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

Good day, and thank you for standing by. Welcome to the ProQR Analyst Event Conference Call. [Operator Instructions] I must advise you that this conference is being recorded today. I would now like to hand the conference over to your first speaker today, Sarah Kiely. Please go ahead.

Thank you, operator, and good day, everyone. I am Sarah Kiely, Vice President of Investor Relations and Corporate Communications at ProQR. We are very pleased to share with you today an overview of our clinical stage pipeline of RNA therapy for genetic eye diseases as well as to highlight our RNA editing technology platform. Briefly, some logistics. This webcast can be accessed under the Events section of our website at www.proqr.com and will be available for replay later today. The slides for the webcast can be downloaded from the webcast player or directly from our website. I would like to bring your attention to the live captions that are available for this event. During the call today, we will make forward-looking statements. There are risks and uncertainties associated with an investment in ProQR, which are described in detail in our SEC filings. On Slide 3, you will find the agenda in today's speakers. Daniel de Boer, our Founder and CEO, will open the call providing an overview of the business. Dr. Aniz Girach, our Chief Medical Officer, will then highlight our clinical stage programs, including a deep dive on sepofarsen. We anticipate sharing the top line results of our Illimunate Phase II/III trial of sepofarsen in late Q1, early Q2 of next year. Today, we will also provide an update from our InSight Phase I/II extension study. At ProQR, the patient is at the center of all we do, and we are very pleased to be able to include some examples of the patient experience from the Phase I/II and extension study of sepofarsen Dr. Girach will also review our QR-421a program for Usher syndrome in retinitis pigmentosa, provide an update on QR-1123 for autosomal dominant retinitis pigmentosa and give an overview of QR-504a for Fuchs endothelial corneal dystrophy. Finally, Gerard Platenberg, our Chief Innovation Officer, will review our Axioma and Trident RNA editing platforms. Following the presentation, Smital Shah, our Chief Business and Financial Officer, will join Daniel, Aniz and Gerard for a Q&A session. In order to include your question on today's call, we request that you call into the telephone numbers provided or submit a question via the webinar platform. I will now hand over the call to Daniel.

Thank you, Sarah, and good day, everyone. Since the inception of our company, ProQR is focused on RNA technologies that allow us to develop potentially life-changing medicines for patients with high unmet need. Over the years, we have made tremendous progress towards this. And today, we are closer to achieving that vision than we've ever been. In the early part of next year, we will read out the Illuminate Phase II/III pivotal trial of sepofarsen. And when positive, we plan to file for registration on the back thereof. Today, we will take you along on a deep dive on sepofarsen, reviewing the development program, the data generated to date, a deep review of the pivotal trial and the potential next steps. We will also walk you through the other clinical programs in our pipeline as well as our RNA editing platform technologies. Two strategic pillars underpin our approach. We operate at the intersection of genetic eye diseases and innovative RNA technologies. We are experts in RNA oligonucleotide science with an extensive RNA toolbox. Gerard Platenburg, our Chief Innovation Officer; will highlight our RNA editing platform technologies later in the presentation. Our founding scientific hypothesis and enduring commitment is the use of RNA oligonucleotides to target genetic mutations in the RNA to restore normal protein function. Further, we have focused our pipeline and team on genetic eye diseases, building our networks here and developing deep expertise in ophthalmology in-house led by Aniz Girach, our Chief Medical Officer; and Naveed Shams, our Chief Scientific Officer. We are applying this focus and expertise in RNA and ophthalmology through our pipeline of potential therapies for genetic eye diseases. Inherited retinal diseases or IRDs comprise of a group of mutations across 300 genes that cause retinal blindness, often leading to vision loss in childhood, like, for example, in LCA10. It is estimated that more than 5 million people live with an IRD. And except for a few thousand patients, there are no treatment options available, and we intend to change that. Although each individual program that we develop is targeting a rare population of patients, our strategy is to develop a portfolio of mutation-specific medicines that together can treat tens of thousands or hundreds or thousands of patients with genetic eye diseases. Today, ProQR has a deep pipeline with 4 clinical stage programs, of which 2 are currently in pivotal stage. As I mentioned earlier, we will give a comprehensive overview of the sepofarsen clinical trial development program today with Illuminate readouts anticipated in late Q1 or early Q2 of 2022. In addition to our focus today on sepofarsen, we will also take you through some updates on our other clinical stage programs. Beyond the 4 clinical stage programs, we have a deep pipeline of dozens of earlier stage preclinical programs for other genetic eye diseases, of which a few are depicted on this pipeline slide. Our partner programs are depicted at the bottom of this slide. Earlier this year, we announced a partnership with Yarrow Biotechnology, a company incubated by RTW on an undisclosed non-ophthalmology target. And we have now announced our first partnership around our Axioma RNA editing platform technology with the exclusive license of up to 5 targets through Eli Lilly. This transaction was a significant milestone for ProQR, providing a valuable endorsement of our technology, platform and capabilities as well as substantial funding. We look forward to the potential to further selectively partner out programs in this manner, keeping anything related to the eye exclusive to ProQR. Now I'm going to turn the presentation over to Aniz, who will describe some of the advantages of our RNA and IVT approach ahead of taking a deeper dive into sepofarsen and in the rest of our clinical stage pipeline. Aniz joined us as Chief Medical Officer in 2018 and is a board-certified ophthalmologist with 25 years of experience in the industry and with several drug approvals under his belt, and his work across big pharma as well as biotech and start-ups and having worked in biologics in small molecules and in gene therapy previously. With that, I'll now turn it over to Aniz.

Thanks, Daniel. As Daniel described, we're working at the intersection of RNA and genetic eye disease. The eye is particularly suited to RNA therapeutics for a variety of reasons, and these include the eye is a small and enclosed organ, and therefore, this requires smaller doses of drugs, leading to limited systemic spillover and a cleaner safety profile. We have the ability to deliver drugs directly into the target area within the eye, which also allows us to see the impact of the drugs on the end organ by direct examination or imaging techniques, such as optical coherence demography or OCD. Finally, the eye is known to be a relatively immune privileged site, which means that there is a lower chance of systemic auto antibodies against drugs. The advantages of the eye as a target organ are accentuated by using RNA therapies, which have the specific benefits as follows. Antisense oligonucleotides are naked molecules, which means they do not need to be housed within viral vectors, as is the case with gene therapy. This has the advantage of not exciting the body's natural immunogenicity against the drugs. And consequently, there is little, if any, inflammation observed when compared to gene therapy. Additionally, for RNA therapies, there is no need for prophylactic perioperative oral steroids, which can sometimes lead to serious complications, Furthermore, not relying on viral vectors means that RNA therapies are not confined to treating small transgene-based diseases like most gene therapies. The next 2 features, intravitreal administration and broad distribution, are expanded upon in the next 2 slides. This slide illustrates the 2 main ways of currently delivering drugs to the back of the eye. Our RNA therapies are delivered via routine intravitreal injection or IVT injection, whereas most gene therapies are delivered via the subretinal surgery method. Being able to be delivered via an IVT injection is a huge advantage of RNA therapy. An IVT injection is a simple in office-based procedure with relatively minor complications. In comparison, subretinal surgery is a much more complex and demanding procedure; requiring 3 holes to be made into the eye to introduce the light source, irrigation and also instruments. This type of surgery often requires an overnight stay in hospitals, requires general anesthesia, needs to have a specifically trained retinal surgeon to perform the procedure safely and potentially leads to significantly more serious complications, such as inflammation, hemorrhage, leaking entry sites leading to hypotony or infection, retinal tears or detachment and long-term cataracts. Typically, most inherited retinal diseases or IRDs are degenerative diseases, which start in the periphery retina and progress centripetally towards the center of the macula. RNA therapies achieve a broad distribution across the entire retina, which enables targeting of diseases at a much earlier stage of degeneration whilst the disease is still in its early stages in the periphery and thereby preventing their progression to more severe disease stages. In contrast, typical gene therapies administered by subretinal surgery can only target a small area in the center of the macula because the current technology doesn't allow for widespread transfection to occur. This means that these drugs can typically only target central diseases or end-stage diseases. Moving now from some of the broad aspects of why we are excited about RNA therapies for the eye to the more specific and our most advanced program, sepofarsen or Leber's congenital amaurosis type 10 or LCA10. LCA10 is one of the most severe and blinding retinal dystrophy, which typically affects young children and leads to complete blindness. LCA10 occurs most frequently because of an absent or defective CEP290 protein, which is due to a mutation at the CEP290 gene. CEP290 protein is expressed in the connecting cilium of the photoreceptors and is needed for the stability and protein transport within the photoreceptors to enable them to function adequately. Let's hear about LCA10 from Dr. Ian McDonald, who is a Professor of Ophthalmology at the Department of Ophthalmology and Visual Sciences at the University of Alberta in Canada and who has had 30 years experience in treating patients with LCA10 and other inherited retinal diseases.

So LCA10 is due to what we call disease-causing or pathogenic variants in 2 alleles or 2 copies of a gene called CEP290, and this particular gene makes a protein that is in the transition zone of the photoreceptors in between the outer segments, the business end that intercepts light and the cell body. There's a primitive apparatus called the cilium, and the connecting cilium in between the 2 that traffics material up to the photoreceptor outer segments, the so-called business end for LCA10. For about 30% of patients who have LCA10 variants in the CEP290 gene, the variants are in the noncoding sequence of the gene. So imagine a gene having building blocks called exons, and then there's some intervening sequences that get shuffled together to make the RNA that then makes the protein. And by including an extra piece, it throws off a whole sequence, slowly over time will result in a degeneration of the retina. The opportunity here is to use an RNA to block that sequence, just sandwich something right across there. So whoosh, the machinery of transcription goes right by that didn't see it, not even there, and produces a normal protein. Sometimes we think about these therapies as stopping progression. But my gosh, with this RNA therapy, we're actually improving vision. Although it's within a clinical trial at the present time, the results are so compelling. And the contrast between no treatment and this one, a valid treatment in which we would benefit from having more experience treating younger individuals, I think it's outstanding.

We are developing sepofarsen, formerly named QR-110 for CEP290 mediated LCA10 due to the 2991 and 1655 ATG mutation. This mutation is the most common cause of a significant decrease in CEP290 protein within the photoreceptor cells in the retina. More specifically, this mutation is a single nucleotide substitution in the CEP290 gene that creates a new supply site, also called a cryptic supply site between exon 26 and exon 27. During the splicing of the pre-mRNA, this leads to the formation of pseudo exon in the mRNA, which in turn, codes for a premature stop codon. Thus the mRNA is not translated into the full length CEP290 protein. Once CEP290 protein is abnormal or absent, there is a disturbance in normal protein transport to the outer segments of the photoreceptor cell leading to a shortening of the outer segment and its inability to perform its light-transducing function. Sepofarsen aims to repair the underlying mutation in the RNA by splice sight correction. This RNA splice correction allows the production of a normal wild-type CEP290 protein, which has the potential to restore vision in patients with LCA10. LCA10 is an ultra-orphan disease, which we believe affects conservatively 2,000 patients in the Western world. There are no approved drugs for LCA10. We are developing sepofarsen with the goal of restoring vision in patients or preventing patients' vision loss in those who are diagnosed very early in life. Sepofarsen has been granted orphan drug designation in the U.S. and EU and received Fast Track and Rare Pediatric Disease designation from the FDA as well as having the prime designation by the European Medicines Agency. The Phase I/II trial showed encouraging signs of efficacy and safety and will be reviewed in more detail in subsequent slides. Furthermore, in January of this year, we announced that the Phase II/III Illuminate pivotal trial had completed enrollment. We expect the top line data from this trial in the late Q1, early Q2 time frame. This slide highlights the clinical trial development program overview involving sepofarsen. In the Phase I/II clinical trial, we reported encouraging clinical data in patients showing rapid and significant but also durable improvement in vision and a favorable benefit/risk profile prompting the start of the Phase II/III study called Illuminate that is currently ongoing as a global clinical trial. I will recap the data from the Phase I/II trial in a moment. Following the positive Phase I/II trial, we opened an extension study called the InSight study in order to continue to get further insights on safety and efficacy beyond the Phase I/II trial as well as to study sepofarsen in the contralateral or fellow eye. Last summer, we shared a snapshot of data from the Phase I/II Insight open-label extension study of sepofarsen. We were encouraged that the observed treatment response in the second eye dosed was consistent with the first treated eye. This data was presented earlier this year at ARVO. And today, we will share an update from that extension study. Our mobility core study is designed to evaluate if a mobility course using multiple light levels, simulating real-world conditions can detect changes in vision in subjects with the phenotype representative of LCA type 10. And earlier this year, we began a pediatric assessment of sepofarsen in the Phase II/III Brighton trial, which includes patients under 8 years of age. The primary objective of that study is to evaluate safety and tolerability in this patient population. We'll now go through each of these in more detail starting at the beginning with the Phase I/II study. The clinical development of sepofarsen began in the second half of 2017 with a Phase I/II open-label, multiple dose, dose escalation, global multicenter study to evaluate the safety and tolerability of sepofarsen. This trial was completed in 2019 and enrolled 5 children age between 8 and 17 years and 6 adults greater than 18 years of age, who have LCA10 due to either 1 or 2 copies of the 2991 and 1655 ATG mutation in the CEP920 gene. Participants received up to 4 intravitreal injections of sepofarsen into one eye every 3 to 6 months. There were 2 doses studied, the target registration dose of 160 micrograms of loading, followed by 80 micrograms maintenance. Or the higher dose of 320 micrograms loading and 160 micrograms maintenance. The primary objective of the trial was to evaluate safety and tolerability. Secondary objectives include the assessment of pharmacokinetics and improvement of visual function and retinal structure through ophthalmic endpoints, such as best corrected visual acuity or BCVA, full-field stimulus testing or FST and navigation assessed via mobility course. Sepofarsen was observed to be well tolerated. During the study, in total, 8 cases of cataract or lensapacities were observed, 3 in the target registration dose of 160 micrograms loading and 80 micrograms maintenance and 5 in the higher dose cohort. All subjects who had lens replacement surgery regained their pre-cataract vision. 4 cases in 3 subjects, all retinal findings were observed in the now retired higher dose of 320 micrograms loading 160 micrograms maintenance dose group. Two incidences of mild sistered macular edema were resolved with topical treatment, and 2 incidences of subclinical retinal thinning stabilized within 2 months of last dose without additional treatment. In the Phase I/II trial, improvements in vision were observed within 3 months of sepofarsen treatment and were maintained throughout the 12-month period. Improvement in BCVA was observed and supported by improvement in performance on the mobility costs and improvement in FST. The graph on the left shows BCVA change from baseline for individual subjects and equal 6 patients at the target registration dose of 160 micrograms loading and 80 micrograms maintenance, where at month 12, the change from baseline was a minus 0.93 LogMAR, equivalent to approximately 9 lines of improvement or 45 letters approximately on the ETDRS chart. BCVA is an accepted registration endpoint for treatments of retinal diseases with a generally-accepted threshold for clinically meaningful improvement of a minus 0.3 LogMAR or 3 lines or 15 letters on an eye chart in the U.S. At month 12, this threshold was exceeded in the treated arm but not in the untreated eyes. On the basis of these encouraging findings, we started the Phase II/III Illuminate trial, which I'll describe later in the presentation. Now we will turn to the Phase I/II extension study for the InSight trial. Following the Phase I/II trial, patients were eligible to roll over into the InSight extension study for longer-term follow-up and where they could have the second eye dose. The primary purpose of the study is to continue treatment of the patients in the Phase I/II trial and collect additional data. Due to COVID, not all patients have been happy at traveling extensively and across border sometimes. And therefore, the number of patients included here and the number of visits performed reflects the environment we face currently. With that, we were very pleased that 9 of 11 subjects in Phase I/II chose to roll over into the InSight study. Two subjects elected not to roll over for personal reasons. Eight subjects have been dosed so far in the extension study, and 5 of which have been dosed in the second eye. All subjects have been switched over to the Phase II/III target dose regimen of 160 micrograms loading and 80 micrograms maintenance. Today, we'll share an update from the fixed engine study focused on the impact the treatment has for the patient. This slide is a busy slide. However, it contains some important information. On the left-hand column are the individual patients who rolled over into the InSight study with all the treated eyes listed. The next column describes their baseline visual acuity in both eyes, either light perception, hand motion, parting fingers or on the chart, meaning vision better than or equal to 2,800 on the ETDRS chart. We assessed BCVA, blue and red FST, hand mobility cross across both eyes. A tick signifies a favorable response in that endpoint, a no signifies no response, and there was some data not available or measured signified by missing data. It is very encouraging to see that the vast majority of patients responded in both eyes on multiple endpoints. With regard to safety. We have only seen cataracts, but no evidence of any new retinal thinning or CME in the study. We have seen this encouraging data across multiple endpoints. But what does this really mean for the patient? The next slide describes anecdotal reports from patients to their treating physicians about their vision. It's encouraging to hear of reports such as Patient 2 saying that he could reprint and make out bus numbers and traffic light. The homozygous patient #11, being able to read smaller font and a wider field of vision. One patient who could now see the holes in a slice of bread and even a patient able to drive more safely now. This slide is an extract from the Journal Major Medicine and is a patient case study report of the homozygous patient #11, who despite having relatively well-preserved best corrected visual acuity at baseline was able to read smaller font and achieve a larger field of vision. This slide describes the biggest responder, a patient who, when injected in his first eye, went from light perception vision to being able to read print and make out bus numbers and traffic light. When he had the second eye treated, he had a very similar improvement in the second eye as well. After sepofarsen treatment, he could read letters, read traffic light colors and even travel independently. This slide describes how patient #3 went from being hand motion vision over LogMAR 2.4, which is legally blind vision, to being able to see the letters on an eye chart after sepofarsen treatment, as illustrated here on the graphic. Let's hear from this patient directly about his experiences from the Phase I/II and extension study.

Pretty much diagnosed when I was born with some sort of eye problem. There was lots of talk of like he just has RP. Lots -- some said is LCA. But they said, well, he's too old now for LCA. When I was born, they noticed there was a problem with my eyes. And over the years, I just could not see as well as others. Couldn't see as far, had limited peripheral vision. As I got older, my eyesight slowly got worse and worse. About 20 years ago, I lost the ability to read and write. Just couldn't see the computer screen any more or books or anything like that. And then about 5 years ago, I was -- my wife and I owned a salvage business, and I would get lost in our salvage yard just because I couldn't find my way back to the office. Just couldn't work anymore. And I was looking for other -- any sort of treatment that would help at all. I had found out about a clinical trial of a drug that was looking for people to -- for clinical trial subjects on this drug. So the expectations were that I had nothing to lose because the vision was almost gone anyway. So if I could volunteer to help out with a drug that will help others that would keep what vision they had from before from getting any worse, that would be the -- just be awesome. As the study has gone on here in the clinical trial, the vision has improved quite a bit. I can read larger text. I can read quite a bit of the text on my phone and stuff without assistance. I can see the tape measure again, which makes my job so much easier. I'm more productive. The color has come back. I could see colors again, which, well, makes the electrical a little easier. You don't get the tickle from the electricity as much. And just moving around is just easier. I can find tools I dropped, things like that. Door frames are straight or windows are not as crooked. I don't get lost in my own yard. I can find my way back to my house and stuff because I could see it again. And the most enjoyable thing about the improved vision is just the ease of doing daily everything. Like it was -- if you can't read, it's a real problem. You can't do anything without asking somebody what does this say or where is this. And I can see it from a distance now. The clinical trial with the increased vision has given me more independence and confidence. I just -- I wouldn't have gone downtown by myself before, and now I will. I will walk to a buddy's house to see him and have a beer or something instead of saying, hey, you want to come over? We have kind of a Christmas light show here in the area, and it's just where you get in your car. You drive through the trees. And they put up Christmas lights everywhere. And the colors of the LED lights, the stuff, is just amazing. And I was kind of just thrown back by how vibrant and brilliant everything was. And I've never seen color that good before. Even in my early days before my vision got really bad, I don't remember color being as good as it was. It just pops and makes you feel awesome. And my wife was with me and we're driving through town, and yes, I just -- I could see her face and the flashing of the different lights and colors. Yes, she's just a beautiful woman, and I love being around her. And she's there for me all the time and does -- well, we travel lots together and we do all sorts of fun things. And yes, just having -- being able to see her face and her expressions just is awesome.

We will now turn our thoughts to the remainder of the studies in sepofarsen development program, starting with the mobility co-study. The main objective of the mobility course study is to evaluate the feasibility and variability of the mobility course in patients who have a phenotype of LCA10 with a view to validating this endpoint for clinical trials. The trial, which was performed at 17 sites across 9 countries, is completed now with 48 patients included in the final analysis. The data analysis is currently underway. And once finalized, we aim to approach the regulators about the next steps regarding potential validation of this as an endpoint for future studies in inherited retinal diseases. Next, we'll touch on our BRIGHTON study, which is an evaluation of sepofarsen in the pediatric population aged under 8 years of age. The objective of the BRIGHTON study was to evaluate the safety and tolerability in pediatric subjects less than 8 years of age with LCA10. The study consists of an open-label dose escalation phase followed by a double-masked randomized part. 10 sites in up to 7 countries are participating in the trial, which aims to enroll subjects with BCVA between light perception and 20/50 vision on the eye chart. The first patient was dosed in the open-label dose escalation part earlier this year. The dose escalation phase has now completed with 5 patients dosed to date. The next phase is the randomization phase, which will include 5 patients on 40 micrograms and 5 patients on 80 micrograms to be dosed every 6 months for 2 years. We anticipate enrollment to complete by the end of the first half in 2022. I'd like to turn our focus to an overview of the Phase II/III Illuminate trial. The Phase II/III pivotal trial for sepofarsen or the Illuminate trial is a multicenter, randomized, double-masked sham-controlled study. The key inclusion criteria includes LCA10 subjects needing to have the 2991 and 1655 ATG mutation in the CEP290 gene. They need to have an age greater than 8 or equal to 8 years of age and a BCVA between 0.4 to 3.0 LogMAR, which is equivalent to 20/50 vision on the eye chart up to hand motions on clinical testing. The trial exceeded its enrollment target of 30 patients with the eventual 36 patients being randomized across 3 arms: a target registration dose, a lower dose and a sham arm. The primary endpoint in this trial is best corrected visual acuity or BCVA at month 12 comparing the active treated arms against the sham procedure. Post 12 months, subjects will be able to continue in the study for longer safety follow-up, and sham patients will be able to cross over to an active treated arm. Having completed enrollment of the pivotal trial in January of this year, we would expect to share top line findings from this trial in late Q1 or early Q2 next year. Although rare diseases often get approved on the totality of a data package and, in practice, not necessarily dependent on statistical significance at a group level, on this slide, we will review the statistical assumptions that we used to power up the Illuminate trial. The primary analysis is an ANCOVA analysis, utilizing baseline BCVA as a covariant. We control baseline BCVA differences across subjects and adjusted for multiplicity. Three comparisons will be made: sepofarsen 160 micrograms loading and 80 micrograms maintenance versus sham, sepofarsen 80 micrograms loading and 40 micrograms maintenance versus sham, and the pooled doses versus sham. With a sample size of 36 patients, we have more than 90% power to detect a clinically significant change in BCVA, which is the primary analysis, with an alpha of 0.05. We are very excited that this data will now come in the near future. And given all that we've heard from our patients, the benefit/risk so far, we are very confident in this program. As we think to the next steps, once we have the data, we will meet with the regulators to chart out the path forward. If the data meet all of the criteria for clinical and statistical significance, which we feel optimistic about, although, of course, the trial is masked so we have no knowledge of the data, then we will decide and outline the filing strategy for the program and some aggressive internal goals for getting this to patients as quickly as possible. In summary, we have a robust development program for sepofarsen. We have completed enrollment of Illuminate our Phase II/III trial in January of this year and aim to have a readout of the top line data in late Q1, early Q2 of 2022. If approved, sepofarsen has the potential to be the first therapy to address this high unmet medical need for patients with CEP290-mediated LCA10, who would otherwise face blindness. Moving now to our second clinical stage pipeline program, QR-421a, which is aimed at the USH2A gene, which is a gene where mutations can cause Usher syndrome or nonsyndromic retinitis pigmentosa, ultimately leading to blindness. Usher syndrome or nonsyndromic retinitis pigmentosa have similar visual consequences and only differ with the presence of a deafness in the syndromic form of the disease. Typically, this is a slow degenerative progressive disease that starts with patients experiencing night blindness in their teens. This is followed by a progressive loss of visual field that progresses into developing tunnel vision. In the late stage of the disease, patients start to lose central vision, after which they go completely blind, which typically happens in their 40s or 50s. The main reason the disease develops is due to a nonfunctional or absent ushering protein, which is expressed in the connecting cilium of the photoreceptors and the ear and is responsible for structural integrity and optimizing function of the photoreceptors. Mutations in exon 13 of the USH2A gene can disrupt the production of usherin, which is required for healthy photoreceptor structure and function. QR-421a aims to induce a skipping of exon 13 from USH2A pre-mRNA, leading to an in-frame deletion in the USH2A mRNA. Since exon 13 encodes for a repetitive part of usherin protein, excision of exon 13 is expected to lead to a truncated, however, functional usherin protein. Because of this exon skipping approach, QR-421a is not specific to a single mutation but targets any mutation present in exon13 of the USH2A gene. We are developing QR-421a as a potential treatment for vision loss in Usher syndrome and nonsyndromic retinitis pigmentosa. We believe there are at least 16,000 patients with this mutation in the Western world, and the Phase I/II program is in partnership with the Foundation of Fighting Blindness. In March of this year, we reported results from a planned analysis of the Phase I/II Stellar trial, demonstrating concordant benefit on multiple measures of vision, including visual acuity, visual fields and the objective measure of optical coherence tomography or OCT after a single dose of QR-421a. QR-421a was also observed to be well tolerated with no serious adverse events reported. Based on these findings from Stellar trial, we plan to advance QR-421a into 2 pivotal Phase II/III trials by year-end. QR-421a also has a number of regulatory designations, including orphan drug designation, fast track designation and rare pediatric disease designation from the FDA. This slide highlights the completed and anticipated development program for QR-421a. The Phase I/II Stellar clinical trial has completed now. Following the encouraging results from the Phase I/II trial, we opened an extension study called the Helia study in order to generate further safety and efficacy data beyond the Phase I/II trial, and this will also give us the opportunity to gather data on multiple dosing treatments as well. We are also getting underway with our pivotal trials of QR-421a called the Sirius and Celeste trial. I'll detail these more in the next few slides. I'll start, though, by recapping our data from the Phase I/II Stellar trial. This was the summary of the safety and efficacy at the time of the interim analysis earlier this year. I'm also pleased to share some new updated data with longer follow-up on BCVA for these patients. The primary endpoint of the study was to assess the safety of the drug. QR-421a was observed to be well tolerated with over 3,700 patient follow-up days and with up to 2 years of follow-up in this study. Importantly, no serious adverse events were noted, and there were no cases of inflammation. There were 2 cases of pre-existing cataracts that were observed, one in the treated eye and one in the untreated eye of the same patient. Both were considered not treatment-related. Cataracts are known to occur as part of the background disease in usher syndrome in over 30% of the patients. No new cataracts were reported in the study. Cystoid macular edema or CME is frequently associated with retinitis pigmentosa and is part of the natural history of the disease in over 30% of the patients and is usually managed adequately with topical eye drops. No new cases of CME occurred during the study. One participant with preexisting CME was enrolled into the 200 micrograms cohort. The CME progressed during the study but was classified as mild and was managed with standard-of-care topical therapy. Now moving on to the efficacy readout at the time of the interim analysis. After a single injection, the Stellar trial achieved all of its objectives, including demonstrating target engagement in retinal photoreceptors as demonstrated by a benefit in best-corrected visual acuity or BCVA, static perimetry and accompanying secondary endpoint. We have seen a robust outcome in advanced patients in BCVA, which is the gold standard vision endpoint and the endpoint used most frequently to register therapeutics in ophthalmology as well as static perimetry for early-to-moderate disease patients. There is a concordant benefit observed in other secondary endpoints as well, including the objective structural assessment of photoreceptors by OCT imaging and other measures of perimetry such as microperimetry. The first panel highlights the advanced population and looks at the endpoint of BCVA. The graph demonstrates a mean benefit of 9.3 letters at the 1-year time point. And again, this is observed after just a single injection. BCVA is the gold standard for registration of ophthalmology drugs. And therefore, we were thrilled to see such a positive response on this endpoint, especially in the advanced population. This data formed the basis for the upcoming pivotal Phase II/III Sirius trial. The chart in the middle of this slide looks at static perimetry for the early-to-moderate population, namely a decibel or more improvement at different number of retinal loci across time, a potential registerable endpoint. And after a single dose of QR-421a, there was a higher number of mean retinal loci that had a greater than or equal to 7-decibel improvement in the treated arm when compared to the untreated arm. These findings were the basis for the upcoming pivotal Phase II/III Celeste trial, which I will describe later. We're also highlighting here the OCT imaging data, which is an objective measurement using cross-sectional images of the retina. We are measuring ellipsoid zone or easy area, which is the layer of the retina, which represents viable photoreceptor cells. And we are looking at the percentage change from baseline in easy area on the y-axis. In the treated eyes, after a single injection of QR-421a, we see a stabilization of the easy area, while we see a decline in the untreated eyes in keeping with the natural history of the disease. This easy area data is a very important data point as this is an objective confirmation of the BCVA benefit that we see in the BCVA graph as well as the other endpoints evaluated in the trial. Looking at the duration of response now. These graphs also highlight in gray boxes the approximate 6 months duration of response in the QR-421a-treated eyes after a single injection, especially on the objective endpoint of OCT. In summary, we saw that participants respond on the endpoints that are related to the baseline disease state, and we saw that the different endpoint outcomes move in concordance with each other. I'd like to share some new longitudinal data on the BCVA outcome measure now. The left-hand side panel is looking at the BCVA change from baseline up to 48 weeks in the all treated population. Here, we saw, as previously noted, a 6-letter benefit in favor of the treated arm after a single injection of QR-421a. We now have a building body of data at the 72-week time point on this BCVA endpoint. In keeping with the natural history of the disease, the BCVA gradually declines with time in the untreated eyes, whereas the QR-421a eyes have a stabilization of BCVA throughout the study period, such that after 72 weeks, there is an 8 letter benefit observed in favor of the drug-treated arm, again, just after a single dose. We know that the baseline BCVA was a strong driver of the efficacy observed. And as expected in the advanced patient population, we see a larger effect in the QR-421a-treated group than was seen in the total population. Whilst the drug-treated eyes in green here have maintained the stabilization across the entire 48-week time frame, the untreated eyes have deteriorated more rapidly as expected due to the natural progression at this stage of the disease. The advanced population demonstrates a mean benefit of 9.3 letters at the 1-year time point, which is well above the noise of the measurement. And again, this is observed just after a single injection. If we now look at the new 72-week follow-up data, we'll see the treatment benefit has further extended to a mean 13-letter benefit after a single injection. BCVA is the gold standard for registration of ophthalmology drugs, and therefore, we are thrilled to see such a positive response on this endpoint, especially in the advanced population and after just a single injection of QR-421a. This is the basis for the upcoming Sirius study, which I will describe later. Now again, following the Phase I/II trial, we opened an extension study called the Helia study in order to generate further safety and efficacy data beyond the Phase I/II trial. And this was also to give us the opportunity to get more data on multiple dose treatments. The Helia study is underway already, and we anticipate sharing an update from the extension study by the end of 2022. We are now preparing to enroll the first patients in our Phase II/III trials of QR-421a, having aligned with the regulators on our protocols, which I will now review. We plan to start 2 Phase II/III clinical trials tailored to the 2 very distinct populations using BCVA and static perimetry as primary endpoints. The first trial, named Sirius, will focus on the advanced patient population where BCVA will be the primary endpoint. The Sirius trial is a double-massed, randomized, sham-controlled, 24-month multiple dose study, including approximately 80 patients aged 12 years and above and including both homozygous and heterozygous patients and ushers and nonsyndromic retinitis pigmentosa type of patients. The baseline BCVA needs to be between 30 to 68 ETDRS letters on the eye chart in the study eye, which corresponds to less than 20/40 Snellen equivalent. The primary endpoint is change from baseline in BCVA at month 18 versus sham. And the key secondary endpoints include OCT, FST, perimetry and other quality of life measures. The trial design is very similar to the sepofarsen Illuminate study, comprising of 3 dosing arms: dosing arm 1, which is 180 micrograms loading and 60 micrograms maintenance applied 6 monthly; dosing arm 2 being 60 micrograms loading and 60 micrograms maintenance again applied 6 monthly for masking of investigators here; and a sham dosing arm for masking of patients. We expect to start this trial by year-end 2021. The second trial, named Celeste, will include an early to moderate population with static perimetry as the primary endpoint but is otherwise a similar trial to Sirius. As these are such distinct populations with such distinct characteristics, we decided to structure this as 2 parallel studies that will give us 2 shots on goal for registration. The Celeste trial is a double-masked, randomized, sham-controlled, 24-month multiple dose study, including approximately 120 patients aged 12 years and above and including both homozygous and heterozygous patients and usher syndrome and nonsyndromic retinitis pigmentosa type of patients. The baseline BCVA needs to be better than or equal to 69 ETDRS letters in the study eye, which corresponds to better than or equal to 20/40 vision on the Snellen eye chart in the study eye. The primary endpoint is change from baseline in mean sensitivity using static perimetry at month 12 versus sham. The rationale for choosing the primary endpoint at 12 months in Celeste is based on the fact retinal sensitivity data from the Stellar trial, where we see the improvements occur very early on and peak in keeping with the half-life of the drug. Therefore, with multiple dosing in Celeste, we expect the improvements to occur early and be maintained out to 12 months. And therefore, there's no reason to wait until 18 months for this primary endpoint readout. In contrast, the Sirius study has an 18-month primary endpoint time point. Because with BCVA, we are expecting a maintenance of effect with QR-421a, and the delta between the arms is more driven by the loss of BCVA in the control arm, which can take longer and is in keeping with the natural history of the disease. Key secondary endpoints here include OCT, BCVA, FST and quality-of-life measures. The trial design is otherwise very similar to the Sirius study comprising of the same 3 arms and the same frequency of 6 monthly dosing starting at 3 months after the loading dose. We expect to start this trial also by year-end 2021. So in summary, to date, we have observed that a single dose of QR-421a demonstrated clinical proof of concept with benefit observed in treated eyes compared to the untreated eyes in multiple concordant measures of vision. We're now moving forward into 2 pivotal trials due to start imminently, and we also look forward to an update from the Helia extension trial by the year-end 2022. Moving now to our third clinical program, QR-1123, which is for P23H mutation in autosomal dominant retinitis pigmentosa. QR-1123 was discovered by Ionis Pharmaceuticals and in-licensed by ProQR in 2018 and is designed for the treatment of P23H mutations in autosomal dominant retinitis pigmentosa. Autosomal dominant retinitis pigmentosa runs a very similar course to autosomal recessive retinitis pigmentosa, which is nonsyndromic retinitis pigmentosa in that patients are born with normal vision, then they experience night vision problems in early teen age, followed by progressive loss of their visual field, ultimately leading to tunnel vision. And then finally, all their vision is lost and they go completely blind. This tends to occur a little slower than other forms of autosomal recessive retinitis pigmentosa and patients go blind typically in their 70s. The most prevalent mutation associated with autosomal dominant retinitis pigmentosa is the P23H mutation, also known as 68 C2A in the rhodopsin gene. Rhodopsin is the light-sensitive pigment in rods in the retina. The mutant P23H rhodopsin protein is misfolded and toxic to the rod photoreceptor cells, causing loss of vision. Although some wild type protein is being made, there is substantial evidence that the mutant P23H rhodopsin protein elicits a dominant negative mechanism, first that it diminishes the function of the wild-type protein as well. QR-1123 is an allele-specific gapmer that aims to suppress the formation of the mutant protein by selectively targeting the mutant RNA and causing its destruction by a mechanism called RNA ACE H1 cleavage without affecting the wild-type RNA. With reducing the mutant RNA, we believe the toxicity-induced loss of the photoreceptors and subsequent loss of vision can either be stopped or potentially reversed. P23H mutation in the rhodopsin gene causes autosomal dominant retinitis pigmentosa. P23H is the most prevalent mutation associated with autosomal dominant retinitis pigmentosa in the U.S. accounting for approximately 2,500 patients. There are no approved therapies for these patients. With QR-1123, which is also administered intravitreally, we aim to prevent vision loss or to restore some vision in these patients that have vision loss. After encouraging early data on efficacy and safety from the Phase I/II Aurora study, which we will review in the next few slides, the next steps for this program is to proceed with the repeat dosing study. Now Aurora is a first-in-human study of QR-1123 in adults with autosomal dominant retinitis pigmentosa due to the P23H mutation in the rhodopsin gene. The trial included a single dose escalation in which an intravitreal injection of QR-1123 is administered to one eye. The primary objectives of the trial include evaluation of safety and tolerability. Along with that, we were also seeking to look for signs of target engagement based on the pharmacodynamic signal to inform the next steps of development. We have completed dosing patients in the Phase I/II Aurora study, 11 patients were enrolled across 5 single ascending dose cohorts. And today, I will share an overview of the safety and efficacy findings and review the next steps for QR-1123. Overall, I am pleased to share that our key objectives were met. A single dose of QR-1123 was found to have a manageable safety profile and appeared to be well tolerated. Across all doses evaluated, there were no serious adverse events and no evidence of vitreal inflammation or retinal thinning. Cataracts are known to occur more frequently in this inherited retinal disease population. In the Aurora study, there were 9 of 11 patients with cataracts in both eyes at baseline, 3 cases of cataract worsening were observed during the study. Cystoid macular edema is known to occur more frequently in autosomal dominant retinitis pigmentosa also and occurred in 7 of 11 patients at baseline in 1 or both eyes. Dose-dependent cystoid macular edema was the most common finding manageable with topical standard of care. Overall, dose levels of between 75 micrograms and up to 300 micrograms were considered to be better tolerated. And combined with the findings and efficacy, which I will walk through in the next slide, we have identified that dose range for further development. With regards to efficacy signals in the Aurora study, I'm delighted to report that we have seen signs of target engagement across the majority of the patients and across different endpoint studies. We know that QR-1123 is a gapmer design and is, therefore, different from sepofarsen and QR-421a. And this is reflected in the reduced half life, which is 5 weeks in contrast to sepofarsen and QR-421a whose half-life is in the order of 4 to 6 months. This is important because the maximum effect can be anticipated at around 5 weeks in the Aurora study due to the single injection of the drug. And indeed, we found that the maximum benefit in best corrected visual acuity was observed after 5 weeks of treatment and declined thereafter, consistent with the half-life of the drug. At the higher doses, as mentioned in the previous slide, the safety findings confirmed as the efficacy measurement. And therefore, we will focus our development on doses up to 300 micrograms moving forward. At 5 weeks, in all -- across all subjects, mean BCVA showed a benefit of plus 1.4 letters in the QR-1123-treated eyes. In doses that we plan to take forward the 75 to 300-microgram groups, the mean BCVA benefit was plus 5 letters while the maximum benefit observed was plus 7 letters. With regards to retinal sensitivity and again at the 5-week time point, across all subjects, the mean total retinal sensitivity improvement between treated eye minus the untreated eye on static perimetry was plus 50 decibels. This is comparable to the QR-421a peak benefit of plus 40 decibels noted in the earlier Stellar single-dose study. And across all subjects again, mean number of retinal loci with the greater than or equal to 7-decibel improvement from baseline was greater in the treated eyes compared to the untreated eyes and again comparable with the QR41a data previously. So in summary, QR-1123 is well tolerated. After a single injection, we observed consistent evidence of target engagement in different endpoints and across different doses, especially with doses between 75 micrograms through to 300 micrograms. So armed with this data, we aim to proceed to a repeat dosing study to start next year. Moving now to our fourth clinical stage program of QR-504a for Fuchs endothelial corneal dystrophy. Fuchs endothelial corneal dystrophy is a common age-related bilateral degenerative disorder of the corneal endothelium, which leads to a progressive loss of endothelial cells that results in corneal edema and ultimately loss of vision. Fuchs is the most common corneal dystrophy to require curatoplasty, accounting for approximately 3.1% of all penetrating keratoplasties done and 47.1% of all endothelial keratoplasty in the U.S. in 2015. Several genetic loci have been identified in patients with Fuchs disease and a strong association has been discovered between Fuchs disease and trinucleotide repeats or TNR in the transcription factor IV or TCF4 gene in chromosome 18. The genetic basis of the most prevalent form of Fuchs Type 3 has been attributed to the CTG T&R expansions in the TCF4 gene. TCF4 is a widely expressed gene, yet TNR expansion in TCF4 only causes disease in the corneal endothelium. In Fuchs, the TNR expansions are transcribed into aggregation prone RNA molecule, which caused the formation of characteristic nuclear RNA foci. These foci sequester various proteins, such as the essential mRNA splicing factor muscle blind-like slicing regulator 1 or MBNL1. This sequestration of MBNL1 causes widespread misplicing, eventually resulting in the Fuchs phenotype. Fuchs endothelial corneal dystrophy is a common disorder occurring in over 250,000 individuals in the Western world. Currently, no treatment options are available to address the underlying cause of Fuchs, and the disease management is aimed at reducing symptoms only. The only effective therapy for late-stage Fuchs is corneal transplantation. The availability of donors, the risk of rejection and the inherent risk of an invasive procedure are some of the limitations of this procedure. A high unmet medical need exists, therefore, in this sight-threatening condition. The clinical progression of Fuchs starts with early guttae formation due to debut of dead cell. This progresses to fluid pump failure in the endothelium, leading to fluid collection in the cornea. At this stage, patients will experience light scatter and glare effects. Further progression of the disease leads to significant corneal clouding due to the edema, which results in loss of vision. Usually, at this point, surgery is contemplated to prevent end-stage corneal decompensation and scarring. In patients with Fuchs, the ratio between the long and short isophorm of MBNL1 is altered. And therefore, quantifying the splice ratio of MBNL1 transcripts serves as a useful biomarker for this disease. This biomarker was used in preclinical experiments of QR-504a in primary cells explanted from patients with end-stage Fuchs dystrophy. These cells were treated in the lab with QR-504a. And as is presented on the slide, the isophorm ratio of MBNL1 is normalized in cells after treatment. We have also shown that intravitreally delivered QR-504a reaches the corneal endothelium in mice. Thus, in the focus study, we aim to deliver QR-504a to the corneal endothelium using the intravitreal route as this is a routine route of administration in ophthalmology. The Fuchs focus study is an open-label, single dose, dose escalation, exploratory study to evaluate safety and tolerability and molecular biomarkers that targets engagement in the corneal endothelium following a single intravitreal injection of QR-504a in approximately 10 patients with advanced Fuchs endothelial corneal dystrophy Type 3 scheduled for corneal transplantation. And the type of corneal transplantation is descemet membrane endothelial keratoplasy or DMEK. Following DMEK surgery of the first eye, eye 1 in this case, corneal endothelium will be collected to assess the biomarker. That is the ratio of MBNL long to short form, and that is the same measures, as I've just showed you in the in-vitro cellular model earlier. At least 4 weeks prior to the scheduled DMEK in eye 2, the patient will receive a single intravitreal injection of QR-504a in eye 2. Following the DMEK in eye 2, corneal endothelium will be collected for molecular biomarker assessment. Data generated from eye 1, the untreated eye, will serve as a useful intra-subject control for data generated from eye 2, the QR-504a treated eye. The trial is now open for enrollment, and we can expect to share the first data next year. As you can see, we are excited to have a rich pipeline of 4 clinical stage assets, of which 2 of them are in pivotal trial status. Furthermore, we have an even more enriched pipeline of products we're working on in our innovation area, which will be elaborated upon by our Chief Innovation Officer, Gerard Platenburg. Our Chief Innovation Officer, Gerard Platenburg, is a co-founder of ProQR, and today, will give a presentation on our RNA-editing technology. Gerard has a long-standing career in RNA science, having been active in the field for over 2 decades. Amongst other things, Gerard initiated the first human trial of exon skipping ever and is really considered a key opinion leader in the RNA field. I will now hand over the call to Gerard.

Thank you, Aniz. ProQR's founding scientific hypothesis and enduring commitment is the use of RNA oligonucleotides, the target genetic mutations in the RNA to restore normal protein function. Depending on the genetic mutations, we have an extending RNA toolbox, out of which several clinical programs have been developed, as you have heard earlier today. Today, with great pleasure, I'm going to spend the next 20 minutes on ProQR's-RNA-based additive platforms, Axiomer and Trident. On the left, the Axiomer platform technology enables single A-to-I editing in RNA using editing oligonucleotides or EONs to attract the endogenous machinery to a targeted adenosine. G-to-A mutations make up half the snips that are associated with disease. Therefore, this platform has a huge potential to treat currently untreatable diseases. And then Trident. This platform also uses endogenous machinery to edit uridines in to pseudouridines using single-stranded psEONs throughout the applicable to correcting premature termination codons or PTCs but also to modulate protein function. PTCs account for approximately 11% of all disease-causing mutations known today, and Trident can potentially result in medicines for those mutations. So both invented at ProQR, we are focused to establish the ground goals for EONs design and developed strong intellectual property protection, combined with a very strong key opinion leader base in this field positions us well to further development of these promising technologies into the clinic. Let me start with our most advanced platform, Axiomer, the technology invented at ProQR, which enables us to convert adenosines into inosine in RNA. Adenosine Deaminase Acting on RNA, or ADAR and its genes were first discussed in 1987. ADARs induce adenosine to inosine RNA editing, which is one of the most common forms of RNA editing. ADAR is able to both modify and regulate the output of messenger RNA as inosine is interpreted by the cell as guanosine. ADAR has also been found to change the functionality of small RNA molecules. And recently, ADARs have been discovered to act as a splicing regulator with their editing capability or RNA binding function. A-to-I RNA editing is a very frequently occurring natural process. Our Axiomer or oligonucleotide erected RNA A-to-I editing platform evolved from the mechanism that, that nature develops. Certain double-stranded RNA targets are engaged by ADAR, as you can see on the left, and the specific adenosine in the RNA is deaminated resulting in an inosine. On the right, you see that ProQR created synthetic editing oligonucleotides or EONs based on what we saw in nature. This mimics the double-stranded RNA target sequence that is recognized by endogenous ADAR, which is then able to deeminate a specific targeted inosine. This can correct the mutation or can be used to diversify the function of the targeted messenger RNA, allowing us to recruit endogenous ADAR and to make edits in the RNA wherever we want. Diving a bit deeper into how we design our EONs, there are basically 2 regions. Firstly, the ADAR binding domain or ABR, which provides the specificity to the target region; and secondly, the editing-enabling region or EER, which enables the actual A-to-I editing to be performed by ADAR. To optimize our EON design for stability and potency, we started varying defined regions in the ABR without compromising ADAR interaction. We then started -- we exchanged the stability, providing modifications in the EER with new chemistries that still provide stability but with improved potency. We used 2 medium throughput assays, a rigorous in-vitro stability assay and a biochemical editing assay followed by the proper cell-based assays. This process yields EONs to take further into development. I will give 2 examples in which we have optimized sequence regions in our EONs involved in EER and ABR, starting with modifications in the EER. For the ADAR catalytic domain where the A-to-I conversion takes place, the EER is very important to getting close to the adenosine in the target messenger RNA. The catalytical domain of ADAR was studied very carefully and the deaminase domain of the wild-type ADAR proteins contain a glutamate amino acid acquisition 488, which interacts with the cytidine nucleotide, which is the orphan position. There is a natural occurring muted ADAR protein with hyper-editing properties, and that mutant ADAR protein has a net position a glutamate residue. And this context was found earlier to be the cause of hyper-editing activity of this mutant ADAR protein. With dZ nucleotide modification in the EER position, the enhanced interaction found in natural mutant ADAR protein is inserted, thus mimicking its hyper-editing activity. On the basis of this, the EER in the EON was modified with a special base called dZ to bring the target adenosine in closer vicinity of the catalytic domain and with success because it yielded a tremendous increase of activity. Now let's look at the ADAR binding region or ABR. The ABR provides for a target vesting RNA binding allowing ADAR to dock based on structural analysis and modeling several locations in the ABR are chemically modified. In this case, to edit sequence for 2 RNA target called actin B. As can we see, backbone or sugar modifications lead to a huge increase in efficacy, which is now being applied in different designs. Axiomer has a broad range of applications, as discussed. And as announced earlier, together with our partner, Lilly, we are developing Axiomer in liver and nervous system applications. At ProQR, we're developing oligonucleotide-based approaches for inherited retinal diseases, so also based on Axiomer. In short, our IRD platform uses oligonucleotide to address specific mutations causing disease. Intravitreal delivery of AOMs allow for infrequent dosing with broad distribution in the eye. In combination with our retinal organized model, we feel we have a unique platform for precision IRD medicines. Starting with the retinal organoids. These are essentially lateral media retinals from stem cells or induced pluripotent stem cells and can be derived from healthy in-patient cells. Here, we have a few images of typical organoids. They are approximately 1 to 2 millimeters in diameter, and they contain most of the retinal cell types. You can see the photoreceptors, especially the outer segments. You will see the intranuclear layer, outer nuclear layer and ganglion cell layer. And the next image, there are staying for the cone photoreceptor marker opsine and then for the raw marker rhodopsine. Lastly, the ganglion cell layer visualized by the neuronal marker, TUJ1 and the layers are much the same as found in normal retina, so essentially formed an ex vivo retinal structure. We have previously used these organize for our clinical program for LCA10 and USH2A, and they make an excellent model to study PK/PD4IRD application. To investigate the editing capabilities in these retinas, we tested that EON for the 2 RNA target actin B. The retinal organoids were grown and incubated genetically, so with no exogenous carrier. High levels of base editing are obtained in these retinal organoids even in the range of the other piece tests mode of actions, making this system excellently suited for testing our next-generation Axiomer-based IRD leads. As previously discussed, we will be announcing EON leads for an IRD target for Axiomer later in 2022. In summary, we believe Axiomer has unique and attractive propositions in a few of genetic diseases. We have been optimizing the EON designs and shown excellent editing levels in retinal organoids, and this could open up the way for the application of Axiomer in the field of IRDs. Aligned with our corporate strategy, Axiomer allows ProQR to fully exploit this RNA editing technology in the development of medicines for genetic eye diseases. And in the coming 12 months, we plan to announce more details on the next targets where ProQR will present with Axiomer. Beyond Axiomer, we have another emerging RNA-editing platform technology invented at ProQR called Trident. With this technology, we can make similar but different edits to the RNA, editing uridines into pseudouridine which allows for the selective suppression of non submutations or premature stock codons. As with Axiomer, it also uses single stranded EON or, in this case, psEONS o harness the endogenous pseudouridylation machinery. Premature termination codons or PTCs, account for approximately 11% of all disease costs mutations known today. PTC causes translation to stop, resulting in a truncated protein as well as degradation of the messenger RNA by a process called nonsense mediated DK or NMD. Trident can provide sequence-specific read-through of the PTC and inhibition of NMD, resulting in full length protein correction. ProQR, together with its academic collaborators, delineated the structure of the guide RNA and as with Axiomer through structural analysis and modeling further optimization was done, resulting in a single [ harpin ] structure. Using in-house developed biochemical assays, the psEONS were also chemically modified for optimal interaction with the enzyme complex and efficacy. As an example, collaborators test the Trident in the test system, and this system has a mutation in the beta-globin gene creating a PTC that results in a lack of beta-globin protein and degradation of the mutated RNA. Very specific guide RNAs were designed and incubated with a mutated beta-globin messenger RNA. We observe sequence and guide specific read-through of the PTC and inhibition of NMD and that led to an increase of corrected beta-globin messenger RNA protein. So I'm very proud to have introduced the second and first new RNA-based editing platform, which shows the commitment of ProQR to develop RNA-based medicines for unmet medical needs based on the innovations in the field. And with this summary slide, I would like to hand over the call to Daniel.

Thanks, Gerard and Aniz, for walking us through the progress in our research and development activities. I'll now take a moment to summarize our recent achievements and highlight anticipated upcoming milestones. For sepofarsen for LCA10, the Illuminate trial completed enrollment in January of 2021, following a randomization of 36 patients aged 8 years and older, received either sepofarsen at the target registration dose, a lower dose or sham treatment. The primary endpoint for this trial is mean change from baseline in best correct official acuity at month 12, and we anticipate to report top line results from the Phase II/III Illuminate trial in late Q1 or early Q2 of 2022. Enrollment is ongoing in the pediatric Brighton trial, which got underway earlier this year. The primary objective of this study to evaluate safety and tolerability of sepofarsen in patients under the age of 8. For QR-421a for Usher syndrome, based on the findings of the Phase I/II stellar trial, we are advancing this program into 2 pivotal Phase II/III trials: the Sirius trial in advanced patients and the Celeste trial in early to moderate patients. For both studies, we now have agreement with the FDA on the protocol and today have announced doses that we will test. We are on track for these studies to be underway by year-end. Each trial could potentially serve as the sole registration trial. We have also started enrolling patients over from the Phase I/II Stellar trial into the open-label extension study, Helia, which will enable patients from the Phase I/II to continue access to the treatment and have their second eye treated as well. We expect to be able to share an update from the Helia extension study by the end of next year. For QR-1123, our autosomal dominant retinitis pigmentosa, we are pleased to share the first clinical update today that QR-1123 is well tolerated and demonstrated consistent target engagement in doses of 75 micrograms through 300 micrograms. We intend to move into a repeated dosing study next year with additional details to follow. For QR-504a for Fuchs endothelial corneal dystrophy, which is our first front-of-the-eye program, our molecular proof-of-concept study in patients is underway and we anticipate sharing a first update from that program in the next year. On the innovation side of the business, in September, we were pleased to announce that we had entered into a licensing and research collaboration with Eli Lilly related to our proprietary Axiomer RNA-based editing platform. Under the agreement, we received $50 million upfront and are eligible to receive up to approximately $1.25 billion in milestones plus royalties. This agreement is around 5 targets in the liver and nervous system. We intend to develop targets in the eye with Axiomer in-house, and we'll share more details about this in the second half of next year. Additionally, we intend to advance another genetic eye disease target into preclinical development in 2022. Before we move to the Q&A portion of today's event, we will take a look at the key value drivers for ProQR. We are developing RNA therapies to transform the lives of people with genetic eye diseases. With our lead program, sepofarsen for CEP290 mediate LCA10, we are on the cusp of the readout from the pivotal Phase II/III Illuminate trial in late Q1 or early Q2 of next year. With a comprehensive development program, we aim to provide the best-in-class and first-in-class therapy for patients with LCI10 that could have a significant impact for these patients and their caregivers as we have shown with several examples in the Insight extension study today. Behind that, QR-421a is following in the footsteps of sepofarsen in Usher syndrome and nonsyndromic retinoid pigmentosa, a significantly larger opportunity. In the near term, we will be underway with 2 pivotal trials of QR-421a, Sirius and Celeste, either of which could potentially serve as a sole registration trial for this program. Our confidence in this program is further bolstered by the building body of data at a 72-week time point, as we shared today. Behind this, we are building a deep genetic eye disease pipeline with QR-1123 for autosomal dominant retinitis pigmentosa and QR-504a, our first front-of-the-eye disease program. And there are a number of additional programs behind these to further build value over time. With our recent partnership with Lilly, our RNA-based editing programs have rightfully come into the spotlight with ample opportunities to further selectively partner in areas outside of the eye. Finally, we have developed deep expertise in ophthalmology in-house led by Aniz Girach, our Chief Medical Officer; and Naveed Shams, our Chief Scientific Officer, who together bring robust experience with 19 regulatory approvals between the 2 of them. So with this combination of programs, our experienced R&D development team and approximately EUR 156 million on our balance sheet taking us into 2023, we're very well positioned to execute on our strategy. Operator, we'll now move to Q&A.

[Operator Instructions] And your first question comes from the line of Dae Gon Ha from Stifel.

Congrats on all the progress. Maybe I'll just ask 2 before I hop back in the queue. One on sepofarsen and the other on Usher syndrome. So maybe Daniel or Aniz, on the sepofarsen, the InSight data that you presented today I was just looking at patient 2 and patient 7. If you could provide a little bit more commentary on, say, patient 2 why the BCVA improvement did not quite materialize in the mobility benefit. And for patient 7, any thoughts on differences in the treatment benefit between the 2 eyes? And then as it pertains to the Sirius and Celeste, I appreciate the update today and clarity. Given that one is now -- or Sirius is 18-month endpoint and the other is 12 and your commentary still seems to be in terms of one of those trials still sufficing for regulatory approval, how are you thinking about that strategy of a potentially Celeste reading out sooner than that? Would you be filing based on that without waiting on Sirius? Or would you wait on both in any case?

Yes, Daniel, I can take those questions.

Yes. Go ahead, Aniz.

Thank you. So the first question was on the InSight, and you were asking about patient #2 and patient #7. Now of course, remember that these -- this was part of the Phase I/II extension study, and these patients started off in the Phase I/II study. So of course, these patients were a heterogeneous population. And the patient 2, as you know, started off with light perception to start off within both of the eyes. I had a great response on both BCVA and FST as well. Now we know that the different eyes progress at different rates. And also, we don't sure how long these eyes have been at light perception before the treatments have been advocated. And so it's unsurprising to see that actually the mobility course, which is still being validated, isn't necessarily falling in the same way. Now patient 7 is very unusual. This patient had FST data, which actually was missing, unfortunately, because the baseline evaluation wasn't done according to the same protocol. If you look at the actual FST data, it actually showed improvement within the in-frame element of it. But of course, not having the same protocol makes it incredibly difficult to be able to make any conclusions out of that. Patient 7 was, on the eye chart, much better vision. And that patient found that they had increased contrast sensitivity, was able to see many things. They certainly had an improvement in vision in the first eye treated. And if you ask the investigator, didn't seem to be an obvious reason why this patient didn't have an improvement in the second eye. We know, of course, drugs may have different treatment effects on different eyes, of course. So I think that that's -- we'll be exploring this in much more detail with longer-term follow-up with the InSight inside data. And of course, what we need to do also is we'll be able to get much more insight after the Illuminate data is out on treatments on both eyes. Now your second question was related to the Sirius and Celeste endpoints. Indeed, Sirius is at the 18 time point, Celeste is at the 12-month time point. Now it depends on how quickly we can enroll these 2 different trials. Of course, Celeste is a bigger trial, 120 patients in total. Sirius is 80 patients in total, approximately. So it could well be that actually in terms of enrollment, by the time we get to the end of the trial, they may actually be very coincidental with each other. But at the end of the day, if the enrollment is quicker in one of the trials, that's the whole advantage we have here on having 2 shots on goal, where we have an ability to be able to -- depending on the benefit/risk that we see, whichever trial finishes first, we can actually speak to the regulators at that stage and map out the next steps, which, of course, could include a potential filing if the regulators feel confident about it as well.

And your next question comes from the line of John Wolleben from JMP Securities.

A couple for me as well. Maybe one on sepofarsen and one on Usher. With the primary endpoint of BCVA and you want to see a 0.3 LogMAR change, is that -- has FDA said to you that they want to see an improvement from baseline in 3-line improvement? Or is this a difference? For example, can you improve by 2 lines in placebo, lose a line and then that satisfy the criteria? Or what's the best way to think about meeting that primary endpoint?

Yes...

Aniz, just go ahead to address the question.

Thank you. Thanks, Daniel. John, so the idea of the 0.3 LogMAR is that it could be either a gain of 0.3 LogMAR in the treated arm solely or it could be the delta between the 2, the treated and untreated. As long as the delta between the 2 arms at a mean level is greater than minus 0.3 LogMAR or 3 lines difference, that's essentially the fulfilling the criteria.

And what's your expectation for vehicle treatment over a year in visual loss?

And are you referring to the sepofarsen program or the Usher program?

Yes, yes. sepofarsen, sorry.

Well, in the sepofarsen program, remember that a lot of these patients started very poor baseline, so they've lost a lot of significant vision already at baseline. And based on the Phase I/II data, we actually see a significant improvement in BCVA. And if you look at the control arm in the Phase I/II study, they tend to be around the test-retest variability, and so we don't expect the control arm or the sham arm in the Illuminate study to lose much more vision because they've probably lost a lot of vision already. But we do expect based on our Phase I/II study that actually if the drug works as well as it did in the Phase I/II, where we saw almost a 9.5 lines improvement in vision, that that's the kind of improvement that we're looking towards here. Of course, the clinical threshold is only 3 lines of improvement here in the U.S.

That's helpful. And just one on Celeste, if I may. Can you tell us how you're actually measuring static perimetry for the primary endpoint? Is it number of foci that improved by some decibel or is it mean improvement? Just how are you actually going to measure the primary there?

Yes. So we're looking at a mean change from baseline. And really, we've had a fair amount of dialogue with the regulators about this. We know that the FDA has some very specific views about what it requires. It requires at least 5 retinal loci within the area that you're looking at. And the change needs to be greater than or equal to 7 decibels. And that's exactly what we are powered up to do.

And your next question comes from the line of Brian Cheng from Cantor Fitzgerald.

Congrats on the update today. So I have a few. So on LCA10, it seems that patient 11 who has the homozygous mutations, that patient has a great response on both visual acuity and light sensitivity. So can you comment on whether there is a significant difference in visual acuity among the patients with 1 versus 2 copies of the mutation? And then in the Illuminate trial, can you remind us if there is stratification for homozygous versus heterozygous?

Sure. So let me take that question. In terms of the patient 11, indeed, that was a homozygous patient. In general, there is not a difference in the baseline visual acuity that we observed either if you're a homozygous or heterozygous. I think that the disease is actually much more complex than that. Even though this particular patient was homozygous and had the best vision at baseline, that's not always what we see in the natural history of the disease. And if we look at the Illuminate study, this was really -- the basis of Illuminate study was based out of the Phase I/II study. And we found that the main predictor of response was baseline BCVA, and that was hand motional better. And that's why we enriched the population in the Illuminate study with patients that have got hand motional better vision, and there was no need for us to be able to stratify for 1 or 2 copies of homozygous versus heterozygous because at least as we look at the Phase I/II data, all of these patients responded, whether you were homozygote or heterozygote on BCVA and FST as well.

Okay. And maybe on Usher, it's great to see that you now have the final design in hand for Sirius and Celeste both agree with the regulators. And one thing that we noticed is that the placebo patients in both trials are now able to cross over to the treatment after the primary endpoint at either 12 months or 18 months depending on the study. So can you provide some color on the feedback from regulators on this crossover? And then also, are there any specific differences in what the U.S. versus EU regulators will want to see in your data package at the time of filing since it looks like you'll probably be presenting both study at the same time to the regulators?

Yes. So in terms of the crossover, in fact, the regulator is actually very happy with providing that access. I think they have a precedence of doing that. They asked the Luxturna Group's path to be able to do that also. So in that pivotal trial after the primary endpoint readout, patients did also cross over into the treatment arms. So that's certainly in keeping with the precedent that's there and also the advice that we've got so far from them. Now with regards to either EU versus U.S. preferences or what the end product will be, I would say that it's probably early days at this stage because, of course, at this stage, we -- when we talk to the regulators, we are really talking about what the trial design could look like, what the primary endpoints would be and not so much the end product at this stage. But that's certainly the kind of discussions that we'll be having with the regulators as time goes on.

[Operator Instructions] And we will go to Smital for the questions submitted by the webcast.

Thank you, operator. So we did get a few questions online. The first question is related to Axiomer. It says, given your focus on the eye, what is your strategy for Axiomer and Trident. Dan, can you take that one?

Yes, sure, happy to. So in this approach, we are operating at the intersection of innovative RNA science and genetic eye diseases. So we will use these platform technologies to develop medicines for genetic eye diseases, which is our internal core therapeutic focus. However, having that said, these technology platforms can be used in many other organ systems that can target thousands of mutations. So to that extent, we will selectively partner with others to drive these exciting technologies forward in other disease areas and capture the broader value of this proprietary platform. As an example to that, we have entered recently into a partnership with Eli Lilly on 5 targets in the field of liver and nervous system. And under this agreement, we received $50 million upfront and are eligible to receive up to about $1.25 billion in milestones and royalties down the line. So we think Lilly is a great first partner for us to have as these guys are experts in RNA science, and they are the type of selective partnerships that we plan to do going forward. So all of this is in addition to the work that we are doing to develop medicines for genetic eye diseases based on these technologies.

Then there's another question related to Axiomer. Maybe, Gerard, you can take this one. Can you summarize which genetic eye diseases would make more sense to target with Axiomer?

Yes. Thank you, Smital. I think it's a little bit early to say which specifically we're going to target. We found that there's quite a list of over 1,000 [ guttae ] mutations. So we are carefully evaluating that list for the best targets, and we will get back with our -- with more news on which targets we'll develop in the second half of '22.

Great. I believe there's a couple more questions in the queue. Dae Gon, do you have a question?

And we do have follow-up questions from Dae Gon Ha.

Great. Just a couple more. I guess one clarifying question on Sirius and Celeste. Sorry if I missed this. Would you mind clarifying what the powering assumptions are for the Sirius and Celeste trials? And just to switch over to 1123 on ADRP program. Given the natural progression is somewhat slower than Usher, I guess, should we be thinking a very similar playbook of 2 different population trials going forward? Or are you thinking more towards one or the other? I'm just kind of more thinking about is BCVA the more relevant metric or static perimetry going forward. And then lastly, in terms of the safety report from 1123, you kind of hone in on 75 to 300 microgram, recognizing it's a small sample size so far. When you saw 2 cystoid macular edemas, were they also dose dependent? Or were they both from the 300 microgram? Or were they pretty dispersed?

Yes. I can take that. So I think I remember the sequence of your question. So I think the first one is about the powering assumptions on Sirius and Celeste. So yes, we basically have powered up the next study with a pivotal trial according to the standards normally used, which is 90% power with alpha of 0.05. And through multiple simulations and modeling, we've been able to then get to the numbers of patients that we've got here, 18 in Sirius and 120 in Celeste. Your second question was on 1123 and the slow progression and how it relates to endpoints. Indeed, you're right, 1123, autosomal dominant retinitis pigmentosa is very similar to Usher syndrome or nonsyndromic retinitis pigmentosa, except it's a slower progressing disease. And so, indeed, it's a rod-mediated disease and primarily at the beginning. And then the -- so as it progresses to the visual field deterioration, then certainly retinal sensitivity could be a very good market to look for in terms of improvement there. And then I think that the deterioration progresses even further to hit the center of the macular when the central vision is affected and the BCVA is affected, then I think the BCVA could be also another index. So depending on the progression speed of these diseases, we might be able to capture both of those events in one trial, although I think we'll just have to see in the next Phase III trial what kind of patients we can include here and actually just try and map out what the actual progression rate is, whether we can get both phenotypes in one trial. But indeed, there is an option here for multiple endpoints there depending on the baseline stage of the disease. And then I think you mentioned -- your last question was related to 1123 and the CME occurring into patients. Yes, we do see a mixture of CME events. I would need to come back to you on that because I can't remember exactly which particular dosing arm they came in. So that's something maybe we can follow up with you off-line.

Next follow-up question comes from the line of Jon.

Just a short one in Illuminate. I wanted to check if you're allowing pseudophakic guys in the study, either on treatment or on the vehicle -- sham-treated arm. And then also, I know the focus today is on the clinical programs, but I know you brought on Theresa recently as the Chief Commercial Officer. I wonder if you could discuss a little bit about the infrastructure you're putting in place, hopefully, for -- following the success of Illuminate early next year.

So maybe, Daniel, I'll take the first clinical question, and then I'll hand over to you for the Theresa question. So I think, Jon, you mentioned that it's pseudophakes that you're referring to. So we take all comers. They don't get stratified into one arm or another. Pseudophakes can be entered into any one of the 3 arms in the Illuminate study. And ultimately, of course, pseudophakes will not develop any cataracts because they've already had a cataract extraction done. And so that's the good thing with pseudophakes at this stage. Now it's unusual to have pseudophakes included in something like the Illuminate study. Typically, we tend to see younger patients that are actually included in the LCA10 program. But we do sometimes see middle-aged patients also there that might have had a cataract extraction already. So of course, we master the data, we don't know what kind of baseline demographics are included with regards to pseudophakes. We will get that readout in the first quarter next year. So yes, be keen to also look at that kind of data.

Yes. Thank you, Aniz. And Jon, let me address your second question. So yes, we're really pleased to have onboarded Theresa Heggie as our Chief Commercial Officer recently. Theresa has tremendous experience in the rare disease commercial space, and that includes some significant global rare disease experience at Shire; and then after that, more recently, as a Senior Vice President of Commercial at Alnylam, where she was heading up the ex U.S. commercial activities and where she led the launch of several RNA therapies. So Theresa comes with tremendous leadership experience, and I think she's a great addition to our management team. And Theresa and her team are currently working on the early launch preparations to ensure we are ready to launch sepofarsen successfully if and when we get approval. I think, yes, with that, Theresa is a really good addition to our management team. So I think in addition to these commercial capabilities, we have stellar leadership on the R&D side, where we have a deep expertise in ophthalmology in-house, which is led by Aniz Girach, Medical Director, our Chief Medical Officer; and also Naveed Shams, who is our Chief Scientific Officer, who, together, bring robust experience with 19 regulatory approvals between the 2 of them. And our Chief Innovation Officer, Gerard Platenburg, is one of the pioneers in RNA oligonucleotide science and has over 2 decades of experience in that field, including launching the first ever exon-skipping clinical trial. So we feel very comfortable about the experience around the table in guiding this pipeline and eventually products as we move forward.

Okay. If there are no more questions in the queue, operator, there's a couple more that we got online. I'll try to paraphrase. These are related to the sham treatment in P1 related to the untreated eye. It says, will the untreated eye in the Phase I trial, would it benefit from less nystagmus? So is the benefit that we saw, would that be driven by less nystagmus? And then when we take that to the next trial, do we expect the sham to behave differently from the untreated eye? Aniz, can you take that one?

Yes, I can. Yes. So certainly, the Phase I/II study, we did see a minus 0.2% logMAR improvement in vision in the fellow control eye, the untreated eye. And it's believed that, that may be related to the fact that, of course, these patients with LCA10 have gross nystagmus. There is fine oscillator movement that affects their vision. And if you were to improve the vision in the treated eye, which is what happens in some of these patients, then automatically, the nystagmus level in that high would reduce and nystagmus in the bilateral event, which was centrally controlled by the brain, and therefore, automatically, the nystagmus in the fellow eye, the untreated eye, would also reduce and allow for slight improvements of vision to occur automatically there. So indeed, we did see that in the Phase I/II study, I think. Now having said that, in the Illuminate study, we are using an external sham control, so totally separate patients. It's not -- the control is not within the same patient, it's a separate sham control arm where both of the eyes are untreated. And therefore, we do not anticipate seeing the same artifact going on in the sham patients in the Illuminate study. I hope that answers that question, Smital.

Yes, it does. Then one more question online. Would you consider negotiating co-development, co-commercialization rights with partners going outside of the eye, to participate in that upside without having to do the heavy lifting? So maybe that's one you can take, Daniel. Again, it's likely related to Axiomer.

Yes. Happy to, Smital. So yes, I think at ProQR, we are very focused on genetic eye diseases, and we are building our expertise with significant synergy across the pipeline and the portfolio in developing RNA medicines, specifically for genetic eye diseases. However, some of our platform technologies are applicable to other therapeutic areas and other organ systems as well. And we do want to make sure that these technologies are pursued in those other therapeutic areas. And to that extent, we do absolutely consider partnering with others. And recently, we did the partnership with Lilly that we talked about today. And there is potential other structures that we could consider down the line as well. I think at ProQR, we do remain focused on genetic eye diseases. That is our sweet spot. I think that's where we build tremendous expertise and where we can really leverage the synergy across the portfolio. So for therapeutic areas outside of that, we would indeed work with partners that we would rely on for the heavy lifting in that part.

Got it. Given they're coming up on time and there are a few more questions, maybe we will follow up with investors with the additional questions after this call. So with that, Daniel, I'll turn it over to you for closing, and then we'll get back to the rest.

Yes. Thank you, Smital. So with that, I then want to thank everyone who's on the call for joining us today. We will look forward to keeping you posted on our progress as we work towards bringing treatments to people living with genetic eye diseases who would otherwise have no treatment available. Thank you all. Have a great day. Bye.

This concludes today's conference call. Thank you for participating. You may now disconnect.