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

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 the findings for our Phase I/II Stellar trial of QR-421a for Usher syndrome and non-syndromic retinitis pigmentosa as well as the next steps for the program. Briefly, some logistics. The webcast can be accessed under the Investors 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. We will first go through our presentation and then open the call for questions. In order to include your question on today's call, we request that you call into the telephone numbers provided in today's press release. 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 and today's speakers. Daniel de Boer, our Founder and CEO, will open the call with some brief remarks. Then Dr. Aniz Girach, our Chief Medical Officer, will discuss findings from the trial. Then Daniel will provide a brief update on our business. Following our prepared remarks, Smital Shah, our Chief Business and Financial Officer, will join the team for the Q&A, after which we will conclude the webcast. And with that, I will now hand the call over to our CEO, Daniel de Boer. Daniel?

Thank you, Sarah, and good morning, everyone. At ProQR, we are developing a pipeline of RNA modulating therapies for a wide variety of ophthalmic diseases, especially for inherited retinal diseases, or IRDs, such as Leber's congenital amaurosis type 10, Usher syndrome-associated retinitis pigmentosa and autosomal dominant retinitis pigmentosa. IRDs are responsible for significant loss of quality of life and productivity on a global basis. Between 2 million and 5 million people live with an inherited retinal disease, and. Except for a few thousand patients, there are no treatment options available, hence, millions of people live with an IRD without any form of treatment. At ProQR, we intend to change that. Our platform of RNA modulating therapies has the potential to address these blinding diseases by aiming to stop or reverse vision loss in these IRD patients. After positive findings in our lead program of sepofarsen earlier, we will today present the data from the clinical trial for second program, which is a first-in-class treatment targeting Usher syndrome and non-syndromic retinitis pigmentosa, a slow progressing disease that causes significant loss of quality of vision and, as a result, loss of quality of life. Given the progressive nature of the disease, patients with Usher syndrome and non-syndromic RP live with a terrible uncertainty of not knowing how much vision they will have lost the next day. As the interest of the patients is and always has been a North Star, we will first take a look at the patient perspective by listening to Molly Watt. Molly lives with Usher syndrome and is a member of ProQR's Patient & Caregiver Steering Committee and participated in an expert perspective school last year, from which we will now take a look at a short clip. [Presentation]

Thank you, Molly, for sharing your perspective. Now it's my pleasure to introduce Aniz Girach, our Chief Medical Officer and a board-certified ophthalmologist. Aniz will walk us through the results of the QR-421a Stellar trial on today's call.

Thank you, Daniel, and good morning, everyone. As an ophthalmologist and with over 20 years of experience in the industry, I'm very excited with the results from Stellar Phase I/II trial and would like to take this opportunity to share this with you today. I'll walk you through the data that shows that this trial achieved all of its objectives, including demonstrating target engagement in retinal photoreceptors, as demonstrated by benefit in best corrected visual acuity or BCVA, static perimetry and accompanying secondary end points. QR-421a was also demonstrated to be safe and well tolerated. As a result of this exciting data, we have already discussed the next steps with the FDA in moving forward with our plans for pivotal studies to support registration as soon as possible. We have seen a robust outcome in advanced patients in BCVA, which is the gold standard vision end point and the end point used most frequently to register therapeutics in ophthalmology; as well as static perimetry for early to moderate patients. There was a concordant benefit observed in other secondary end points, including the objective structural assessment of photoreceptors by OCT imaging and other measures of perimetry, for example, microperimetry. Before I take you through the trial results, we will first take a few minutes to introduce QR-421a and walk through the natural progression of the disease. QR-421a is an RNA therapy for retinitis pigmentosa due to mutations in exon 13 of the USH2A gene. Exon 13 mutations are found in at least 16,000 patients in the Western world. QR-421a is designed to produce a truncated but functional usherin protein required to maintain the structural integrity and function of the photoreceptors. A defective usherin protein leads to progressive vision loss and leads to Usher syndrome and non-syndromic retinitis pigmentosa. Approximately 50% develop hearing loss, which is called Usher syndrome. The disease without the hearing loss is also referred to as non-syndromic retinitis pigmentosa. QR-421a aims to prevent patients from going blind. We are proud and grateful to have received $7.5 million in funding from the Foundation Fighting Blindness to support the conduct of this trial. We have also received the appropriate regulatory acknowledgments via orphan drug designation in Europe and the U.S. and received fast track designation from the FDA as well as rare pediatric disease designation, which will give us a resellable priority review voucher and approval. We completed the enrollment in the Stellar Phase I/II trial last year and are today announcing the second and final set of interim data from this trial. We will first look at the disease and disease progression before we go into the trial results. Mutations in USH2A gene lead to a progressive photoreceptor cell death that starts on the outer edges of the retina and gradually moves inwards, leading to a slow but progressive form of visual field loss. The progression of the disease can be captured in 2 separate but interdependent ways: visual field loss and visual acuity loss. Starting in their teens, patients experienced night blindness, which is followed by a progressive loss of visual field, leading to tunnel vision, as is depicted with illustrations on the left. Then in mid-life, patients started to develop a progressive loss of central vision, which is used for sharp vision such as for reading. This is typically measured by a letter chart, as depicted on the images on the right. The patients developed a combination of visual field loss and loss of sharpness of central vision, ultimately leading to total blindness. Whilst both eyes generally progress at the same rate, the progression rate between patients can vary a lot. Therefore, in order to mitigate for these confounding variables, when analyzing a data set in this disease, experts believe the best control is the untreated or contralateral eye in the same patient. On this slide, we showed the disease progression over time for Usher syndrome or non-syndromic RP. Patients are born with normal vision, and they can see both the full field and have sharp central vision, as is illustrated in the image below on the bottom-left side. They then start to lose peripheral vision in their teens that steadily progresses to tunnel vision, as is depicted in the red line and the image in the center left at the bottom. As the degeneration approaches the center of the macula, their central vision starts to deteriorate, as depicted by the green line and the image in the bottom-right -- center-right side. Ultimately, by the time a patient gets into their 50s or 60s, they go completely blind. Therefore, depending on how far a patient's disease has progressed, the phenotype is quite different from patient to patient. As a result, different end points will be informative at different stages of the disease. Two separate subpopulations can be identified based on their baseline visual acuity. The early to moderate population that have a visual acuity that is near normal, these are patients with only peripheral visual field loss but relatively preserved central vision. They are on the left side of the vertical dotted line. The advanced population, on the other hand, have less than 70 letters at baseline or worse than 20-40 vision on Snellen chart. These patients are on the right side of the dotted line. The advanced patients have lost the majority of the visual field already and now have compromised central visual acuity as well. Each of these 2 subpopulations is expected to respond on different end points depending on the baseline status. In the early to moderate population on the left, where central vision is not yet threatened, we should see a stabilization in visual field in the treated eye versus a continued decline in the untreated eye. Whereas in the advanced population on the right side of the chart, where central vision is threatened, we would expect stabilization of visual acuity or prevention of decline of vision in the treated eye versus a continued decline in the untreated eye. The objective of QR-421a is to restore functional USH2A protein to prevent cell death and arrest the disease progression. Given QR-421a distributes to all parts of the retina, we have a unique opportunity to target this disease at all stages, preferably as early as possible to prevent vision loss; and for those that have lost a lot of vision, to stabilize the vision they have left. This slide summarizes the Phase I/II Stellar trial design, consisting of 3 different doses tested in 20 patients with a follow-up period of 2 years. For each patient randomized in the treated arm, one eye was treated with QR-421a, and the fellow untreated eye was control. For the sham randomized patients, one eye underwent a dummy intravitreal procedure, but there was no drug treatment administered and no penetration of the eye. The sham arm was utilized for masking purposes only. However, given the different rates of progression between patients and small and, therefore, typically unbalanced sham arms, experts believe the best control is the untreated contralateral eye in the same patient. The goal of this single-dose study was to identify the registration end points, the dosing interval based on onset, durability and weaning off of effect and the target patient population for the next study. This slide looks at the baseline demographics of the population studied. 20 patients were enrolled in the study, of which 6 patients were randomized to sham, receiving no QR-421a treatment. 14 patients received active treatment at 3 different single doses of QR-421a and were balanced well between early to moderate population, 8 patients; and the advanced population, 6 patients. In general, we have a well-balanced set of patients included in the trial, representative of the broader population. If we focus on the treated arm, we see a roughly equal distribution of homozygous versus heterozygous, early to moderate versus advanced and non-syndromic RP versus Usher syndrome distribution. The most important characteristic is the disease stage or patient baseline, differentiating the advanced and early to moderate patients. Moving to the sham, there is more imbalance evident in this group of patients. And therefore, although the sham group provides the necessary masking, it isn't the best comparison for detecting an effect. Also, at the top of the graphic, you can see that patients are followed up from between 3 months and 2 years. So this is a very mature dataset to draw meaningful conclusions on. Today, we will focus on the data up to the first 48 weeks in the study, where there are multiple patients at every time point. Beyond 48 weeks, there are only 1 or 2 patients per time point and are, therefore, not as informative to draw meaningful conclusions at the mean level. Now let's take a look at the results of the trial. This slide summarizes the trial results. I'm delighted to announce on that this trial met all of its key objectives. The drug was observed to be safe and well tolerated with no serious adverse events reported. Clinical proof-of-concept is established on BCVA and static perimetry with concordant responses in important secondary end points such as OCT imaging and microperimetry. Furthermore, we have collected the key information to take the program forward, including the appropriate registration end point, the dose and dosing interval to be used. And the optimal study population has been identified for the next trial. We will, therefore, wind down the Stellar trial and offer the trial participants to roll over into an open-label extension study, where they'll be offered continued treatment with QR-421a. As a next step, we will start 2 parallel Phase II/III pivotal studies by year-end in 2021, 1 in early to moderate patients and 1 in advanced patients, with an aim to get this drug approved as soon as possible. We will come back to the design of the pivotal studies after we take a look at the data. As you will see through the next few slides, the most important factor in measuring efficacy is the patient baseline disease stage, whether a patient is advanced or early to moderate. But before we do that, let's take a look at the safety. The primary end point of the study was to assess the safety of the drug. QR-421a was observed to be safe and well tolerated with over 3,700 subject follow-up days and with up to 2 years of follow-up in the study. Importantly, no serious adverse events were noted, and there were no cases of inflammation. Two cases of preexisting cataracts were observed, one in the treated eye and one in the untreated eye of the same patient. Both are considered not treatment related. Cataracts, of course, 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 this study. Cystoid macular edema, or CME, is frequently associated with retinitis pigmentosa and is part of the natural history of the disease occurring 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 subject with pre-existing CME was enrolled in the 200-micrograms cohort. This CME progressed during the study but was classified as mild and managed with standard of care therapy. We're pleased to see overall the QR-421a shows a safe and well-tolerated profile in this study. Now we will take a look at the efficacy data in the study. We will start with the end points that are most relevant for the advanced population, including best corrected visual acuity. And this is shown on this slide, best corrected visual acuity, or BCVA, as measured by the ETDRS letter chart in all treated patients. The y-axis is the change from baseline in ETDRS letters, where a downward motion is a decline in vision. The x-axis is time duration in the study in weeks. And the number of patients at each time point are given in the brackets. The green colored line is the treated eye, and the yellow colored line is the fellow untreated or contralateral eye. There is a striking stabilization of BCVA throughout the course of the study in the treated eyes as compared to a natural decline in BCVA in the untreated or contralateral eyes. This amounts to a mean 6-letter treatment benefit at the 1-year time point with the drug-treated eyes compared to the untreated eyes, which represents the natural progression of the disease. This is over the noise of the measurement. And of note, this is after a single injection. This sustained stabilization of vision is consistent with the long half-life of QR-421a. An additional note is that this graph includes all treated eyes. So of course, it includes the early to moderate population that have a relatively good central vision due to earlier disease and can therefore not respond on this end point. So let's take a look at the BCVA in the advanced population, where BCVA is already declining. As expected in the advanced population, we see a larger effect in QR-421a treated group than was seen in the total population. Whilst the drug-treated eyes, in green, have maintained their 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 as expected, this population is what drives the overall BCVA response. And again, this is observed after just a single injection. This is really encouraging finding on the most important registration end point. The durability of response here is consistent with the half-life of the drug. So the difference between the treated eye and the untreated eye is what we call the BCVA benefit. That is depicted here by the dotted gray line. On this slide, we are looking at a single line representing the benefit, showing the difference between the eyes, that is the treated eye minus the untreated eyes at each time point, with an upward motion representing a benefit in favor of the treated eye. There is a consistent upward movement of a single line curve nicely showing a net benefit in favor of the treated eyes compared to the untreated eyes, which ends up at being 9.3-letter benefit at 48 weeks. BCVA is, of course, the gold standard for registration of ophthalmology drugs, and therefore, we are thrilled to see such a positive response on this end point especially in the advanced population. On this slide, we can see OCT imaging data. OCT, or optical coherence tomography, imaging is an objective measurement utilizing cross-sectional images of the retina. We are measuring the ellipsoid zone or EZ area, which is the layer of the retina which represents viable photoreceptor cells. And we are looking at the percentage change from baseline in EZ area on the y-axis. OCT images the central 6 millimeters of the retina, so any effect observed on this end point will be on patients that have progressed disease within the macular area. In the treated eyes, after a single injection, we see a stabilization of the EZ area, while we see a decline in the untreated eyes in keeping with the natural history of the disease. After approximately 9 months, we see the treated eyes decline, perhaps indicating the need for a second dose and, hence, indicating the dosing intervals needed in the next study. This suggests a durability of the effect of 6 or more months, which is in line with the half-life of the drug. This EZ area data is very important since it is an objective confirmation of the BCVA benefit that was shown in the previous slides as well as the other end points to come. This slide illustrates the microperimetry data looking at the seeing points that are defined at baseline. Microperimetry measures the retinal sensitivity or the visual fields in the central 30 degrees of the retina. Here, we see a concordant stabilization of the treated eye out to 6 months after a single injection with a deterioration in the untreated eyes over the same period of time. Again, we see that in future trials, redosing at 6 months' time point will be appropriate. The microperimetry data further reinforces the results observed in BCVA and OCT imaging since all these end points cover the anatomy or function of that central macular area. This demonstrates that patients have a benefit on visual acuity, as measured by the ETDRS letter chart on retinal structure by the objective measurement of OCT; and benefit on retinal sensitivity in their visual fields concurrently, 3 end points that move in concordance with each other. In order to identify the target population for the next pivotal trial, we looked at the predictors of BCVA response by baseline disease characteristics of the patients that had a benefit of 5 or more letters. The test, retest variability of the BCVA end point in the study was approximately 4 letters on the ETDRS visual equity chart. And therefore, a 5-or-more-letter benefit was used as a threshold for response. We can see from this analysis on the left that the major driver for response on BCVA is the baseline disease stage. We see that 50% of the entire population had a benefit of 5 or more letters at the 1-year time point. Importantly, as we had expected, we see 100% of the advanced disease population responding on this end point with the benefit of 5 or more letters; whilst in the early to moderate group, there was only a 14% response level and the sham group having no responders at all. As is depicted on the graph on the right, all the advanced patients responded on BCVA, irrespective of being either homozygous or heterozygous, either non-syndromic RP or Usher syndrome, or irrespective of the dose. With these results, we can continue clue that QR-421a can target over 16,000 patients potentially that have an exon 13 mutation, irrespective of genotype or disease type. Now that we've looked at the advanced patients, we will take a look at the early to moderate patients. You will remember earlier, we mentioned that in the earlier disease population, patients tend to lose visual fields, which is best measured using static perimetry. On this slide, we look at the total retinal sensitivity analysis, which captures the difference in retinal sensitivity improvement in the treated eyes and the retinal sensitivity improvement in the untreated eyes across all treated patients. An upward motion here is a benefit in favor of the treated eye. We can see that after a single dose, there is a rapid onset of benefit in the treated eyes when compared to the untreated eyes, which then wanes off over time. This is an extremely encouraging signal to see such an improvement in total retinal sensitivity across all treated patients. Now we have seen these encouraging findings on a total retinal sensitivity improvement graph, let's take a deeper look into static perimetry. Here, we are looking at the number of locations or loci in the retina that have improved by 7 decibels or more from baseline in retinal sensitivity, which is the threshold for clinical significance. In the green line, we see the treated eyes. And in yellow, we see the untreated eyes. Although we see both lines improve, we see that the treated eyes do better at all time points than the untreated eyes out to 6 or more months, when the drug effect of a single dose is likely waning off. Of note, this slide is including all treated patients, whilst, of course, this end point is really meant for early to moderate population. On this slide, we look at static perimetry for the early to moderate population and look at the same end point as the last slide, namely a 7 dB, or decibel, or more improvement from baseline at different number of retinal loci across time. The magnitude of improvement observed in the treated eyes is larger here in the early to moderate population when compared to the all-population slide previously. We now see that the bulk of the response is in the first 6 or so months after treatment, which again lines up with the half-life of the drug and the expected durability of the effect after a single injection. Of note, an improvement of 7 decibels or more across 5 retinal loci is FDA-approvable end point. Based on this data, we can conclude that static perimetry is an informative end point that can be used for the early to moderate population. In summary, there was a striking benefit observed when the total retinal sensitivity improvements were compared between treated and untreated eyes. The regulatory threshold for clinical significance, that is to say 7 decibels or more improvement, was achieved across more retinal loci in the treated eyes than seen in the untreated eyes. This was even more pronounced in the early to moderate patient population, where we see that 7 out of 8 patients qualified as a responder, as is shown in the graph on this slide. And the benefits on static perimetry after a single dose were consistent with the half-life of the drug. All this data fills us with confidence in selecting static perimetry as the primary end point for early to moderate patients in the Phase II/III trial. The data so far has included a comparison with the fellow untreated eye because experts recommend this to be the best comparison due to the heterogeneous nature of Usher syndrome or non-syndromic RP. Despite the fact that the sham group was enrolled primarily for masking purposes, we have summarized the sham data here in comparison. Added on top of the graph you saw earlier, we have now added the sham data on the change from baseline in BCVA in the advanced population in the gray line. Since the best control is the other eye in the same patient, we will take a look at the benefit analysis on the right side of this slide. You saw this graph earlier in the presentation as well, the green line representing the difference between the treated and untreated eyes in the QR-421a treated group. The gray line now represents the difference between the sham eyes in the same patients. We can see that the sham eyes move in sync with each other and don't exceed the noise of the assay, while the treated eyes have a 9.3-letter benefit in favor of the treated eyes. This data clearly highlights the difference in outcomes in BCVA between the QR-421a group and sham groups, leading to a total of 12.3-letter difference at week 48, a very meaningful response. This slide displays separate graphs of the data from OCT, BCVA and static perimetry, with the sham treated group overlaid on top of the QR-421a treated and untreated groups. This data further confirms how the sham data behaves like the untreated eye and confirms the natural history of the disease. Now looking at the duration of the response, this graph highlights in gray boxes the approximate duration of response in the QR-421a treated eyes after a single injection on the different end points. As one of the key objectives of this trial was to establish dosing interval, we are pleased to see the clinical data matches our preclinical data and is in line with the half-life of the drug. This confirms a 6-monthly dosing interval that we will use going forward. Therefore, in summary of the trial results, we see that QR-421a was safe and well tolerated in over 3,700 treatment subject days with patients followed up to 2 years. We have accomplished clear clinical proof of concept consistent with the baseline disease stage after just a single dose. We have identified registration end points of BCVA for an advanced population trial and static perimetry for an early to moderate population trial. There is further supportive data from an objective end point using OCT imaging as well as further retinal sensitivity supportive data using microperimetry. We saw that participants respond on the end points that are related to their baseline disease stage, and we saw that the different end points move in concordance with each other. We see that all tested doses were active, as was predicted by our preclinical modeling. And we see a durability of effect of 6 or more months. As these lines are completed with our preclinical modeling, we have a lot of flexibility to pick the dose level that will be given once every 6 months. In this trial, we have collected all of the information we need to move forward into the pivotal stage to get this drug registered for patients. We have discussed these detail already with the FDA and have agreed with the FDA to formally submit protocols for the start of the Phase II/III trials. As discussed and agreed with the FDA, we plan to start 2 Phase II/III clinical trials tailored to the 2 very distinct populations using BCVA and static perimetry as primary end points. The FDA agreed with our proposed 6-monthly dosing frequency and confirmed that given the favorable safety profile, we don't have to do any more dose ranging. The first trial, named Sirius, will focus on the advanced population, where BCVA will be the primary end point. The second trial, named Celeste, will include an early to moderate population with static perimetry as the primary end point. As these are such distinct populations with such different characteristics, we decided to structure this as 2 parallel studies that will give us potentially 2 short-term goal for registration. The Sirius trial is using the gold standard of best corrected visual acuity, or BCVA, as the primary end point. As we know that only people with advanced disease can respond to this end point, this study will only include patients that have advanced disease showing some loss of visual acuity at baseline. Therefore, patients in this study will have a visual acuity of 20-40 or worse, which means that they can read everything but the smallest lines on the eye chart. As you see on this slide, we will be enrolling approximately 100 patients in the sham controlled, randomized study with 2 active arms, which is favored by the FDA. Subjects in the active arms will receive 2 different doses of QR-421a every 6 months. The primary end point here is BCVA. And given the effect size observed in this population, we anticipate evaluating the primary end point after 18 months of follow-up and potentially an earlier interim analysis at a 12-month time point. In this study, we will include secondary end points such as OCT, microperimetry and mobility course, amongst others. The goal will be to stabilize the BCVA in the QR-421a treated eyes, whilst the control arms would deteriorate in line with the natural history of the disease. As BCVA is the gold standard in ophthalmology drug development, it's anticipated that the positive benefit-risk readout on BCVA will get QR-421a registered as a potential drug for patients with an USH2A exon 13 mutation. This trial design will be fine-tuned with the regulators, and the study is expected to start by the end of the year. In parallel to the study for the advanced patients, we plan to start the Celeste trial to further study the early to moderate population. In this trial, we will study the same QR-421a dosing regimens but now include only the early to moderate population, people that have well-preserved central vision but affected peripheral vision. In this study, the primary end point will be static perimetry at 18 months' time point. And the key secondary end points here will include mobility course, BCVA and OCT, amongst others. The goal here is to be able to see an improvement in static perimetry in line with the regulatory-approved threshold data already seen from the Stellar trial. For both studies, we are planning for an 18-month primary end point readout, but we'll consider to potentially add in an interim analysis at month 12 in the final trial designs once we have alignment with the regulators. The 2 studies now give us potentially 2 shots on goal for registering this drug in a broad population. In conclusion, I'm pleased to have shared with you today the exciting results from the Stellar trial. In this trial, we have observed QR-421a to improve visual function and to be safe and well tolerated. We are looking forward to moving this drug into pivotal trials now to support registration of QR-421a for Usher syndrome and non-syndromic retinitis pigmentosa. I would like to take this opportunity to thank the trial participants, the caregivers, the investigators and all the staff for the hard work and dedication in this study. We look forward to continuing to work together together to get QR-421a approved in the future and to help everyone that can benefit from this therapy. I will now hand over the call to our CEO, Daniel de Boer.

Thank you, Aniz, for walking us through these very encouraging data. We are very pleased with the outcome of the Stellar trial, and we look forward to advancing QR-421a to pivotal testing and, ultimately, registration to get it to patients worldwide. This is now the second time we have been able to show vision benefits in a debilitating inherited retinal disease in 2 separate disease-causing mutations, which is an important validation of our broader platform. This builds further confidence in the rest of our pipeline, consisting of multiple programs for other IRD-causing mutations, where there is significant unmet need for patients. As I mentioned earlier, there are millions of people with an IRD who have no treatment available. At ProQR, we plan to change this and are applying our platform to develop RNA therapies for mutations that cause IRDs. 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 of thousands of patients with IRDs. And with the data and next steps shared today, we have made a significant step in further derisking this strategy. To that end, we have a pipeline of first-in-class RNA therapies with currently 4 drugs in clinical stage. Our lead drug sepofarsen completed enrollment in a pivotal trial earlier this year. And now our second program, QR-421a, is advancing into pivotal trials as well. Now that the platform is confirmed by a second program with such encouraging clinical data, we see a significant opportunity in further expanding the use of this platform into thousands of other IRD-causing mutations. We plan to further build out our strategy for inherited retinal diseases focusing on 5 core pillars. First, as I shared earlier, patients like Molly are our North Star, and we focus on significant unmet medical needs from their perspective. There are millions of people that live with an inherited retinal disease that have no treatment option whatsoever, and we plan to change that. Second, we build this platform based on validated science and a productive in-house discovery engine, in which we had programs for over 50 IRD-causing mutations. As we understand the underlying genetics, each molecule is designed as a precision medicine to target a specific mutation that causes an IRD. And given we know that genetic mutations have caused the diseases, we can apply rational design in our discovery process, designing these potential new therapies on a computer to specifically address the disease-causing mutations. This allows us to rapidly select new development candidates. Our drugs have a favorable therapeutic profile with a long half-life that enables infrequent dosing. And by using the routine IVT administration, the drug has delivered to all parts of the retina and, therefore, has the ability to target progressed, so end-stage or central disease, as well as early-stage peripheral disease, as we showed today. Our third pillar focuses on our translational platform using human retinal organoids to test new drugs on human retinas before we start a trial, allowing us to accurately predict activity and dose levels. The platform has successfully predicted the efficacious dose levels in sepofarsen and now in QR-421a. And we are continuing to advance the model to achieve full predictability by establishing in vitro-in vivo correlation that allow for precision development. The fourth pillar on our strategy focuses on the deep connections that we have in the expert clinical trial sites and key opinion leaders to execute our clinical development programs and also the vast experience our global team has in ophthalmology drug development. This provides synergies across our clinical development efforts but also from a commercial perspective. It also provides us with deep know-how on the development of inherited retinal disease drugs and the selection of future targets. With the vast R&D experience of Aniz as well as Naveed Shams, our Chief Scientific Officer, that have collectively taken over a dozen drugs to markets and have been key in developing some of the most successful drugs, including Lucentis, and cultivating an experienced KOL network around them, we are trailblazers in this space of inherited retinal disease drug development. The fifth and last pillar is where the commercial synergy comes in. We are building a commercial infrastructure to the approximately 35 specialist centers in the Western world and see the vast majority of the patients with all different source of inherited retinal diseases, a platform we can leverage across our portfolio that will provide significant commercial cross-portfolio synergies. And IVT administration allows our drugs to be administered routinely, which provides significant market access advantages. In the coming 12 to 15 months, we have a significant amount of news flow across our pipeline. Our lead program sepofarsen for LCA10 is currently in a pivotal study. And in January, we announced that this study is fully enrolled, and we are now awaiting the 12-month primary end point readouts, which we are expecting in the first half of next year. In a pivotal study, we are including patients of 8 years and older, so to collect some safety data in children below the age of 8, we will start a pediatric study in the next few months. We then anticipate to file for registration in Europe and the U.S. after the readout of the pivotal trial. And later this year, we plan to share an update from the InSight open-label extension study in sepofarsen. Our second program is QR-421a for Usher syndrome and non-syndromatic RP, on which we presented the data today. We will now progress QR-421a cohorts into pivotal phase with the objective to register the drug and get it to patients. We will wind down the Stellar trial and offer the participants to roll over in a long-term open-label extension study called Helia, in which they will be offered repeated dosing in both eyes. And we look forward to sharing updates from this study with you as we progress. Our third clinical program is QR-1123 for a specific mutation causing retinitis pigmentosa. This program is currently in a Phase I/II trial, which is also fully enrolled. In this study, we are following the participants until we take a data cut later in this year and announce that data, based on which we will then decide on the next steps for that program. We have learned a lot from the analysis of QR-421a, and these learnings will be relevant in the development of the QR-1123 program. Although the disease is genotypically very different, it is phenotypically very similar. So we are looking forward to that later this year. And last but not least, our QR-504a program for Fuchs endothelial corneal dystrophy. This program is ready to start enrollment in the next few months, and we anticipate to announce data from this study in the first half of next year. So a lot of exciting updates in the near term on the bath to deliver medicines to patients in need. I want to thank everyone for their participation on today's call. We're excited to have shared this very encouraging data update with you today and to move the drug forward into pivotal stage. I will now hand the call over to the operator for questions.

[Operator Instructions] And your first question comes from the line of Josh Schimmer of Evercore ISI.

Congrats on the encouraging results. I have 3 hopefully quick ones and I think most for Aniz. First, how are advanced versus early, moderate-staged disease patients defined? And how clearly separated were those 2 groups? And then we've talked about how 7-decibel improvement is quite a dramatic effect size. Why do you think some of the vision sites in the control eye had that magnitude of effect? And then lastly, when do you expect we'll see more detailed data with some of the other vision measurements such as DAC and FFP?

Yes. Thanks, Josh. And hopefully, you can hear me okay. This is Aniz. Your first question was the definition of advanced versus early to moderate population. We took the advice of our KOLs and experts in the field who suggested using 70 letters on the ETDRS scale, which corresponds to about 20-40 vision, which is essentially a doubling of the visual angle and is a significant milestone point in the visual acuity loss that happens. And so that made sense for us to be able to use that. I know that, for example, in the RUSH2A protocol, the FFP have also used a similar cutoff as well. Your second question was related to the 7-decibel improvement. And yes, indeed, 7 decibels is a very significant improvement there. You had mentioned that there were some control patients that also saw a response there. Indeed, we do see, of course, a test-retest variability, whether you call it that or whether you call it a learning effect. Really, the key thing here is that we find that at every time point, there are more patients who have a higher number of retinal loci that respond in the treated eye compared to the control eyes. And so that's really important. We do ensure that actually we try and keep the control level of response as low as possible. And in fact, we're one of the unique companies who adopt a methodology of having multiple tests. So we do 3 tests for static perimetry at each time point, and we take the average of the last 2, which have been showing to be a much more accurate and predictive way of reducing noise in the system. Now of course, ultimately, we know that the control patients will have some kind of response. We know that actually patients in even other trials, such as the Lucentis trials, have shown up to a 30% response rate in 3-line gainers. And yet, of course, as long as the treated eye is superior to the control eye and that shows statistical significance and that there is a positive benefit-risk shown, the FDA is, of course, able to approve those drugs. I hope I've answered your questions there, Josh.

Yes. And then a more detailed data presentation?

Yes. We are, at this stage, of course, just issuing high-level data, mean-level data. We will be -- we are actively working on more detailed analysis at this stage, and those will be released in a peer review journal or presentations shortly to come.

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

Congrats on the data as well. I think just 2 from me. We know FDA typically considers a 3-line or a 15-letter improvement, clinically meaningful in visual acuity. In your discussions, do you have any sense if that's the hurdle in Usher syndrome? Or is it a different bar given the unmet need and no proof therapies?

Yes, Jon, that's a very important question. Of course, everything depends on the baseline of BCVA. And we know that Usher syndrome, non-syndromic RP is a very slowly progressive disease. We know that there are 2 ways of analyzing the data. One is the mean BCVA response or the second is a responder analysis. And the responder analysis can be either a 3-line gain, like we saw with some of the drugs previously, historically, or indeed in the case of drugs such as Lucentis and Macugen, there was a preservation of vision. That's to say a loss of less than or equal to 3 lines in vision loss. In our analysis, you saw very clearly that with the treated eyes, we're able to maintain their vision, stabilize the vision for up to 48 weeks with just single one dose, whereas the fellow eyes waned away and they deteriorated. Now at the 48-week time point, we have a 9.3-letter delta between the 2 eyes. And indeed, as we think about projecting out to the 18-month primary end point analysis for our future trials, we believe that we will get the -- we will power up for a 15-letter delta there. Indeed, if you look at some of the early data that's there, that we've not shown because of small numbers of patients, that number is actually very realistic. So we feel that we'll get there especially in light of the fact that we will be able to, of course, use a targeted population, have multiple dosing available to us. So those are the key areas in which we can actually hopefully get the FDA-approvable end point of the 15-letter mean change from this arm.

That's very helpful. And the last one from me, I might have missed this. The EZ area data in the microperimetry you presented, was that from all patients or just advanced patients? And did you see a difference in those end points between the early and the advanced?

Yes, good question again. And the data you saw on these concurrent end points were really on the ITT population. So that's the all treated population. And so we wanted to keep it at high level because I think these are supportive end points. Remember that in terms of the 2 primary end points that we will be using, we'll be using BCVA for the advanced population, and that's why the advanced population data was shown. And that was, of course, more robust than the all population, as you'd expect. In the early to mid-population -- disease stage population, we saw static perimetry being presented in, again, the ITT population but also the early to moderate population to show that actually it's the baseline that drives the outcome measure. The other end points are really supportive data. You're right that, of course, EZ is a very important supportive end point because it's an objective end point. And therefore, it really allows for an objective evaluation and supportive of all of the earlier end points that we've seen so far.

And your next question comes from the line of Emma Nealon of Cantor Fitzgerald.

My congratulations on the data as well. On a patient level, are you able to give any color on the BCVA benefit for the 2 patients who have the cataract and the CME? And then also just curious if you can talk a bit about the frequency of these events in the context of the natural history of the disease. And then I have a follow-up.

Yes. Yes, really good question. So really, we saw that one patient who had bilateral cataracts, both of these had to be removed or with cataract extractions. That person's visual gain was maintained. There was no detriment to that patient. Cataracts tend to occur very frequently as part of the inherited retinal diseases. And as part of Usher syndrome and non-syndromic RP, that can occur up to 50% in the natural history of the disease. And that's also the case with cystoid macular edema. Here we have reports of up to 50% that actually occur of CME at baseline. And the one patient that's had a existing -- pre-existing CME baseline that got worse, that patient's vision has not been affected at all. And this patient is being treated with the standard of care therapy.

Great. And then for the pivotal studies, can you just talk about how you plan to select the 2 doses there and what additional data we might get from the current Phase I/II on long-term safety or efficacy that might be important for that decision and whether it would be the same doses in both studies for advanced and early, moderate patients?

Yes. So as you know, the FDA is very keen on having 2 concurrent doses and then also an additional sham arm in the pivotal studies. What they normally do is they ask for a target registration does. And then it's up to you as a sponsor to include a second dose. That second dose is really there just for masking purposes only. And so as we work through all of our data sets and also look at our the preclinical modeling, that will really inform us better on the exact doses that we need to take forward. As you saw in the presentation, actually, the good thing is that we have a very wide therapeutic window. We have all of the doses that responded, and therefore, we have a nice option there to be able to choose any 1 of those 3 doses. And further, working through this with our preclinical folks and modeling, we'll be able to define the exact target registration dose to move forward. And then we'll be able to then, at that stage, figure out what an alternative dose for masking purposes would be. Now it's likely that the doses will be similar in both of those 2 studies. And I think that all of the data analysis that is ongoing is really going to be able to inform the exact target registration dose ultimately.

[Operator Instructions] And your next question comes from the line of Keay Nakae of Chardan.

Yes. Just going back to the static perimetry measurement in the control patients, you talked about taking the average of the last 2 or 3 tests. Any other procedural protocol, methodology that you could use in the Phase II/III to control the noise there?

Yes. This a very important question because, of course, as we think about the Phase II/III, ideally, we want to limit the amount of noise to as low as possible. Of course, in addition to using a triplicate measurement and then taking the last 2 measurements to reduce the noise, we also very carefully select the instrumentation. And at the moment, we are using the Octopus 900 Pro, which is the favorite instrument of choice for static perimetry and retinal sensitivity by the FDA. In addition to that, we will employ a raft of extra training and certification process to ensure that all sites can actually do this very accurately, like we did in the current study. And I think that, that will further enhance the robustness of the data that we see at the end of the day. And I think...

Okay. And then second question...

Go ahead, please, Keay.

No. No, go ahead and finish your thoughts there.

I was just going to say that I know from experience that actually many other companies don't employ triplicate measurements. And therefore, I think in speaking with our experts in the field, they were very happy at the measures that we were already putting in place to get this data. I think importantly, we will see some noise in the control. The test-retest variability exists. But I think as long as our treatment arm is superior to the noise and that we are -- we have a positive benefit-risk, I think those are really the key things at this stage.

And then in terms of the actual sites that would be involved in the 2 studies, how much overlap are you anticipating there will be?

Indeed, there will probably be a significant amount of overlap because, in general, as you look globally, both U.S. and ex U.S., there's probably about 25 to 30 sites globally that actually see these patients with inherited retinal diseases and, in particular, patients with the Usher syndrome or non-syndromic RP. And these are many of the sites that we actually know very well. We have deep embedded collaborations both with our sepofarsen program, LCA10 program, as well as the existing Usher's program as well. And therefore, it's likely that many of these sites will contribute patients to both of these trials concurrently.

And your next question comes from the line of René Wouters of Kempen.

Congratulations on the results. Maybe a few quick questions from my end. So can you indicate the size of the groups of advanced versus early/moderate patients? Second question, maybe I missed it, but what are the doses that we'll use in the Phase III trials -- Phase II/III trials? And a third question, do you believe that 6 months is the best dosing interval as there seems to be a decrease in treatment effects already between the 12- and 24-week measures in several of the end points?

Yes, great questions. So let me maybe try and remember the 3 questions. So firstly, you asked about the size of the 2 groups. The advanced population has 6 patients in total. And the early to moderate stage patients have 8 patients in total. Now you'll remember that actually in the advanced patients in the BCVA, all 6 out of 6 were responders. And in the early to moderate patient population, 7 out of 8 were responders on a static perimetry. You then asked about the doses that we are likely to use in Phase III. As you saw from the breakout of the doses, luckily, we have a very wide therapeutic window there. And that's in keeping, I think, with all the nucleotides in the eye in general. We're able to then, therefore, choose the appropriate dose based out of all of our preclinical models that we'll be doing. And therefore, what we want to do is, ideally, look at the preclinical modeling, and we have to then make an assessment on which doses we ideally want to move forward. And that's active work in progress. You then also asked about the duration of the dosing. In general, if we look across the different end points, it seems like we have a waning away of the effects around the 24-week time point. And this is in keeping with a lot of our preclinical work and preclinical modeling that we had as well. And therefore, it seems likely that by giving a second and then subsequent dose on a 6-monthly basis, that will be able to keep the efficacy at -- and maintain at a reasonable rate. So hopefully, that will be the case. We'll be doing some further deep dives in the preclinical modeling around this to be able to be better inform us with that and then, of course, getting some validation through presenting this to the FDA formally in order to get their buying into the final trial design.

Got it. And maybe as a quick follow-up on the first question I actually asked, more in general terms in the general Usher population, what is the breakdown between people that will classify as advanced patients compared to early, moderate patients?

Yes, got it. As you know, it's about 16,000 patients in total, roughly split in half between those 2 particular subtypes, so half in the early to mid-population and then half in the advanced population type. Now it's important also to mention that each trial can get approved for all of the patients, so we don't need to have both of those trials getting approved for individual patient subtypes. We have those initial discussions with the FDA, and we'll get confirmation of that formally. But that was made very clear that -- and of course, it would make sense, right, that if you have -- you have one of the trials getting positive, that, that would then unlock the door for the mechanism of action to work across all of the patients and then to be able to then treat the patients as early as possible, of course.

There are no further question at this time. I would now like to hand the call back over to Daniel de Boer for closing. Thank you.

Thank you, operator. We're pleased to have shared with you today these encouraging findings from the QR-421a Stellar trial, and we look forward to moving this drug now forward into pivotal testing. I want to thank everyone for joining the call today, and we will now conclude this call. Have a nice day, everyone.