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

Good afternoon, and welcome to the ProQR Expert Perspectives Call on Usher Syndrome. [Operator Instructions] Today's call is being recorded, and a replay will be made available on the ProQR website at the conclusion of the event. At this time, I'd like to turn the call over to your host, Dr. Aniz Girach, Chief Medical Officer at ProQR. Aniz, the floor is yours.

Thanks, Hans, and a very warm welcome to everyone who's joining us today. My name is Aniz Girach. I'm the Chief Medical Officer for ProQR. I'm an ophthalmologist by training also. And my background is that I've spent the last 25 years working in the industry, working for big companies as well as smaller companies and biotech and start-ups as well as having the pleasure of -- and the honor of having worked on a number of ophthalmic approvals in the past. I've also had the opportunity to work on biologics as well as small molecules, and then more recently with my last job, with gene therapy as well. At ProQR, we are working frantically to create transformative RNA therapies for severe genetic rare diseases. We're a small company, about 150 people. Our headquarters is based out of Leiden in Netherlands, and we have a base in Cambridge, Massachusetts as well. Although our technology, which is based from RNA and oligonucleotide therapy, has a platform that's broadly applicable across different therapeutic areas, our focus is really the inherited retinal disease space. Our pipeline consists of 3 clinical-stage assets. The first one is a pivotal trial involving sepofarsen in LCA Type 10. The second is involving QR-421 in Usher syndrome, and that's going to be the basis of our discussions here today. And the last one -- last clinical-stage pipeline is on QR-1123, involving a Phase I/Phase II trial, which is related to autosomal dominant retinitis pigmentosa. And we will touch on that later on. Today, we're hosting the first call in our Expert Perspective series, where we take a deeper dive into one or more of these diseases. And we'll be focusing on many aspects of the disease, for example, the natural history of the disease, end points, clinical diagnosis and some of the more hot topics that are related to those disease areas. Our goal is really to provide the perspective of the experts here. We have a physician expert, and we have a patient expert joining us today. And I'm delighted today that actually on today's call, we have Dr. Robert Koenekoop, who's joining us today, and we have Molly Watt also joining us remotely. Dr. Koenekoop is a professor of pediatric surgery, human genetics and ophthalmology at McGill University in Canada. He's also the Director of the Laboratory for Retinal Genetics and Therapeutics. Additionally, he is Chief of Pediatric Ophthalmology and has been involved in numerous global clinical trials for patients with inherited retinal diseases. He is truly a world expert in the field of IRDs. Dr. Koenekoop is also a current investigator in our QR-421 trial, the Stellar trial. Molly Watt is a 25-year-old tech, web, accessibility and usability consultant. She suffers from Usher syndrome type 2a, and we'll hear more about that later. She is also a motivational speaker, a children's author, an illustrator and a blogger, an international ambassador and advocate for those living with key challenges. She works to raise awareness of Usher syndrome, deafness and blindness and accessibility and inclusion areas. And so we're pleased to have both of you join us here today. We will have some time, as Hans said, to have some question-and-answer session at the end of the call, where we'll be joined by Daniel de Boer, our Chief Executive Officer for ProQR; and Smital Shah, our Chief Business and Chief Financial Officer. [Operator Instructions] On today's call, I have been informed, I need to tell you that they may be forward-looking statements. There are risks and uncertainties associated with an investment in ProQR. Please review our SEC filings, which are available on our website for more information. So let's get cracking. let's get into the discussion. So I'm going to just start with Dr. Koenekoop first. Dr. Koenekoop, do you want to tell us a little bit more about the practice that you have and the kind of patients that you see in your everyday practice?

Yes. I finished my training at Johns Hopkins and that -- for 1 year, I saw patients with inherited retinal degenerations with [indiscernible]. And it inspired me so much, and it looked so complicated and unmet -- with such a huge unmet need that I decided to open a practice at McGill, specifically for patients with inherited retinal degenerations. And I remember, in 1995, we would have a full day clinic of these patients. And my secretary sent a thousand letters to family doctors and optometrists around Quebec, and the patients started calling. And now I have seen 6,000 patients with these various terrible diseases. And my main interest in the beginning after I finished my training at Johns Hopkins was to understand the disease better because there were no genes at that time. There were no proteins, no known pathways, and therefore, no treatments. And I just wanted to get a handle on the genetics because I have a PhD in molecular biology. And so it was an incredible thing to witness 2 or 3 revolutions in a row: first, the genetic and the genomic revolution; then the imaging revolution and now a revolution in therapeutics. Because we have to remember, these are terrible diseases. There's about 2 million patients around the world with IRDs. Most of them have retinitis pigmentosa. And inexorably, these diseases lead to blindness. We'll get into that more later.

Thank you. That's very helpful introduction. So we will dive into many of those topics that you've just mentioned there, Dr. Koenekoop. If I can just kick off by asking you, of course, we're going to focus more on Usher syndrome here. What is Usher syndrome? And what types are there?

So Usher syndrome is one of the main IRDs. Usher syndrome is a disease that is syndromic with hearing loss and with vision loss due to retinitis pigmentosa. There's 3 types of Usher syndrome. The most significant one is type 1, where the hearing loss is very early in near birth and the RP commences in childhood, and there's vestibular balance problems. Then there's type 2, which is a little bit later onset but still in childhood. But the RP starts in adolescence, and there is no vestibular disorder. And type 3 is adult onset, hearing loss, progressive, and RP, progressive. And so these 3 types of Usher syndrome are -- there's about 500,000 patients with Usher syndrome like this around the world. And the most -- there's about 10 genes known, and they all work together near the -- in the photoreceptor and in the hair cell and in the vestibular system.

And so can you elaborate a little bit more, Dr. Koenekoop, on what the causes of Usher syndrome are?

So the causes of Usher syndrome are mutations in different retinal genes that have vital, vital functions in the rods and in the cones photoreceptors. Specifically, the Usher proteins or genes are expressed in a tiny area between the inner segment and the outer segment and are thought to be very crucially involved in the transport of proteins from the inner segment where they're made to the outer segment where they work.

And that same usherin protein is also evident in the cochlear apparatus in the ear as well. And is that why the link is there between the hearing loss and the vision loss that occurs?

That's exactly right.

And so how do these patients present to you as an ophthalmologist? And what age would they typically present?

Because I'm a pediatric ophthalmologist with a subspecialization in adult IRDs and children's IRDs, patients come to me a little bit earlier than to most other ophthalmologists, especially because I'm one of the few people in Canada that does this kind of work. But I would say that the most common reason that an Usher patient comes to me is because of night blindness and then followed by the progressive night blindness, profound, and also visual field, which normally is about 80 degrees in each eye, 90 degrees in each eye. So humans have about 180-degree visual field when both eyes are open. But with Usher syndrome and because of the RP, the retinitis pigmentosa and the photoreceptor death, the -- you get tunnel vision. And so very slowly, the 180 degrees becomes 160 and 100 and then becomes smaller and smaller. And at a certain point, the patients start to stumble and to fall and to have trouble mobilizing. That's another key reason that parents bring their kids in if they stumble, especially in low light situation. But another reason that I might get a referral from an Usher patient is from a colleague in ENT, ear nose and throat specialists, colleagues, collaborators, who wonder in their hearing loss patient whether they also have retinitis pigmentosa. So I do the genetic testing. I do the -- all the workup for these patients. They might not even have eye symptoms yet, and they still are referred to me.

Very helpful. So I'm going to turn over to Molly at this stage now. Molly, you suffer from Usher syndrome. Can you tell us how you -- what kind of symptoms you experienced and what your journey was to diagnosis?

Yes. Sure. So I was born severely deaf. I was considered one of the luckier ones, should we say, because I was born in '94, and it took 18 months for me to be diagnosed with a hearing loss. And this was mainly parent intuition. I wouldn't respond to noises. My parents would walk into the room to try and get my attention by saying my name, and I would just never -- and I blew lots of raspberries. And my mom said, to my doctor, "I think Molly's not hearing properly." Had a hearing test, and got my first care of hearing aids at 18 months old. There onwards, my child was a very much happy normal, if you like, childhood. I went through mainstream, had lots and lots of speech therapy. So I was able to sort of string a sentence together by the age of 6. So it was quite intense. Lots and lots of speech therapy, so very grateful that my parents went down that route. And then it was actually towards the end of primary school. So from between the age 11 and 12, when I was at -- in the classroom, I was struggling to lip read, and for a deaf child, that's quite challenging. Obviously, you rely on all the visual clues, gestures, and lip reading was something that I was heavily reliant on. And I was also struggling with headaches, and I was struggling to read the whiteboard in the classroom. And so it was actually my teacher of the deaf in the class that I had at school, who said to me, "Oh, you might need reading glasses." And 2 of my best friends had glasses at this time. So it seemed like a reasonable explanation. She said, "It might be why you're getting headaches. You might be straining your eyes. Go and get an eye check." And again, I was one of the really lucky ones, to be honest with you, because in this small town where I live in Maidenhead, I went to a normal optician, Vision Express. And my optician had been reading up on Usher syndrome, of all conditions. And he just said -- he said to my parents, "Do you know why Molly is deaf?" And they said, "No, we were just told it was a technical blip, happens sometimes." That was that. And the optician said -- and I remember, it was about 11 or 12. And he kept saying, "Do you mind if my colleague comes in and looks at your eyes?" I could hear people coming in to look at my eye.

So it's just all tickets then.

Yes. This is it. And well, I think because of the deaf side of things and my constant trips back and forth to the audiologist, so I was quite used to having quite a lot of adult attention. So I think as kind of a naive 11-, 12-year old, I kind of didn't really think much of it, but I did think there was something not quite right. But my parents described that day being really quite stressful because that I think there might be something not quite right at the back of Molly's eyes, and I think it's linked to her hearing loss. So I've got referred to appointment after appointment and received my Usher syndrome diagnosis by the age of 12. They said to me -- they said to us, Molly has Usher syndrome type 2. And what they had experienced at that time was that many people with Usher 2 don't experience a massive progression in their sight until they're in their late 20s, early 30s. I went from being partially sighted at the age of 12 to severely sight-impaired, politically correct for blind, at the age of 14, so a lot of my sight. Fast forward, I'm 25 years old now and I've had a fairly stable 5 degrees in one eye. But my deterioration happened very quickly visually. And yes, that came with a lot of challenges, as you can imagine, but yes.

Right. Right. And we'll touch on some of those challenges in just a moment. I want to turn to Dr. Koenekoop because one of the key questions that often comes to us is, what's the difference between Usher-syndrome-related retinitis pigmentosa and non-syndromic retinitis pigmentosa? Can you help understand what the difference is there?

Yes. So Let's talk about one very common gene, USH2A, which is Usher 2A gene. Mutations in that gene cause the protein to not work. And it can cause Usher syndrome type 2, which is the syndromic form. But other mutations in the same gene can cause just retinitis pigmentosa with normal hearing. So that's an example of a gene that can cause the syndrome, hearing loss and RP, or it can just cause the RP, non-syndromic.

So the visual effects of both of these conditions are exactly the same. Is that correct?

That's correct.

Okay. And that's very helpful to know. So as we think about our clinical trials and as you're enrolling patients to do with visual trials, these are ocular trials, it's not so critical to think about Usher syndrome versus non-syndromic RP in terms of how the disease and the phenotype is going to behave. Is that correct?

That's correct.

Okay. Well, that's very helpful clarification there. So I want to then move -- so we've talked a little bit about the diseases and the epidemiology of the disease. Dr. Koenekoop, what happens then with these patients? So these patients are having a reduction in their visual fields with gradual progression. How quickly does that happen? And what does that lead to? And what is it that you can do for them?

So everything in the visual system progresses. So you have narrowing of the field, you have dying of the rod photoreceptors. So you have night lines, which is also progressive. And that even though the disease starts in the rods, and the night blindness is one of the first signs, there's a second wave of cell death where the cones start to die. And when the cones start to die, you start to lose color vision and central vision. And we'll be talking about this much more later, but this is called visual acuity. So in summary, patients with Usher syndrome or RP have night blindness, which is progressive, visual field loss, which is progressive, and inexorably leads to complete blindness over about a period of 20 years. But like Molly said, it can be very, very early and very devastating. And then later in the disease, color vision and visual acuity are attacked and decreased. And roughly, the process is variable, depending on the patient, the genetic background and the strength of the mutation in the Usher genes. But it lasts about 20 years. And patients -- there is currently no treatment for these patients.

So what is it that you can do for these patients? If they come to you, Dr. Koenekoop, what do you say to these patients?

So my role is to make sure the diagnosis is correct. So I do all the visual tests. I do imaging, and we'll get into that later. I do all those tests, and I do genetic testing. So there's 250 genes that can cause IRDs, and there's about 10 different genes that can cause Usher syndrome. And so there's a lot of genes. So we have the technology now where we can test all the genes at the same time. And within 6 weeks, we can get a result. So number one is proper diagnosis and exactly -- it's not good enough to say you have a retinal degeneration or you have an IRD. That's not acceptable anymore. We have -- it's gene-specific. It's -- there's many different types of diseases. And so this is the molecular diagnosis. And then the rest of the testing is to determine the phenotype. And so we also do staging. So we diagnose the patients clinically. We diagnose the patients molecularly, and then we diagnose patients' severity. And so there are some -- so patients are seen once a year because patients can get treatable diseases like cataracts and cystoid macular edema. These are phenomenon that are caused by the retinal degeneration. That part is treatable. But the Usher and the RP itself is not treatable.

And so that's very helpful to understand. Molly, I'm going to turn to you. Of course, diagnosis of Usher syndrome is, in your words, on the table there. But what does it mean to you as a patient? How did it affect you? What are the kind of things that you can't do now that you were able to do before or the things that you miss?

Yes. I think Usher syndrome is such a complex condition and affects so many sort of parts of your life. And it does really depend from person to person how it affects you as a person. For me, because I got diagnosed, I was very -- 11, 12. I was hormonal. I was changing schools. I desperately wanted to just fit in. I just wanted to be like my friends. And the one thing I really struggled in early on -- because I've been deaf my whole life and gotten on very well wearing hearing aids, and all my friends were very good and patient. But it's where my sight deteriorated so quickly, I was adamant that my hearing had worsened. And I remember saying to my mom and dad, "Oh, I need a new hearing aid because I can't hear, I can't hear." And went to the audiologist, and they were like, "No. It's the same." And that was when I actually realized that my sight had gotten so much worse. I was obviously relying on my vision that much. As soon as it got worse, I felt deafer. And so for me, because I had gotten so used to being that deaf child and then losing that bit of vision that I so heavily relied on and so quickly, as a teenager, that was really, really hard to deal with and sort of overcome. And I was going through all these transitions with education and things. During my education, I was very much a guinea pig. No one really understood Usher syndrome. There were a lot of stereotypes around what deafness and blindness is, let alone deaf/blindness together. I had a teacher of the deaf and teacher of the blind, and they didn't know about the other. So I was always educating everyone. And I didn't really properly fathom what was going on to myself properly either. So it was really, really, really hard. I would say things like, having friends around me really helped, but I also struggled with kind of those points in life where my friends were excited to learn to drive. And obviously, at 16, I couldn't do that. So I was blind and just sitting back and watching my friends all do what they could do and I couldn't. So definitely, emotionally, I really struggled with a lot of mental health anxieties, depression. I really struggled at my school getting the right support, really trying to understand what I needed and asking for that help. So yes, I think it's been a long and tough journey. And really, I wouldn't be here if it wasn't for the support of my family and friends, and not only the support but them being so proactive and wanting to do something about it rather than us just sitting at home and just worrying. So yes.

Well, you're a very strong character, and we do take our hats off to you. I think it takes some guts and some perseverance to come through all of this. So thank you for giving all of us hope as well to carry on. Now you mentioned that you were genetically tested. That's very important. And I want to turn to Dr. Koenekoop at this stage. I think Molly was quite lucky to have been genetically tested so quickly and rapidly at a relatively young age, but that's not always the case worldwide. Is that right? And how accessible is genetic testing where you live and in other areas of the world?

Is this for Molly or for me?

Dr. Koenekoop, if I can ask you to address that question about genetic testing, please?

Okay. So genetic testing, when I first started in 1995, we did genetic testing as a research tool, and we were able to get grants to do that. And a lot -- some patients benefited from that, but it wasn't official. Now in the last 5 years, what we've seen is a revolution in genetic testing, where it can be done within 6 weeks and all the genes can be tested at the same time. And about 60% or 70% of the patients that we send for genetic testing gets a positive result. The patient is -- starts by seeing someone like me or an ophthalmologist or a retina specialist or ENT specialist. And then patients are sent to genetic testing centers with genetic counseling because there's a lot of information that has to be transmitted. So the genetic testing is actually now done by genetic counselors who typically work at university centers like McGill, like in London and in the big cities. Most big cities in Europe and in North America and Canada have genetic testing centers, where patients are counseled, blood is taken, consents are signed and then the results discussed with the family. And so...

And how expensive is it to get genetic testing done?

So it's about $2,000 to do genetic testing. And I'm happy and proud to say that all the provinces of Canada now provide genetic testing and counseling for free -- for IRD, sorry.

Yes. And that's great news for Canada and I think further great news for the U.S. is that the FFB, the Foundation Fighting Blindness, have got a My Retina Tracker available for physicians, also for ophthalmologists. And ophthalmologists can request free of charge genetic testing through that website portal. So it's great news that now more and more people can get free genetic testing done through that portal as well. So thank you for that insight. So we've talked a little bit about the natural history of the disease. We've talked a little bit about the genetic diagnosis here. You mentioned, Dr. Koenekoop, that there are no treatments out there. There's no therapies out there. And the only thing you can do is palliative care for some of the complications of the disease, but you can't really treat the underlying diseases yet. And of course, there are companies like ours that are, of course, focusing on trying to do clinical trials for these kind of diseases. Now one of the challenges that we face in performing these clinical trials is which end points to use, which are the relevant end points, and of course, the regulatory overlay on top of that. Dr. Koenekoop, can you just maybe comment a little bit about what type of end points that could be out there? And how they could present themselves as what the value add, depending on the severity of the disease that could be there?

Yes. So end points are evolving also, and the technology is getting better and better, but let's go through some of the major end points. Always, we have to remember in choosing end points for clinical trials or for just regular clinics is the regulatory aspect. So for instance, visual acuity measured by ETDRS is a regulatory end point. Humphrey visual field, which measures the sensitivity and the size of the [indiscernible] retina, is accepted. And we also have other types of visual fields, kinetic visual fields, that measure the exact size of the remaining field. Normal is 180, like I said, with both eyes open, and Usher patients often have only 10 or 15 degrees of visual field leftover. Then we have a very exciting visual field called the dark-adaptive chromatic visual field, where we can map and determine the sensitivity of the rods, which is a novel innovation. We have full-field sensitivity threshold testing, FST, which can be done in -- with red color for cone function sensitivity and blue light for rod sensitivity. And so what happens in these -- in the full-field sensitivity testing is that the operator comes from very low intensity of light, and the patient clicks the button when they start to see the light. And so for instance, a normal eye would see the light much quicker than, let's say, a diseased eye from Usher disease. But these are end points that we can then follow because they've been shown to be repeatable, and they've been shown to correlate to each other. So the last one is a very exciting imaging technology because we also have to remember regulatory/nonregulatory early disease end points and mild disease end points and severe disease end points. And so we also have a mechanism now to measure live photoreceptors and measure live RPE cells. This is the layer underneath the photoreceptors. So for instance, to summarize, for early and mild disease, we would do -- we would choose end points like full-field sensitivity testing and the rod mapping and the Goldmann and Humphrey visual fields. And for late and severe end point -- severe patients, we would use the live photoreceptors called the ellipsoid zone, EZ line that is a measurement of the remaining photoreceptors or the visual acuity. Because the visual acuity in Usher and all types of RP is -- goes -- deteriorates later in the disease.

That's very helpful. And so if I was to summarize, Dr. Koenekoop, when we're looking in our clinical trials at the early- to mid-stage patients, we're typically performing perimetry, that's to say static perimetry and also the dark-adapted chromatic perimetry, both of those are regulatory approval end points from an FDA point of view. And we also, of course, do FST as well. And that's the group of end points that you can use to explore early to mid-stage of the disease. And you mentioned that when you have much later progression of the disease, that's to say the degeneration is right down to the center of the macula, you now only have central cones areas preserved. And therefore, you have more central vision preserved. There, you mentioned that you have best corrected visual acuity, which is, of course, a regulatory approval end point and also the OCT-related ellipsoid zone measurement. And again, that's a regulatory approval end point. So that's a very nice way of critically looking at the end points here. In your experience in this disease area, are there -- what is the benchmark for clinically relevant improvement here for patients? We've heard typically that the FDA like to have thresholds such as a 3-line gain or a 15-letter gain on the visual acuity chart in other disease areas. But with patients with inherited retinal diseases, of course, the paradigm could be totally different. What's your feeling about that?

Most patients with IRDs who have experienced lowering of their visual field to 10 degrees and complete blindness at night, what they want is they don't want to go blind during the day. So anything that we can do as physicians, scientists, companies, anything that we can do to slow down the progression or to stop the progression so that they don't go blind is an incredibly important benchmark.

And so then, Molly, if I turn to you as a patient who has quite advanced disease, so you have 5 degrees-or-so visual field left now. For us as clinical trialists in companies, if you were to give us some advice of what success could look like, would you want that success to just preserve that vision there, improve that vision? Or what would be a success for you?

I would be happy to have the vision that I have stabilized because I think one of the hardest things about having Usher syndrome is that it's progressive. And also being gone deaf, you're so visual. So it doesn't matter how blind you get. You're still trying to use your residual vision, and it's exhausting. And having to adjust each time it progresses, readjust and then adjust and readjust, is just so tiring. So to be able to have something that actually says right, we can give you something that will let you keep the rest of what you've got forever, that would give me a lot of reassurance. That would relieve a lot of stress from my shoulders because the main scary part about this condition is the fact that it is progressive. I've gotten used to the fact that I've lost what I've got, what I've had even. And the scariest part is knowing that I could lose what I've got now already, and that's scary. Yes.

Right. And Dr. Koenekoop, is this what you hear from other patients as well, what Molly was saying about preservation of vision being even a success as opposed to even improvement?

I think that is beautifully said by -- yes, most of the patients say exactly the same thing as Molly.

Okay. So let me just maybe shift gears here a little bit and just describe the Stellar trial. The Stellar trial is a Phase I/Phase II randomized, sham-controlled, global multicenter trial. It's a single ascending-dose trial. And of course, it's designed -- being a first-in-human study, it's designed to show as the primary end point, safety of the drug. Of course, we always want to try and look at efficacy end points, but these are secondary parameters, of course. And we've done a 3-month interim analysis just recently, and many of you may be familiar with the press release that we put out and the data also for the 3-month interim analysis after the first 2 dose levels. And we were glad to say that, of course, at this -- at that stage, the 3-month interim analysis, we've confirmed safety so far. The trial is, of course, still ongoing. And in addition to confirming safety, which was the primary outcome measure, what we have seen are some glimpses of efficacy there as well. We -- just to remind everyone, we set quite a high hurdle bar for efficacy. Because the numbers of patients were small, we wanted to ensure that any efficacy readouts were consistent and that the benefit was seen across 3 or more end points that we've been studying. And we found that at least 2 responders met that high hurdle bar in the treated arms. And of course, none of the sham-controlled patients met that high hurdle bar of 3 or more end points showing a benefit in the treatment arm compared to the sham-controlled arm. So with that in mind, Dr. Koenekoop, can I maybe turn over to you and just ask you, what was your reaction to the Stellar trial data set that came out as the interim analysis?

I was very encouraged to see 2 patients respond out of 5 at this early stage and not just in 1 end point but in 3 was very encouraging to me. And that's exactly what I'm looking for as a clinician scientist is that it makes sense. So these -- in the first patient, the retinal sensitivity improved. The ellipsoid area has changed. And again, the DAC, the rod perimetry, improved. And in the -- this patient was considered to be mild to moderate. In the severe patients, there were also 3 parameters that improved that are correlated with each other. But because it's later in the disease, visual acuity becomes affected. So in this patient, visual acuity improved by 7 or 8 letters, maybe a little bit more. The rod perimetry was significantly improved. And the retina was more sensitive on FST. So that's extremely encouraging that these 3 parameters are working together, giving us information.

So given the fact that this is a very slow progressing disease, and of course, our trial is 1 year in duration, and of course, we would like to follow these patients out even longer, would you have anticipated at the 3-month time point to have seen this kind of data in efficacy?

No. Three months is very, very encouraging. I would have thought that it would take longer, but it was wonderful to see it.

Well, that's very encouraging for us. Molly, your views -- did you hear about the press release from this trial and the data and the information that was being shared? What were your feelings about this?

It's always very encouraging just -- I mean I'm not a scientist. And I don't know a lot of the lingo and stuff that goes around, I don't really understand. But seeing -- just seeing things like this happening is really encouraging. It puts a lot more faith into what's going to happen, whether it be from my generation and that like me don't know. We'll see. But it does give me a lot of hope. And that's good because when I was first diagnosed 13 years ago, there wasn't anything going on. And there was a serious lack of sort of knowledge around it. And we were kind of doing our own research and even the numbers on what Usher syndrome, how many people had Usher syndrome were very vague. So it's just so encouraging knowing that there is so much research, and things going on now like that in itself gives me a lot of say. So -- yes.

Yes. Well, we'll keep our fingers crossed for carrying on with positive data. Dr. Koenekoop, if I can just turn to you, you are familiar with the sepofarsen LCA10 data that we have, which is a Phase I/II study also but with 12 months' worth of data. Given that set of data where we showed improvement in visual acuity of more than 5.5 lines on average across all of the 11 patients and then given the data that you're already beginning to see here, what does that tell you a little -- what -- does that give you comfort about knowing the role of RNA therapeutics and oligonucleotides in terms of a platform level so that -- is there anything that we can learn from the cross-fertilization between the 2 areas that we've seen data on?

Yes. I get a lot of confidence out of putting the 2 together because the technology is starting to really show that it works. Antisense oligonucleotide RNA-type therapy works. I can tell you that I think that. And to put the trials together gives me more confidence that these 2 ASOs are similar and working to improve the different end points. The one end point that I was very happy with also in the sepofarsen trial was the mobility course, which really puts a lot of visual parameters together and allows you to really assess whether a patient is mobilizing better under different lighting conditions. It's a wonderful addition to our armamentarium.

Right. And it's interesting, I'm going to use that as a nice segue. Mobility course was, of course, the primary end point for the first gene therapy that was approved, Luxturna. We get a lot of questions about what is the difference between gene therapy and RNA therapy. Can you expand on that a little bit? And maybe give us an idea of what the compare and contrast is between the 2 technologies?

So gene therapy refers to replacing the normal gene with a viral vector with surgery under the retina. And the viral package has a cassette with normal gene and a promoter and other things and is placed in the subretinal space, which is a very delicate surgery. And this is how the gene therapy for RPE65 Luxturna was done. It requires anesthesia, and it requires subretinal surgery, and it's delicate. And with RNA therapy, it's naked. So there's no viral vector. The RNA is developed and constructed and then very simply, injected into the eye in what we call an intravitreal injection. And then the RNA goes to the right spot, and it edits the mutation. So it leaves the gene alone. And that's fascinating because in gene therapy, you're bombarding the subretinal space with a foreign gene that's never been there. But with RNA therapy, what you're actually doing is you're fixing the car. You're fixing the motor. You're fixing the gene, and the gene stays.

And did you want to comment on the stage of disease when the 2 technologies can work in, hopefully, in terms of when could they be applied? When is the ideal time for gene therapy to be applied versus when could the RNA therapy be applied?

That's a great question. I think that gene therapy has a huge role, but it's probably more efficacious later in the disease stage because we have to go under the fovea. And RNA therapy has a wider early and late applications.

And in terms of ease of application, I think you mentioned that the intravitreal administration is much simpler. Do they both require general anesthesia?

No. The intravitreal injection is done in the ophthalmology chair in an adult. It takes 5 minutes. There's local anesthesia, and the needle is placed in the eye very carefully. And the patient is followed for 1 hour. But there's no general anesthesia. It's in the ophthalmology chair.

And in terms of complications, which one is more fraught with issues and complications?

Obviously, you can get complications with both intravitreal injections and subretinal surgery, but the subretinal surgery is much more delicate, and there's possibilities of hemorrhage and retinal thinning and retinal holes and infections. While with intravitreal injections, that is not an issue. You're not touching the retina. There is a possibility of infection, of course, so these patients have to be monitored very carefully. But the level of complexity is much lower in intravitreal injection.

Okay. I'm just mindful of the time. And really, I want to leave enough time for some questions at the end also. Just a quick wrap-up, in terms of the Stellar trial, this is, of course, still ongoing at the moment. And hopefully, we should carry on with the dose expansion that we have within that trial and follow up all of the patients that were already had the interim analysis on. With regards to the broader pipeline, our superfast in Phase II/Phase III trial, the Illuminate trial, the pivotal trial, is also enrolling at this stage. And we hope to be able to finish enrollment as soon as possible, COVID-19 pending. And of course, our autosomal dominant retinitis pigmentosa program, QR-1123 is also enrolling at this stage, and we hope to be able to get into the clinic shortly -- I'm sorry, I just want to correct that. We're in the clinic already with the autosomal dominant RP program, and we hope to be able to progress on that. So I'm going to pause here at this stage. Thank you, Dr. Koenekoop, for your answers. And Molly, thank you very much for your responses as well. I want to invite Daniel de Boer, our CEO; and also Smital Shah, our CFO and CBO, to be able to join us for this part. And I'll hand over to Sarah Kiely, who's our Head of Investor Relations, to be able to take the Q&A portion forward.

Great. Thanks, Aniz, and thank you all for the discussion today. I think this has been really interesting. And we do have a number of questions that we have received. So we'll get through as many of them as we can before the top of the hour, which is our scheduled time.

I'm going to start with, what is the status of natural history studies? And how do they and the control eye in the Phase I/II inform future clinical development?

Dr. Koenekoop, do you want to have a stab at that? And I can also complement that.

There's many, many -- yes, there's many, many natural history studies going on that are sponsored by the Foundation Fighting Blindness Canada, Fighting Blindness USA, and NIH grants have been given. We're studying as a group now in the whole world. We're studying X-linked RP progression, Usher, RPE65, choroideremia natural history study. There's many.

And I think, Sarah, the value of these natural history disease studies is so critical that in the IRD space, we learn what the normal course of the disease would be, how quickly these diseases progress, and of course, what particular parameters and endpoints to look for in clinical trials. So from my perspective, as a clinician working in the industry, running these clinical trials, those are the key things I want to glean out of that. Patients have 2 eyes usually. And therefore, it's important to measure both eyes' functions. There is a subtle nuance there, if I take that question further, that typically in early-stage programs, the FDA is very happy for us to use the fellow eye as a control. And therefore, both eyes act as good controls moving forward. In an interventional trial, the fellow eye is a good comparator. As we move into pivotal trials, the FDA usually prefers to have an external sham-controlled arm. So that's a certain nuance in using various eyes as control data.

Thank you, both. What end points may not be approved now but are expected to be important in the next 2 to 5 years?

I think Dr. Koenekoop touched on that, but maybe you can just elaborate on that a little bit.

I think that there's adaptive optics where you can actually count the cones is a very exciting OCT-type imaging of the retina, which is not approved as an end point but is certainly moving forward. There's pupillometry, which can measure rod and cone function separately through the pupil. And I've seen results of rod and cone function when the ERG, which is the electrical test, shows no detectable function in the retina. There's a functional MRI of the visual cortex, one of my favorites, where we've shown that the visual cortex has changes that are significant after treatment. This is a huge field that is opening up. So adaptive optics, pupillometry, more sophisticated imaging and then functional MRI to measure the blood flow in the visual cortex.

And Dr. Koenekoop, the FST, the full-field stimulus threshold test was used as a secondary end point for the Spark trials, that and also microperimetry has been used extensively in other inherited retinal disease trials. What are your thoughts about those as potential approvable end points in the future?

Yes. They are just getting better and better. The diagnosis instrument, the FST is robust and repeatable and correlates with patient-reported outcomes. Yes, I'm very happy with the FST. And the new rod perimetry from the DAC is solid and robust and also repeatable, very encouraging. And the mobility course, of course, that puts it all together.

So I think, Sarah, what you heard there was we're working on many of the end points such as dark-adapted perimetry, static perimetry, best-corrected visual acuity and OCT-related ellipsoid zone, which are currently already approved. And there are some other endpoints that we're looking at in our Stellar trial that Dr. Koenekoop has mentioned and others that he -- that we're not looking at necessarily at this stage, that are potentials for becoming approvable by the FDA in the future.

And there's another question we've received. From a clinical perspective, which Usher patients might experience the greatest benefit from an RNA treatment approach versus a gene therapy approach? How do you make this determination?

Yes. And I'll ask Dr. Koenekoop to comment on that because that's very much akin to what he was saying about the gene therapy versus RNA therapy.

Can you repeat the question? It was a little bit blurry.

Sure. Yes. From a clinical perspective, which Usher patients might experience the greatest benefit from an RNA treatment approach versus a gene therapy approach? And how do you make this determination if you think about staging or severity of disease?

Yes. I think that we're looking at this right now, of course. And this is a great question. I think that the patients with the most living rods and cones who may be dormant that have not died and have not atrophied, those are the patients with the most dormant cells and with robust signals on their rod and cone perimetry and FST.

And Dr. Koenekoop, maybe to press you more on that. When you think about RNA therapy, do you think it's applicable for early-stage disease and late-stage disease? Or which -- where do you think is the ideal place for RNA therapy? And then again, for gene therapy for subretinal injections, where do you think the ideal stage of the disease would be for treating those patients?

Like I said before, I think that gene therapy has a wonderful role in late-stage disease. But we need viable cells for the gene therapy to work, and RNA therapy more likely earlier.

Okay. And can RNA therapy be used for late-stage disease as well?

I think so.

Okay. Thanks.

We have a question here for Molly. Molly, what was your experience with genetic testing?

Yes. So I was about 15, 16 years old. And my parents were quite quick to jump the bullet about it, about I think Molly needs to know her genetic makeup just we know exactly what trials and things we can get involved with, particularly because my condition progressed so quickly, we wanted to get the ball rolling. It was quite hard to actually get it in the first place. But once we -- once I was put forward, I went somewhere in Oxford, and that bit happened smooth. The guy that we saw, he was great. He asked me some peculiar questions, but I'm sure all relevant. And then it actually took a while to get the results for a long while after that. So I think it's up to a year or 2. It was a long time. But from other people that I know, they -- it was really hard for them to get tested in the first place. So there's a lot of sort of attitudes around how it's not really worth getting testing because there isn't a cure and things like that, which just seems a bit silly. But obviously, there's just a lack of awareness around what is actually out there. But yes -- so it was really because my mom and dad were very proactive. And they would like, no, we want this to be -- we want this to happen. And they were calling up and arranging it. It was very much us doing the work, the foot work to get it done, which I feel like a lot of families wouldn't do that because they've made it too hard. But I was quite unfortunate because -- yes, we got it done. And although it did take a long time to get the results, it happened, it happened.

Okay. And I think we're coming up on time here. So in terms of this point in the call, I'm going to turn it over to Daniel de Boer.

Yes. Thank you, Sarah. So before we sign off, I want to thank Aniz and Molly and Dr. Koenekoop for their participation in this call. I think as Aniz mentioned at the beginning of this call, this Expert Perspective calls we have set up to take a deeper dive and see where fields are moving and see where we, as ProQR, can have an opportunity to really make a difference. I think for me, this call helped us to appreciate the complexity of a disease like Ushers and what a meaningful impact would be for patients in stabilizing their disease like Molly describes, potentially even improving their disease. I think from the Phase I/II interim analysis in our Stellar trial, we feel very encouraged by the early signals. We think that with the responder rate that we have seen at this very early time points that we may be onto something that could really help patients that suffer from Usher A mutations. So we are committed to continue really hard to work on completing that trial and subsequently developing that drug. And we will keep you updated on the progress that we're making there. And of course, I want to also thank all the participants on the call. Everybody that dialed in to listen in to this call, we hope you enjoyed it and that it was helpful to gain a deeper understanding of Usher and the QR-421a program. And thank you for your participation.

Thanks all.