. So ceiling effect is also not an issue there, and it can be used to also look for any improvements.

So that's very helpful as we think about now perimetry and where that is best used. I guess that as we think about DAC perimetry or structural imaging, in the grand scheme of things, where do you think that could fit in?

Well, I think DAC perimetry, as I said, that's also better used in early to moderate disease. The one study that I referenced that used DAC perimetry to look at USH2A show that if you could isolate the rod photoreceptors, you might be able to see a change earlier than, say, static perimetry. Static perimetry is mainly a measure of cone photoreceptors. And so the dynamic in the rod and cone rate of degeneration is different in the RP, right? Rods declined faster than cone. So there is a potential utility there that, that could detect to decline faster because it looks at rods. But again, that's kind of an exploratory stage structure. So I said that we can use it to monitor degeneration, but the level of degeneration for which OCT is going to be useful, it has to be just right. So it can't be -- the disease state cannot be too mild or too severe. So the disease stage is...

And why is that? Sorry? Why is that?

Yes. So the disease state is too mild, right? Remember now, the OCT is an image of the macular area. If the disease state is too mild, the edge of the degeneration zone is beyond the limits of the OCT image. So if you can't detect the edge of the degeneration zone, you can't follow degeneration. If the disease is too advanced, the residual photoreceptor layer becomes quite difficult to visualize and grade.

Okay. That makes sense. Now we also have a couple of other endpoints here that I want to just ask you to comment on. One is navigation. The other one we often hear about is electrophysiology. Can you give us your perspective on the relative roles of those and the utility of those in the future?

Sure. So navigation, also known as a mobility test, it measures a patient's ability to navigate a standardized set of conditions, also in a controlled environment with different light levels. It was key to FDA approval of Luxturna. So it is a good quality of life measure and is FDA registrable endpoint. However, it is a time-consuming test to administer the test takes up a lot of physical space. It also takes time to validate and ensure that there are no ceiling and floor effects and that there is a good dynamic range for the desired patient population and disease state. So for example, the mobility test used for Luxturna, right, for mutations in RPE65 may not be directly translatable to other disease types like USH2A. And by the way, as you know, ProQR has a separate validation study that is ongoing.

Yes. And electrophysiology, do you want to just touch on that just briefly before we move to the next part?

Yes. So ERG, also known as electroretinograms. And specifically here, we're talking about full field ERGs. It's a global measure of rod and cone function from each eye, we use it to diagnose disease. But there needs to be extensive training and expertise in order to administer the test and to interpret the results. It's also somewhat limited by noise, published inter test variability is anywhere from 25% to 40%. So that can certainly limit the ability to detect decline or benefit. In addition, ERG and RP, moderate to advance disease is usually flat or unrecordable. So you're dealing with the problem of a floor effect.

So then the ERG in many of these Usher patients is probably not likely to be that useful at this stage, right?

Exactly.

Okay. So let's switch gears a little bit here. Now we get a lot of questions about the 2 different programs we have ongoing. Sepofarsen program and then also the Usher's program. Help us contextualize this a little bit of, Yang, because I want you to be able to give us an idea of the 2 different diseases, their progression rates, why is it that we choose certain endpoints in certain diseases? What makes sense? And then what's really the ultimate goal? I wonder whether you can just walk us through the slides?

Sure. Yes. So patient baseline and rate of disease progression are really 2 important concepts to understand when it comes to endpoint selection. So I'll reiterate that RP is a very slowly progressive disease. So different endpoints are going to be more useful during different stages of the disease. When looking for benefit to an experimental treatment, a good endpoint must, number one, reveal the natural state of degeneration in a reasonable amount of time. And #2 must not be limited by a ceiling or floor effect, okay? And so you have to choose what the best endpoint is going to be for a given stage of the disease. And, of course, for different disease types. And so for advanced disease and RP, we'll say it again. BCVA, right, it's probably going to be a potentially good endpoint once it starts to decline. Because in early disease patients, BCVA is just -- it's too good, and it's relatively stable. For example, the mean BCVA and Stellar a 0.4 logMAR, right? And that's compared to LCA10, where the BCVA is really bad. It's hand -- worse than hand motions. The ability to demonstrate stabilization in a given treated eye, really depends on the patient's natural history for BCVA to decline. So the ability to demonstrate large improvements depends on the baseline BCVA to be sufficiently low. So regardless of whether you're looking for stabilization or improvement, BCVA has to already be on the decline, right, or already on the lower side. So that's for advance disease. For moderate disease, in RP, static perimetry can be a good endpoint because the patient's peripheral vision is typically quite abnormal to begin with at baseline, and it declines at a steady rate during this time. Thus the static perimetry has the potential to demonstrate either stabilization or improvement in the moderate disease state. Let's see, FST. So we have FST here for LCA10. So FST stands for a full field stimulus threshold. It's also a psychophysical test, right? So the patient has to hit a trigger much like visual field to tell us if they see the light or not. It's basically a very low resolution perimetry with 1 single global flash of light instead of a grid of small dots. And so you don't really get a sense or have any knowledge of the geography of the retinal sensitivity. Either way, the baseline state for FST must be advanced enough for it to be useful. And there's a question of whether or not that's going to be useful in RP, whereas in LCA10, which is a much more severe disease type, it's probably more useful there.

This is incredibly helpful for you to map this out for us. I guess as I'm thinking about the Usher syndrome patients are now focusing more on the Stellar trial itself, we know that Usher syndrome patients can be either early to mid-stage in the progression or even in the advanced stages as well. Some of them may be homozygous or heterozygous, some of them may be suffering from Usher syndrome itself versus non-syndromic RP. Now some people have commented on the fact that with all of these different variables that could be there, looking at a within patient analysis of some of the data could be quite helpful of looking at the treatment eye versus the fellow eye change from baseline. Do you think that could be helpful?

Yes, that's definitely a good point. So the patient's baseline can be very different from one another, right? Within a cohort of patients. And it depends on where they are in their disease course, as we've been discussing. But in addition to that, there's a variable age of disease onset. Thus, even if you age match the cohorts, there can be variable disease at baseline. So when you take that into account, the best comparator for the treated eye is the patient's own untreated eye because the disease baseline is relatively symmetric between the 2 eyes. And then I'll make another point here about rate of disease progression. So there is variability, too, in the rate of disease progression. Not every patient progresses at the exactly same rate. And this is especially true between Usher and non-syndromic RP patients. When Usher patients can have earlier onset of visual disability by 1 to 2 decades compared to non-syndromic RP. So that's another reason why the patients on untreated eye may be the best comparator for the treated eye.

Okay. That's very helpful, Dr. Yang. I'm going to switch gears here a little bit and talk a little bit about the Stellar trial itself. So if we move to the Stellar trial, let me just maybe describe that to some of the folks who may not be so familiar. We're looking at QR-421a as the investigational drug which is aimed at producing functional ushering. And it's being used as part of this Phase I/II first-in-human trial in Usher and non-syndromic RP. So far, we've looked at 3 different dosages across 4 different cohorts, 50 micrograms, 100 micrograms and 200 micrograms. We did perform an interim analysis last year in March, which looked at the patients after the first 2 cohorts. And now we have an opportunity at looking at the second and final interim analysis when we've had at least 3 months of data after the last cohort, the cohort 3 patient has been enrolled. As you know, Dr. Yang, because you're an investigator here in this trial, this is a randomized, single ascending dose trial with a sham control arm that's there, typically looking at a variety of different end points that are noted here. Really, the objective of this particular interim analysis, which is the second interim analysis, is slightly different from the first one. Of course, yes, we want to confirm safety and tolerability in the patient population with QR being treated with QR-421a. We also want to confirm biological activity, ultimately. And confirm whatever we saw at the last interim analysis is still the case here as well. But importantly, in this second interim analysis, we want to be able to really inform us of the next trial design. And the next trial design in terms of the patient population that's there. So ideally looking at any subtypes that are at the sweet spot of improvements with this particular drug. We want to be able to look at the end points, that we've just discussed also, which is the right endpoint to use, in which particular population of patients, at which stage of the disease process itself. And ultimately, we want to look at a dosing arm and frequency of dosing that makes sense. You'll remember that as part of this Phase I/II trial, it's a single administration of the drug only, and therefore, we will not strive multiple dosing yet. And so one of the aims of this interim analysis is to inform us of the exact dose that we want to take forward into the next stage of the trials and then also the dosing frequency because we will get an idea, especially from the pharmacodynamic effect, of when the effect of that first dose wins away and that the patients will be ready for a subsequent dosing to occur. So really, those are the key objectives of this interim analysis, the second interim analysis business to come at this stage. So Dr. Yang. Thank you very much for all of your help so far. I'd like to just summarize what we've talked about maybe in a summary slide. And therefore, if we can move to that last summary slide, please, which is really summarizing. And if we can move to the next slide again, please. So really, I think what I've heard from you so far today, correct me if I'm wrong, is that when we're thinking about the Usher syndrome and the trials themselves and the data, if we're looking at early-to-moderate disease patients, sounds like static perimetry is the way to go to be able to interpret that. When we're looking at the advanced stage of the disease for those patients that are -- that further advance stages, then best corrected visual acuity seems to be the most well-known entity there. Microperimetry could be used, but also, it sounds like the BCVA is the preferred way forward. And at least it's well-established as the primary endpoint from the FDA point of view. And we know a lot more about the BCVA in terms of the noise levels. And what clinical significance values could be associated with it. It sounds like when we think about retinal sensitivity changes, the static perimetry could be very helpful here. And we have also the FDA threshold for approval, which is the 7 decibel change across 5 retinal points. Anatomic changes might be useful if they come in within that sweet spot that you described Dr. Yang, which is that they're not too advanced. So that they're measurable, and yet they don't -- they're not too early so that they go beyond the point of acquisition for an OCT scan. And so those are the key things I wanted to highlight here. Of course, the important thing we've also discussed is that from a patient point of view, stabilization of vision, whatever it may take a form of such as BCVA and other problems, is really important to them. That's really important to highlight and the contrast that we have with the LCA world. And then we touched a little bit on the nuance of maybe looking at the treated eye minus the contralateral eye as ways in which we could maybe control for some of the variables that could be here that could confound the outcome measures. So that's certainly an area that we'll look at and explore as part of this interim analysis. Do you want to add anything else on top of that, Dr. Yang, before we move on to the Q&A session?

That's a quick summary. I don't think I have anything more to add. Thank you.

Well, thank you very much. And just stay with us. And especially, if you have your colleague there with you as well, your young colleague, we'll be wanting to ask more questions of him later on. So I may just turn it over to Sarah at this stage to see if there's been any questions come through from the audience so far.

[Operator Instructions] The first question comes from Emma Nealon at Cantor Fitzgerald.

So how do you think about differences in understanding kind of risk-benefit tolerance in Usher versus LCA10, given different rates of progression and prevalence? And I guess what would you view as an acceptable safety profile in Phase I/II to move forward here?

Yes. Right. Dr. Yang, I don't know whether you want to take this question about what the risk threshold would be, what an acceptable profile for benefit risk could be for a particular patient gain a treatment like QR-421?

That's a great question. As we alluded to earlier, if we look at, say, BCVA, patients with LCA10 already have very poor BCVA to begin with compared to disease associated with USH2A. Now those patients have relatively good BCVA for quite a long time before it declines in advanced disease. So this is inherent in the design of the studies as well as when we think about it is that patients with core vision at baseline, they have less to lose. I mean, granted, these are all early phase studies, and we are interested in safety and -- but if you have one group of patients with low visual acuity and another group with better visual acuity, there is a difference in the way we think about -- it's my lifeline, I don't think this answers to that question. So it does influence the way we design and think about these studies. But we still have the patient's interest. And at the core of what we're trying to do here. And so I would say, on a practical basis, it doesn't change the way we design the studies to ensure that it's safe and that we are looking for safety as the primary endpoint in these early phase studies?

Yes, that's very helpful, Dr. Yang. And I guess, also just to reiterate the fact that this is a blinding disease. And therefore, there was no treatment out there. These patients are literally going blind every day. And therefore, it's important to balance off the benefit risk profile that's there for any drug. Most drugs will have risks associated with them. But it's that careful balance in order to really serve the unmet medical need here.

Great. And then maybe just 1 follow-up. I know you mentioned Luxturna, but as you think about the gene therapy or editing approach to inherited retinal diseases in general and kind of the potential of that down the line if a more specific one were developed, how do you think about an RNA approach for just gene therapy in LCA10 and Usher specifically?

So Aniz, I can take that one. So this question is about RNA therapy versus gene therapy and specifically for USH2A as well. So RNA therapy is a very specific treatment that addresses a mutation or mutations within a region on the gene. Whereas gene therapy augmentation is nonspecific. It delivers a normal copy of the gene. And so it should benefit regardless of the location of the mutations. So that's one difference. However, here's the drawback gene therapy is limited currently by the packing limitations of the vector. And the most widely used vector, AAV, it has a limit. And so the ability to treat mutations in large genes is limited. So for example, USH2A, that gene is too large to pack conventionally -- in a conventional manner into the AAV vector. And so that's where RNA therapy has an advantage, right? We are not delivering a copy of the gene, right? We are actually using RNA therapy to address, right, these specific mutations within the genome. And so it's nonspecific. RNA therapy is not limited by the specificity of the size of the gene. So that's an advantage for RNA therapy. A few other differences, RNA therapy has a half-life. So it requires redosing, whereas gene therapy is typically expected to be one and done. The other big difference is in the delivery of the treatment. So RNA therapy is delivered via a rather routine intravitreal injection that's done in the office. And when treatments are delivered into the vitreous space, you treat the entire retina. So there's an advantage there that you're treating all of the retina. Whereas in gene therapy, it's delivered via subretinal injection during a relatively big surgery in the operating room. And for most clinical trials, you're treating mainly the macular area. So you're not treating entire retina.

It's a great summary, Dr. Yang. Any other questions, Sarah?

The next question comes from Jon Wolleben at JMP Securities.

I guess one for ProQR and one for Dr. Yang. I know you put out some information on the baseline demographics and Stellar and the breakdown between early and advanced patients. So I'm wondering if you could tell us how you categorize early and advanced. And then given the timing and duration of this interim analysis, I'm wondering what Dr. Yang, if you think this is enough time to tease out stabilization in the sham traded patients? Or what are your expectations on the duration of the study?

Thanks, Jon. Great questions. And Dr. Yang, let me take that first question, and then I'll let you take the second part. So yes, in terms of thinking about early to mid versus late categories, these are clinical ways of assessing the patients. And I'm sure Dr. Yang will have also an opinion on this. Typically, what we've done is looked at the BCVA at baseline. And if that starts to deteriorate significantly, we've classed that as an advanced patient. And if it doesn't, then typically, those patients could be classified as early to mid, depending on what piece they're at. It's a little bit more complex than that because we need to look at across the board at other baseline characteristics that are there as well. But broadly speaking, that's a good rule of thumb. You're looking at that. So Dr. Yang, I don't know whether you want to comment on that itself and then a subsequent part of the question.

Sure. Yes. The other thing that can be looked at is the visual field. Now there's always exceptions. But as I said, typically, by the time BCVA begins to decline, the patient has end-stage tunnel vision. So one thing that you can look at for advanced patients is basically the complete loss of all of the peripheral field. And then all you have left is basically a small central field, right? For a patient, it's like looking through a keyhole. So that's typically considered more advanced disease state. I think your other question as to what is the minimum follow-up time or moderate -- in order for us to...

As a stabilization of vision.

Right, exactly. So there has been some minimal studies done on that. And I think the minimum amount of time would be at least 1 year. Patients who are in advanced disease for RP, they do begin to decline the BCVA. And so that would occur on a yearly basis. Once they reach that stage. So once they're in that kind of advanced to end-stage phase of the disease, they can be losing 1 line of vision a year. So you can actually identify those patients. 1 year should be enough for you to start beginning to see a deviation between the 2 eyes.

And of course, just taking that math forward, to see clinical significance, you may even need longer trials. 18 months or 24 months trials potentially. So just to put that out there. Jon, does that answer your question? And do you have any follow-up on that? Do we have time for 1 more question, do you think, Sarah?

There are no more questions in the verbal queue. I'll turn the call over to Sarah Kiley to go over any questions that may have come in over the web.

Great. Thanks, Sarah. We did get a few questions over e-mail, and I think we have time for 1 more. So quickly, I'll ask. Can you contrast the use of IVT treatment versus subretinal gene therapy, in particular, for peripheral diseases. Where do you think some of the opportunities and challenges are for Usher syndrome, in particular with these 2 different pictures?

So Dr. Yang, you may have touched on this already, but do you want to field that question?

Yes. So I'll kind of say a few things again with regard to RNA versus DNA gene therapy. So RNA therapy right, as we're talking about in this study is injected intravitreally. So that is one of the great advantages, right, is that you treat not just the macula, but the entire retina, not includes the peripheral and mid-peripheral retina. So that's really advantageous when you're looking at, right, when you're looking to stabilize early to moderate phase disease, right? And that goes right along with what I was saying earlier about static perimetry being a good endpoint for early to moderate disease. Because you have the chance there to hopefully stabilize, right, the patient's peripheral vision. For gene therapy, as I said, that's a -- you have to do that in the operating room required to the tractotomy. It's a relatively big surgery and you do a subretinal injection in the area that you want to treat. So you have to pick and choose. And the retina can only take so many injections, subretinal injections. And so as I said before, for the most part, most gene therapy clinical trials are doing several injections in the macular area because that's kind of where the most valuable, right, vision is if you have to choose, right, you would choose the macula in order to try and stop the disease progression and allow the patient to maintain their macular function. So there really aren't many gene therapy clinical trials out there that are treating the peripheral areas because of that. And the other challenge in treating peripheral areas in RP is that the pattern of loss in the peripheral retina can be irregular. And so when you're trying to choose which areas to treat, sometimes you may not have one really good area viable tissue. You may have these crescent areas of kind of whispy viable retina to choose from. And that sometimes not as easy of a choice to make compared to most patients having a good macular area that you can -- that is obvious and you can treat.

That's great. Well, look, thank you very much, Dr. Yang. It's been a pleasure to have you there. And also with your associate in mind as well, we'll have to schedule a second follow-up discussion with your junior associate there. But with that, I think we're going to turn it over to Daniel de Boer for some final and concluding remarks.

Yes. Thank you, Aniz, and thank you so much, Dr. Yang, for walking us through the endpoints in usher and all the important insights that you were able to provide. With that, I want to close out the call. Thanks, everyone, for participating on today's call. A replay of today will be available on our website after the closing of this call. Thanks, everyone. Have a great day.

Thanks.