Opus Genetics, Inc. (IRD) Earnings Call Transcript & Summary

Good morning, and thank you for joining us today to delve into our gene therapy pipeline with a focus on our earlier-stage programs. As a reminder, this event is being recorded. Before we begin, I'd like to remind you that during today's call, we will be making certain forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements. Please refer to our annual and quarterly reports and our other SEC filings available on our website. Any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to these go even if our views change. Recording of this event and the accompanying slides will be available in the Events section of the Opus Genetics Investor Relations website later today. So we have a really terrific lineup of speakers and are really grateful for all the key opinion leaders joining us today to share their expertise on the treatment of inherited retinal diseases, including targeted indications for Opus. For reference, you can access speaker bios on the right side of your screen or via the button in the top right corner. Today's agenda is divided in 2 parts. In part 1, we will provide a brief company introduction and scientific overview. Then one of our KOL guest speakers will discuss each disease followed by a summary of our scientific approach for the corresponding indication. We will review our clinical development strategy and approach followed by our first Q&A session on these programs that will be entering the clinic later this year and into 2027. Please note that any time during our presentation today, you can submit a question using the Ask a Question button on the top right corner of the screen. In part 2, we will provide a brief summary of the clinical trial data from our lead programs, LCA 5 and BEST 1. We will highlight the recent epidemiology work we commissioned to better inform the disease prevalence of our 7 current indications. And finally, we are excited to host a panel discussion with several industry experts to discuss patient recruitment and retention in inherited retinal diseases. We will then open the call back up for questions. So I'd now like to turn the call over to Dr. George McGrath, Opus' CEO, to kick off our program.

Thank you, Ben, and good morning, everyone. At Opus Genetics, we're focused on accelerating groundbreaking gene therapies for inherited retinal diseases. We're advancing a portfolio of 7 AAV gene therapy assets built on validated science and a proven delivery approach pioneered by our co-founder and guest speaker today, Dr. Jean Bennett, whose work led to the first approved IRD gene therapy. We hold first-mover advantage across multiple indications supported by broad IP protection, orphan drug exclusivity potential and rare disease regulatory pathways that offer flexibility and potentially accelerated approval. Our approach emphasizes streamlined time lines, capital-efficient development and the ability to progress multiple clinical programs in parallel. We're fortunate to collaborate with leading scientific and clinical innovators in gene therapy, many of whom are here with us today. By building a portfolio that spans multiple rare retinal diseases, we believe we can capture meaningful share in a multibillion-dollar market and deliver multiple approved therapies for patients with severe genetic eye disorders. As you will hear today, our validated scientific approach and early clinical success give us strong momentum as we expand into our next group of promising programs. We're currently targeting 7 inherited retinal diseases caused by genetic mutations. As you think about the indications we're focused on, there are 3 primary buckets of IRDs, the bestrophinopathies, bleber's congenital amaurosis and retinis pigmentosa. We have chosen these programs specifically since they have common approaches that we can leverage, including cell biology, delivery method and clinical trial design. Then we can differentiate as needed for each disease. For example, LCA mutations are typically earlier onset conditions in children, and they are also more macular focused, while the retina pigmentosa mutations have a more concentric loss of peripheral vision. All of these programs are fairly straightforward subretinal IRD gene therapy programs. And one of the reasons we pick these indications is because we can potentially see a rapid proof of concept in clinic. We will go through much of this today as we look towards several clinical trial initiations and data readout in the next 12 to 18 months. We really are building a differentiated gene therapy pipeline. Our company is essentially built as a platform to develop these gene therapies and advance them in a very capital-efficient and time-efficient manner. For LSA-5, we are currently enrolling participants in the run-in portion of our Phase III clinical program. This program has received multiple regulatory designations, including the Regenerative Medicine Advanced Therapy, or RMAT, -- and most recently, we were accepted into the new Rare Disease Evidence Principles, or RDEB program focused on ultra-rare diseases. For BEST1, Dr. Mark Panesi presented our data on the Sentinel patient at the Macula Society in February, and we look forward to presenting our first full cohort of data in September. Our key focus today is to provide you with the disease profile and scientific rationale for our next 3 programs. RO, RDH12 and MerTK that are all progressing into the clinic. Here on Slide 10, we've laid out our planned time lines. And importantly, current cash runway into 2029 will support 5 clinical development programs through multiple inflection points. We are really entering a pivotal time for the company. Based on early success we've had with LC5 and BEST1 and our recent fundraising activities, we are now in a position to accelerate RDH12, MERTK and R in the clinic. This increases our total addressable market in a significant way and gives us multiple shots on goal. We are now funded to achieve readouts in our BEST1 and LC5 programs and also generate clinical data from these additional programs coming online. Currently, we expect as many as 4 clinical trial readouts in 2027. It is important to note that all of our programs treat various forms of rare pediatric diseases with the potential to receive priority review vouchers if approved. It's my honor to introduce our first guest speaker, Dr. Jean Bennett. She is the inventor of Luxturna, which is the first gene therapy approved in the U.S. to treat inherited retinal diseases. She is one of our -- the scientific co-founders of Opus Genetics and remains a key member of our Board of Directors. Today, Dr. Bennett will provide an overview of IRD drug development and discuss the concept of structure function association that underlies all of our programs.

Thank you so much, George. It's my pleasure to be here. I thought to set the stage for the next set of talks, I'd give you a little bit of background about the rationale for selecting the various targets that we've selected. Obviously, the optimal targets have to affect -- have to target the affected cells before they've degenerated. Otherwise, you can't treat them. Ideally, lack of function disease is optimal since one can then reactivate the function and rescue the disease. We want transgene cassettes that will fit within the small cargo capacity of the adeno-associated virus or AAV, and that AAV must transduce the target cells efficiently. The disease has to be severe enough to be able to detect improvement and ideally in a fairly rapid time frame so that we can see this improvement quickly. We need the relevant animal or cell models to be able to develop proof of concept to be able to go forward and ideally select diseases which are relatively prevalent, so we can find enough patients to be enrolled in the clinical trials. The more challenging diseases are those that are developmental conditions, for example, those that begin the whole process -- degenerative process in utero, those would be very difficult to treat. And there are also some technical challenges with large genes fitting them into the small cargo capacity of the AAV. -- ideally, we want disease that progresses fairly quickly because we don't want the trials to have to take 10 years or longer. And it's more challenging if we don't know much about the natural history of the disease or if there's asymmetric disease or if it's extraordinarily rare. So shown in this graph is a diagram of the numbers of genes which when mutated cause retinal degeneration. Over time, the first ones were identified in around 1990, choroideremia and rhodopsin were some of the earliest. And as you can see now, the number has expanded to more than 348 identified genes, and that's in large part, thanks to the human genome project. When we first started and others first started considering gene therapy, gene augmentation therapy, the only 2 genes that were known were rhodopsin and choroideremia. RPE65 or retinal pigment epithelium 65 kilodalton protein encoding gene were some of the earliest ones identified, and those have been targets of clinical trials, choroideremia and RPE65 were targets of Spark Therapeutics and other people, including those that you'll hear later today have been involved in trials for choroideremia. But shown here are additional diseases, which have been identified over the course of this progress in the gene identification. And these are targets that OCU has selected that fit the characteristics that are listed in this slide in terms of optimal targets. In the next slide, we -- obviously, if the retinal structure is relatively preserved, even though visual function is already impaired, it becomes possible to deliver the gene to rescue the function in a therapeutic window when these are still -- the cells are still viable enough to be able to function. And if one can pick the right patients and choose the meaningful endpoints for clinical trials, one can potentially demonstrate benefit. And that's exactly what has happened with Luxturna, which was the reagent that was developed to treat RP65 deficiency. In the next slide, I'd like to show you 2 of the targets that Opus has initiated studies on. One is -- they're both forms of labor's congenital amaurosis. This is a severe early onset form of retinal degeneration, one of the most severe forms of retinal degeneration because it affects children and infants. LCA 5 and RDH12 are both diseases which are first manifest in photoreceptor cells, unlike RP65, which is the gene target of Luxturna. And these are both sillyopathies. They're very rare. But by imaging, we know that there are photoreceptors that are still available and treatable in childhood and young adults. And so that satisfies one of the requirements. There are animal and cell models that can be used to demonstrate proof of concept. However, compared to RPE65, these are more severe and earlier onset. And so we hypothesized that by treating children, we could actually intervene well with the disease and potentially even prevent the disease. And shown to the right are some of the children who are the first to be identified with these diseases. The top one is one with LCA 5 and underneath our EH12 children when they came to visit my laboratory. In the next slide, one of the reasons why these 2 diseases are so dear to my heart is because of the patient and family partnerships that have been made over decades. And starting with LCA 5, a labor's congenital amaurosis conference was held in 1998 that was developed and formulated by parents of a child with LCA. At that point, they didn't know what the cause of his disease was. And they fueled the efforts of academics and really an international consortium to try to figure out what was the cause of this and other forms of LCA. And their child's gene was identified in 1997 -- well, the child was born in 1997. But after this conference, his gene was identified some 10 years later in 2007. That picture on the lower left shows the team at Nyagan in the Netherlands who had discovered this gene. And that fueled a consortium to try to develop a treatment for this particular disease. The family continued to fund projects, including generation of a mouse model of this disease, which was made at Jackson Labs by Patty Nina, sent to my lab. And together, we all developed a reagent, which we showed could actually ameliorate the disease in this mouse model. In our lab, we set up a GMP facility to generate AAV. And then we were lucky enough to partner with Opus Genetics and develop a clinical trial. And shown in the lower right is the team that delivered the first gene therapy for LCA5 in 2023. In the next slide, I'd just like to close by telling you what I think the status of retinal gene therapy is. There's abundant safety data. There are more than 140 different retinal gene therapy clinical trials that have been initiated. There are gene therapy centers around the world and thousands of eyes have been injected. We have a lot of safety data -- there are numerous disease targets that have been tested and are in the process of being tested in the clinic with a variety of strategies, excellent safety data. And now there's familiarity with gene therapy surgical techniques, vector handling and storage, genotype, phenotype correlations, development of outcome measures all over the world. And it's a very exciting time. There are more than half a dozen retinal gene therapy clinical trials, which will read out within the next year, hopefully giving us additional approved gene therapy products besides Luxturna. Now where are we with Luxturna, also known as voretigene, the neparvovec rizzzle. This is the treatment for RPE65, which is now approved not only in the United States and the European Union, but in numerous countries and continents around the world. There is a great deal of long-term durability data that stems from the clinical trial that was run to approve this drug. It's more than 9 years in counting of this durability data. And the real-world efficacy is very similar to that reported in clinical trials. So we're really optimistic that Opus is going to contribute further to development of treatments for these currently untreatable conditions. So I'd like to hand off the next session to Dr. -- actually, let me give this slide. There are numerous obstacles to retinal gene therapy that have been overcome, just as a continuation of where we are. In the 2000s, when we began with LUXTURNA, there was no path. There were no regulatory guidelines. Everything had to be derisked, including the safety of subretinal delivery of AAV and dosing of AAV. There was a lack of genotype patients because there was no reason to genotype them. There was no treatment, no clinical trials in progress. No one had enrolled pediatric subjects for gene therapy clinical trials. We didn't know the status of immune response, whether this would cause rejection or inflammation. And we had no guidelines from the FDA, including whether or not it was going to be necessary to inject the second eye, the contralateral eye, what we needed in terms of control groups, et cetera. There was no natural history data and no relevant outcome measures and certainly no potency assays with which to measure the quality of the product. In 2007, when we began our first retinal gene therapy clinical trial, there was only one approved outcome measure, and that was reading the eye chart. Now there are numerous potential outcome measures, including the outcome measure that was developed during the process of testing Luxturna. That's the multi-luminance mobility test. And they're now virtual reality tests -- there's perimetry, there are anatomical features and also changes in disease progression. So it's a very bright future for retinal gene therapy. And now I'd like to turn the table over to Dr. Fan, who will tell you about RDH12. Thank you very much.

Thanks, Dr. Bennett. That was such a great overview of how far we've come with gene therapy and IRDs, of course, you've been so pivotal to all of that. Let's get into the slides in the interest of time. I'm just going to start reviewing this disease, RDH12, which is truly one of the most devastating forms of early onset retinal dystrophies or degenerations that I see in my clinic. D12 is interesting because it draws a lot of parallels to the severity and intensity of vision loss to RPE65. We know RDH12 accounts for up to 10% of all LCA cases. That makes the global prevalence over 30,000 with a high concentration in the Middle East and North Africa. There are still quite a few patients in the U.S., probably underestimating it at about 2,500 patients. But surely, as we know about all IRDs, the true prevalence is probably a little bit higher. These are images of a patient I see of my clinic, a young patient. As you can see on the images on the right, that you have essentially severe peripheral retinal atrophy. But what's unique about this retinal degeneration as opposed to a disease like retinitis pigmentosa is that you have more macular atrophy, which is central involvement early on in life. And so what you often see in these patients is they'll present in childhood with a diagnosis of retinitis pigmentosa, but then you kind of watch them progress very quickly into losing central vision in addition to peripheral vision, and that can be truly devastating for this patient population. Let's go to the next slide. Not to bore you with the scientific mechanism of action of RDH12, but essentially, as Dr. Bennett was saying, this enzyme and this gene has its function in the photoreceptors as opposed to the retinal pigmented epithelium. So you can see that the job of the photoreceptors, the outer segments is to process light and clear toxic byproducts like alltansretinol, which then can be recycled into the visual cycle. But if you're unable to clear those byproducts, what happens is that the byproducts will build up, they'll dimerize, they'll create oxidative stress and damage to the photoreceptors in forms of entities like A2E, lipofusion and that kind of thing. And so we know in RDH12, this process is very severe and will damage photoreceptors if left unchecked, leading to early vision loss in the disease that we call liver's congenital amaurosis or LCA. Let's go to the next slide. One of the most interesting things that we have found about RDH12 is, in some ways, it is parallel to RPE65, but in other ways, it is not. So the way that it is similar is that it has profound vision loss early on in life. We know that maybe in your teens or childhood, you're about 2,200, but it can steeply decline very quickly thereafter hitting counting fingers or even hand motions or life perception in your 30s and 40s, which is truly devastating and much more severe than a lot of other inherited retinal diseases. Drawing your attention to the diagram on the right, you can see that the OCT image of the patient of RDH12 has more disorganized anatomical layers of the retina as compared to the image of the OCT of R65. However, we have found on electrophysiology that there is better co-mediated sensitivity in patients with RDH12 despite the anatomical disorganization of layers as compared to RPE65, which may suggest because the pathobiology is relatively similar that perhaps these cones are rescuable because they still maintain pretty good sensitivity despite what we see on exam and also on imaging to be more severe retinal disorganization or potentially retinal atrophy. And so there is a therapeutic window here for us to produce a therapy that may mimic that of Luxturna that may be able to treat patients similar in some ways to RPC35 and maybe optimistically be able to rescue in maybe a more efficient way or better way this co-mediate sensitivity before it causes damage to the central vision. I'm going to pass it over to Ash now so we can review the scientific overview. Ash is the Chief Scientific Officer of Opus. Thanks.

Thanks, Dr. Fan. OPGX-RDH12 is an AAV8 vector designed for a onetime subretinal administration to deliver functional copies of the RDH12 enzyme to photoreceptors in order to restore visual function using a photoreceptor-specific promoter. And in our studies, mouse model of RDH12 deficiency was used to test OPGX-RDH12 to test for expression as well as function of RDH12 in the mouse retina. And we demonstrated with Dr. Bennett that OPGX-RDH12AAV restores RDH12 enzyme expression in the mouse retina as shown on the right panel, and in a dose-dependent manner, also restores enzymatic activity and function approaching that of wild-type mouse retina levels. And the RDH12 deficient or as we call it, a knockout mouse model is also highly susceptible to light damage due likely to acceleration of phototoxic stress and subsequent photoreceptor apoptosis. So left untreated, these RDH12 knockout mice treated with high-intensity light exposure to the retina degenerate as shown by thinning outer nuclear layers where the photoreceptor nuclei reside, and you can see that on the top panel. However, AAV8 encoding for RDH12 expression in this published study was capable of preventing this retinal degeneration. And furthermore, mouse behavioral testing used to assess visual function also improved with AAV gene therapy for RDH12 as shown on the bottom half of the panel. And we, therefore, are well poised to now investigate OPGX-RDH12 safety and efficacy in clinical studies. And so with that, I would now like to turn the call over to Professor Robert McLaren to discuss MERTKRDs.

Thanks very much, Ash. And also thank you to Jean for a very helpful summary of the history of the retinal gene therapy, which I've been following myself for over 20 years now. So I'm Robert MacLaren, Professor of Ophthalmology in Oxford, and I've been involved in gene therapy trials for a number of conditions, choroideremia, X-linked retinitis pigmentosa, which take a lot of my time at the moment and also the work we've been doing with age-related macular degeneration. Now MERTK is one of those inherited retinal diseases that can be very severe in early onset and cause what we refer to as labor congenital amaurosis and others very, very poor vision from birth. But more often, what we see is missense changes where patients have a disease that is clearly causing the vision impairment, but still some ability to see things and read the chart. And this particular condition is caused by a mutation in the gene that encodes a protein that is involved with the phagocytosis of photoreceptor disks. And most significantly, the MERTK gene is expressed in the retinal pigment epithelium. And we know this cell, in particular, is readily transducible with low levels of AAV compared to photoreceptor transduction, again, which helps us in terms of predicting the clinical trial outcomes in terms of safety. The prevalence worldwide, I have patients in my clinic and oxate,' particularly high in the Middle East. And my colleague, Alan Alka originally did a MERTK gene therapy trial at the Kingollyye Hospital in Riyadh. And the reason for that was that it was funded by a family, the Aldi family, who unfortunately have MERTK in the family and was really done almost like as an off-label treatment. I was very much hoping that Fazan would continue the program. And in fact, I invited him to Oxford to come and speak about the results of the trial, but it's sort of faded away, unfortunately, at that stage. But we do have some very good examples from that paper that he published on the safety and in some case, efficacy of the treatment administered to a small cohort of 6 patients. So the phenotype, very, very similar to all of these inherited retinal diseases. If you look at the picture on the bottom right, kindly provided by Ken, again, I'm going to comment on your image, I hope you don't mind. But there is some debate about whether we can see subretinal clumps in the subretinal space. And you can see in the bottom right, the retina, the subretinal space. There is certainly good data from the models, the animal models that these are photoreceptor allogments of clump there. And it's one of those things that we look for potentially as a phenotype to identify patients and try and narrow down the genetic testing. So the ability to phagocytose the other segments is all part of the visual cycle indirectly. And so not surprisingly, these patients have night vision loss, peripheral vision loss. And indeed, the actual clinical features are very similar to those seen in many of the other inherited retinal diseases. So if we could go to the next slide, please. So this just shows a little bit more about the mechanism. And you can see that the MERTK receptor is on the surface of the retinal pigment epithelium. So we can translate a lot from the luxtoma program, which is also targeting retinal pigment epithelium to MERTK. And we might expect to see, as indeed we have seen with other inherineases is when you put back a protein that has a critical role in maintaining the structure of the photoreceptor, particularly the outer segment, then you can expect to see an improvement in the outer segment structure. And we've seen that with OCT scans as well. And if you improve the outer segment structure by liamans, you can also expect to improve the retinal sensitivity, which is very important because that gives you a functional endpoint. And functional endpoints are much easier to achieve with a small number of patients than anatomical endpoints in which one would have to wait quite a long time to see a difference in slowing degeneration in a treated eyes compared to untreated eyes. We know that the functional endpoints are well established. I mean it's going to be low lumous visual acuity, best corrected visual acuity, microperimetry. These are the tests we do all the time on our patients, and they're all recognized as being useful tests by the regulators for clinical trial approval. And ideally, we'd like to see something within 1 year improvements, which would justify approval of the treatment. So if we could go to -- so the failure of the MERTK results in accumulation of this outer segment debris in the subretinal space. And there is undoubtedly a window where the function is impaired, but the cells are still there, potentially could be reversed with a clinical trial outcome measure seen very quickly after gene therapy. And that is seen in the animal models. Next slide, please. So again, this just explains a little bit about what I said, the functional loss, okay? So any disease in which there's a loss of function before you get degeneration has a potential opportunity for reversal of functional loss by gene therapy, which gives us a nice clinical trial outcome measure. The reduction in vision, as I said, in most cases, we see it in childhood teenage years. Most patients manage reasonably well. But they do lose vision, and we do have a large cohort of patients who are treatable. And these patients will, in general, have had relatively normal development. They may have problems with in childhood with night vision, but they will be able to use a visual system and gives us an opportunity, a relatively large window in their lifespan where we could perform the intervention, as I said, because primarily of the preserved structure as well. And the phenotype on the right-hand side, again, I mean, to be honest with you, it's very, very similar to all retinal degenerations. But what you have to look at, if you're familiar with the structures of the OCT scan is the bottom scan. And you can see the black line, which is basically the outonuclear layer in contact with the reflected line, which is the retinal pigment epithelium. And this outonuclear layer is relatively well preserved. In other words, the photoreceptors are still there. They're probably largely nonfunctional because the other segments cannot grow. They're not being properly fanocytos. There's debris in the subretinal space, but the cells are there. And when the cells are there, there's a capability of regeneration following gene therapy. And by the way, the reference we've got at the bottom there is the guarding reference, which is the clinical trial led by Cal's a geneticist when he was working in Saudi Arabia. So I think just check. That's pretty much all from me. So I'll hang around for questions afterwards, and I'll gladly hand over to Ash to go through the molecular biology of the treatment. Thank you.

Thank you, Dr. McLaren. Our clinical candidate, OPGX-MERTK is an AAV2 vector designed also for onetime subretinal administration to deliver MERTK gene within RPE cells. And in this case, it uses an RPE-specific promoter. The capsid used AAV2 is the same as that used in the approved product for digene neparvovec or Luxturna, which as Dr. Bennett elegantly described, has now had a long track record of improving clinical outcomes in patients with RPE65 associated IRDs. So the MERTK deficient mouse model, which has been published and established for some time now, allows us to study the efficacy of MERTK gene therapies in a relevant context. This mouse model rapidly loses photoreceptors and concurrently loses visual function, but this decline can be prevented through subretinal injection of AAV and coding for MERTK. Specifically here, gene therapy-treated mice exhibited improved outer nuclear layer thickness as shown on the top right panel and improved electroretinogram or ERG functional responses as shown on the bottom right panel. And furthermore, using another model, this case, a rat model of MERTK deficiency called the RCS or World College of Surgeons rat model of retinal degeneration, we demonstrated that the clinical candidate, OPGX-MERTK was capable of dose-dependently reducing photoreceptor degeneration in this model when compared to a control injection, which had no therapeutic response as outlined by the blue dash line on measures of outer nuclear layer thickness. So with that, we look forward to investigating the safety and preliminary efficacy of OPGX-MERTK in clinical studies. And with that, I would now like to turn the call over to Dr. Lejla Vajzovic to discuss ADRPRO IRDs.

Thank you. Thank you very much, Ash. Good morning to you all. It's truly a pleasure to be here with all of you. It's really a pleasure to be included with such an outstanding, really world-renowned experts and clinicians, scientists and industry leaders. It's super excited to be here because the future of, I think, care of IRD patients is looking really bright. And I commend the Opus Genetics team for working so hard to provide more options for our patients in the future. As mentioned, my name is Lejla Vajzovic, I'm Professor of Ophthalmology, Pediatrics and Biomedical Engineering with tenure at Duke University. As a clinician and surgeon who has been taking care of pediatric and adult retinal patients with IRDs and who has been delivering the gene therapy surgeries for the last 15 years at Duke, I'd like to provide some more perspective on RO specifically associated retinitis pigmentosa, what I see in my clinic, how these patients progress over time and what's really the essence of the disease and why this may be a great therapeutic approach to treating these patients. So let's dive into RO-associated retinitis pigmentosa and one of the most common inherited retinal degeneration that we encounter in our practice. There has been more than 290 disease-causing mutations that have been identified and RO variations account for approximately 20% to 30% of autosomal dominant retinitis pigmentosa cases that we see. Importantly, this is not an ultra-rare disease. Currently, estimates suggest approximately 8,800 affected individuals in the United States and more than 30,000 across the global markets. From a clinical perspective, these patients often first present with night blindness and difficulties in dim environment. So this is really the first complaint we will hear very much from our patients. Over time, they experience progressive peripheral vision loss while maintaining the useful central vision for years to come. I think this combination of meaningful patient population, prolonged disease course, I think, makes an especially attractive target for therapeutic delivery. Next slide, please. Well, let's dive into biology itself. Well one of the aspects that makes RO particularly compelling is that we understand the disease biology exceptionally well. Row encodes rhodopsin, the critical photopigment with the rod photoreceptors that really enables vision in the low light conditions. When mutation does appear, the resulting protein can misfold or function abnormally, triggering cellular stress and progressive photoreceptor degeneration. Importantly, many dominant role mutations act through toxic gain of function or dominant negative mechanism. As a result, these therapeutic approaches most address the mutant protein itself rather than really adding another copy of the gene. So we really want to address that mutant protein than just kind of multiplying and adding new copies. So deep understanding of this disease biology really provides us with stronger scientific rationale for targeting gene therapy approaches for certain. Next slide, please. I think one of the most encouraging aspects of R-associated disease, it's often relatively slow progression. This disease typically begins with raw destruction during the childhood. As I mentioned earlier, it presents with night blindness and peripheral visual field construction over time. But the cone, the central vision degeneration is typically the last one to occur in this disease course. We do understand that there are 2 classes, 2 broad phenotypes that have been described here. Class A patient experience is more of a severe disease with early functional loss, while Class B patients often maintain broad function and preserve retinal structure well into the adulthood. I think this distinction is important because many patients, again, retain viable photoreceptors for years, creating meaningful opportunity for us to intervene therapeutically and hopefully stop their degeneration or at least slow it down. I think the structural and functional data shows that there is definitely room for intervention and the disease progression can very much, as mentioned earlier, in other diseases can be measured as such with imaging and functional testing, providing us now tools to really understand and how to develop clinical trial designs, follow the patients and ultimately report on outcomes. I think before I transition back to Ash, I just want to summarize. I believe Rove represents one of the most compelling opportunities in inherited retinal diseases because it truly combines 3 key characteristics for me. First, we have well-understood disease mechanism; second, meaningful and identified patient population that we can treat. And third, we have a therapeutic window where the photoreceptors remain present and potentially are amenable to interventions. Those characteristics, I think, make RO an attractive target for gene therapy, especially in development. And with that, I'm going to turn it back to Ash to discuss really their OpusRO program. Thank you so much.

Thank you, Dr. Vajzovic. In this case, we're talking about the clinical candidate, OPGX-RO. This is an AAV5 vector. And like the others, it's for onetime subretinal administration for patients with autosomal dominant retinitis pigmentosa associated with RO mutations. OPGX-RO is a mutation-independent single AAV construct for silence and replacement. And this is designed to replace mutated rhodopsin proteins with a functional nontoxic copy, and the vector targets rod photoreceptors using selective promoter technology. We've been fortunate to have demonstrated preclinical safety and efficacy in 2 large animal models of ADRPRw as previously reported. Here, in the canine model in collaboration with Dr. William Beltran of the University of Pennsylvania, we have tested safety and efficacy of the clinical candidate in this model of ADRPRO mutations. The canine model is a mastive, English mastive with a naturally occurring point mutation in row and expresses nearly equal amounts of wild-type and mutated row proteins and captures well, we think the structural degeneration observed in Class B human ADRP patients, as you see on the top right. Within the first 2 years of life in this model, there is a substantial loss of photoreceptors. However, this time course can be accelerated even further with light exposure to enable the study of therapeutic interventions within an efficient window. In fact, with a 1-minute light exposure protocol, rapid photoreceptor loss down to even a single row of outer nuclear layer nuclei can be observed as early as 2 weeks post light exposure in the ADRP row, but not the wild-type canines. And you can see that on the bottom right panel. So this accelerated degeneration model has been useful for us to test our clinical candidate. So here, on the left panel, we can see that the retinas post injection of subretinal AAV and light exposure treatment have exhibited significant outer nuclear layer retention in the treated areas. So the dash lines are actually showing demarcating the subretinal blood boundaries here. And immunofluorescence on the right panel shows rhodopsin and cone staining with conarstin in green and red, respectively. That histology and immunofluorescence confirms our observations in vivo. And what we're seeing here is photoreceptor cell body retention with observation of rod outer segments as well, which was only observed in the subretinally treated areas, not the proximal untreated areas. So in the addition to the canine model, we have also tested on the next slide, OPGX-RO safety and efficacy, in this case, in a humanized swine model of ADRPRow, and this was in collaboration with Dr. Maureen McCall of the University of Louisville. This model exhibits a human p23HR variant, which is highly prevalent in North America. And the retina in this model rapidly degenerates by postnatal day 60, such as there is only residual rod structure and function followed by subsequent cone degeneration. And thus, this also, we believe, accurately models the structural and functional degenerative time course that we see in ADRPR patients. We observed that OPGX-RO here, as shown on the right, preserves rod photoreceptor structure and reduces the aforementioned degeneration. And specifically, if you look in the untreated panel on the bottom left, untreated rods are sparse. They are dysmorphic and rhodopsin is mislocalized in these retinas. However, when we treat with OPGX-RO, we see that it's capable of dose-dependent preservation of rods as shown in the upper right panels -- and in this case, you're starting to see proper localization of rhodopsin and preserved cell morphology. Not shown here, but also previously presented was preservation of the rod isolated full field ERG in treated animals, but not untreated animals. We also have observed preservation of cone structure throughout the study as shown on the upper right panels. And this is also correlated with preserved cone ERGs, again, not shown here, but previously presented. And so with that, we look forward to investigation of OPGX-RO in clinical studies. And on that topic, I will turn the call over to Dr. Sally Tucker, our Chief Medical Officer.

Thanks so much, Ash, and good morning, everybody. As Ash said, I'm Sally Tucker, Chief Medical Officer. If we go to the next slide. As mentioned earlier, when we consider the IRDs we're targeting, that fall into 3 separate buckets. We have the vestroonopatpies, which includes both ARB and BVMD. These patients with ARD generally occurred much earlier on than BBMD. And the progression can be slow and often variable. It results in a defective calcium chloride channel that results in functionality dysfunction of the RPE that results in cone loss, patients often complain metyphoxia, decreased central vision and photophobia. And then in the other 2 buckets, we have LCA and retinitis pigmentosa. LCA, which we have touched upon already, generally occurs from a much earlier onset. Patients are born with the LCA and it affects vision much earlier on and in many cases, from 1 to 2 years with many patients being blind early on. Whereas in retinitis pigmentosa, the vision loss can occur in the adolescents to adulthood. So there can be progression over years. However, regardless, with these patients, they have abnormal red cone functionality, decreased central vision, night blindness, visual field loss that results in tunnel vision and for many patients, niceness. And as we indicated previously, our goal is to reinstate the functionality of the retina in those patients that have structure so that we can then see vision improvements in a relatively short time period. We go to the next slide. This indicates the signs and symptoms of the various IRDs that we're targeting. And what you can see here is that the signs and symptoms really key in the development and design of the protocols for all of our IRD programs with us addressing either structural endpoints or key functional endpoints. So you can see here with many of the signs, we're really focusing in on fuunalystography, funder autofluorescence and SVOCT. -- as Dr. MacLaren indicated, it can be that these changes occur over a longer time period. However, with the symptoms, we're focusing in on better corrected visual acuity, low luminance visual acuity, FSP, microperimetry, contrast sensitivity, virtual reality, MLMT, perimetry, static perimetry and kinetic visual field testing. And then in addition, we also can look at pupilometry and quality of life parameters as well, which are important to consider in those symptoms that might be more hard to quantitatively assess. Our clinical designs follow a data-driven dose exploration approach. So what does that mean? Well, with any Phase I/II study, the primary purpose is to determine safety. We want to ensure that the drug delivery is safe and is well accepted by the patients that it is administered to. But we're also wanting to see an efficacy, and we're wanting to see as maximum efficacy as possible. So what we will do is we take a data-driven approach. We utilize an independent data monitoring committee, and we will present the data to the committee. We're looking for safety. And if the -- there is some efficacy there, but it doesn't represent a maximal approach, then we will dose escalate into higher doses. However, if there is evidence to suggest that a maximal efficacy signal has been reached, we would then progress into a pivotal trial without any further dose escalation. We go to the next slide. We have 3 programs that we are entering the clinic over the next 12 months. So it's an incredibly exciting time. We're expecting RDH 12 to be initiated later this year, MERTK in Abu Dhabi in the first quarter of 2027 and Row utilizing global locations in the second half of 2027. As such, if we go to the next slide, we do have a number of strategic partnerships, one of which is with the RDH12 Alliance. This encompasses the fund for site in the U.S. and eyes on the future in the U.K. And I see the RDH12 is a co-developer in our IDH12 program. We have received funding from the alliance to support the progression of this clinical trial. And we have regular calls to discuss the trial design, providing updates to the patient community. And we are actually at the Family Day, the RDH 12 Family Day that's being held in London this weekend where we'll be providing updates of our current RDH12 program. In addition, we have a partnership with the Abu Dhabi Department of Health. As indicated earlier on, MERTK has a higher prevalence in the UAE and Middle East. and we have received funding to support the execution of the clinical trial there. And we also have other partnerships with Hope and Focus, Foundation Fighting Blindness and other organizations that really help to elevate awareness of the clinical development programs we are running, support our patient enrollments and optimize recruitment to the studies that we run. Moving on to patient recruitment and retention strategies, which are key in the overall success of any clinical development program. It's true that globally, more than 80% of clinical trials fail to enroll in time. So how can we overcome that? Well, we're developing patient education videos -- we want to increase awareness of the IRDs that we are focusing in on, but also help to provide more education to the patients that are considering participation. So we're interviewing patients that have been involved in prior clinical trials, what were the questions that they had, what was the thought process that they went through, how can we provide more material to the patients in a mentorship capacity to support the decision-making that they might have. Where possible, we'll initiate observational studies before moving to the interventional study, which will help to identify IRD patients in a proactive way. And as I said previously, we optimize patient engagement. So where possible, we'll work with patient alliance groups such as the IDH12 group, be involved in family days -- we also have a newsletter that patients can sign up to through our website. And we also reach out across patient databases, utilizing many of the databases from Foundation Fighting Blindness, SyoGenetics, Invitae and others. The other thing that we need to consider is that there is an 88% clinical trial dropout rate in long-standing studies. And with our studies, they have a 5-year follow-up. So it's important to collaborate and consult with patient advisory boards, giving their inputs to our protocol design, making sure that we're selecting the right endpoints and also making sure that we're considering the burden on the patients being involved in the study. And finally, what we are also piloting as part of a way to improve retention in our clinical trials that goes above and beyond the traditional step end that you see in the U.S.-based trials. is that we also want to give something back to the patients. So making sure that we continually educate them throughout the course of the trial, reminding them why they're in the trial and what we're hoping to achieve through the trial, but also providing a coaching initiative to these patients so that they're getting something back in return for their time, which is not insignificant over a 5-year period. And then lastly, we are all about increasing the patient's voice. So this is one of our patients that was recruited to LCA 5 and was actually featured on -- good Morning America. We're not only wanting to increase awareness amongst the IRD community, but more broad than that. What does it mean to a patient living with blindness, the impact that it has on them and the impact that being in a trial can have on them and the treatment and what it means to them. So we're very proud of this initiative and how we've supported Linzay in increasing awareness of LCA 5 in this way. I'm now going to hand over to our President, Ben Yerxa.

Thank you, Sally. We've had a few that have come in. Let me sort through these real quick. So for the first question for our guests, we should probably consider this sort of like a lightning round because we've got a number of questions. But I think for Dr. Fan, MacLaren and Vajzovic, let me read this out loud. So for IRDs that affect a relatively small number of patients, such as LCA 5, RDH 12 and MerTK, how difficult is patient identification? Are there ongoing efforts to increase patient genetic testing? And how motivated are patients to undergo such testing when no treatments are available yet?

I can briefly take some of those questions. I would say, obviously, they're very rare diseases, but patient identification for an IRD specialist typically comes naturally. You get a lot of referrals, not just from the retina community, but also the optometric community and fellow ophthalmologists, general ophthalmologists. So typically, if you're in a referral center, they do come. And oftentimes, you can see multiple rare diseases of the same gene mutation in the same day. I think a lot of a lot of patients are incredibly motivated despite the fact that there may not be an approved therapy just because there's other implications beyond just clinical trial and FDA-approved treatment, including family planning, protecting future generations, genetic counseling, all those things are major factors and perhaps sometimes the primary motivation for genetic testing. And with efforts from OPI and collaborations with FSB, there's been increased availability, at least in the United States to get low-cost genetic testing universally for all patients. I've had no issues testing these patients and almost 100% of them will do it because they're motivated for sure.

Thank you. Dr. MacLaren?

Yes. I mean in the U.K. and I think in Europe as well, virtually everyone will have genetic testing. It's an essential part of the workup of any patient with an inherited retinal degeneration. And indeed, if anything, the electrophysiology is what's gone out window. We tend not to do that very much anymore because we can tell very well from the imaging how advanced the patient is and monitor progression. But I think it's important to think about this as a lot more globally, okay? So I agree that there are individual genes, which are very rare, but the strategy is the same. It involves measurements of OCT measures of visual function. It involves an AAV vector. We know now exactly what the dose is. There will be differences in the requirements of different vector. The shipping manufacturing, don't forget, manufacturing is a key part of regulatory approval that should not be underestimated. It might be sometimes manufacturing is more complicated than the actual clinical trial. And then you've got the administration, the surgery, the subretinal injection, all the technology that's developed quite a lot, followed by the monitoring, the checking for inflammation and all the rest of it. So if you look at all the diseases together, then it becomes quite common. And we're talking about young people as well. So I always say, since we've been better at managing diabetic retinopathy, the inherited retinal les collectively are now probably in the U.K., the most common cause of untreatable sight loss in people of working age. So if that's not an unmet need, where is it? And I think what we've got quite nicely here is like a platform technology that overlaps on many different genes and therefore, has much more -- many more patients just for one single gene disorder.

Very well. And I agree, CMC here in gene therapy. Dr. Vajzovic?

And just to add to those amazing answers really from Dr. Fan and Dr. MacLaren, I would say, in the U.S., everybody that steps into retinal clinic that has any hint of IRD will get genetically test tested. So I think that has been really the crucial change for all of us in taking care of these patients. And not only will the patient result, but really we're discussing the effects of the entire family. And I feel like as a result, due to genetic testing, now we're diagnosing siblings and other family members earlier than we might have done before. So that has been really the big change. And lastly, we have amazing technology to image these patients in clinic these days. So I completely agree that we're relying on imaging more than ever to help us understand the disease and in clinical trials to help us understand responses.

Great. Thank you. Next question, I think I'll direct to Dr. Sally Tucker. This one goes, in general, are you planning on testing these next 3 gene therapies in children or adolescents early on in clinical development? Or will data updates in 2027 likely be in adults?

So the clinical trials will be designed to incorporate the inclusion of both adults and adolescent patients. So how they'll be structured. So similar, if you remember the slide that I showed and the platform approach, it will include 2 adults and then a minimum of 3 adolescent patients. So we established the safety first in the adults before moving on to the adolescent patients. So although the adolescents will be recruited to the study later on, the plan is to include younger patients in this first-in-human study.

Great. Thank you. Question, I think I'll direct to Dr. MacLaren. How much do you think the data from the ex-U.S. trial in EMERGE-K will help the eventual development in the U.S., U.K. and Europe?

Well, it wasn't really done as a proper clinical trial in terms of particularly having a natural history beforehand, which you normally have like a just getting baseline data to the tests are. And then the patients were selected with some very, very end stage because they're part of the family. So I think there's limited data we can get across the cohort. But there was one patient who did particularly well with the vision. And these patients have not had any major side effects and the effects we've seen following the gene therapy with are very, very similar to that seen elsewhere. So I think if I were writing the investigator brochure or preparing the work for the regulators, I'd certainly be citing this trial as a good example of having used the vector before in humans. And I think that would make the process a bit smoother and probably even less requirement for doing NHP work in order to gain regulatory approval.

Great point. Thank you. A question now for Dr. Bennett. For RDH12, could you expand on the similarities and differences from RP65, especially on the preserved current sensitivity. Could you talk about the therapeutic window for RDH12? And is there an optimal treatment age, early childhood versus adolescents? And then finally, one question. On the preclinical RDH12 data, any insights on how much restoration of enzyme expression is required to achieve meaningful functional benefit?

Great questions. The bottom line is we don't know because we haven't run the trial yet, but what -- but this disease is more severe than R65 deficiency. It -- the symptoms are manifest earlier and the degeneration is a little bit faster. But there is a great natural history study that is being carried out and has been carried out by Dr. Smasloman and colleagues, which is giving us a lot of information about the optimal time points and of treatment in terms of the rates of progression. Likely, we will be able to rescue -- I would predict we'd be able to rescue vision at least through adolescents, but probably the best outcomes are going to be in younger children. The other question was, can we predict -- can you repeat the second part of the question in terms of enzyme levels?

So how much restoration of enzyme function like percent restoration of function do you think will be relevant for improving...

Right. Well, knowing that heterozygotes are -- have fairly normal vision, we don't -- we believe that if we restore up to 50% of the level of enzyme activity, that should be sufficient. But even a small amount of enzyme activity should be helpful. And similarly to what we have found with RP65 deficiency, there may be just a rate-limiting step, which we need to overcome to be able to deliver some vision.

Got it. Thank you. So the next question came in. we'll think about who wants to jump in to answer it is how should we think about ranking potential pivotal endpoints for each program? Among the programs in development, do you see clusters of programs for which you expect the clinical development path or pivotal study designs to be the same in terms of like endpoints, number of patients, length of trial, et cetera. So I don't know who wants to jump in on that. Maybe, Sally, do you want to start? So...

I think that it's a little early to determine what our pivotal trial endpoints, primary endpoints would be at this moment in time. I think that all of our assets are rare or ultra-rare. And therefore, we're in this unique position to be able to get regulatory recognition such as RMAT, orphan designation, RDE, which really allows close collaboration and discussions with the agency. And that's certainly something that we I think that with these IRDs as well, there also needs to be consideration of novel endpoints and utilizing novel endpoints and also statistical methodology as well to be able to determine mean net benefit. And these are all things that we can consider when talking to the agency. I think that microperimetry is an endpoint that we're very interested in from determining central macular sensitivity. But I think it's a little early to say whether that would be uniformly utilized as our primary endpoint for all our pivotal trials.

Thank you. Last question in the first part here. Across these defined IRDs, are certain mutations considered higher priority in terms of progression? And does this impact Opus' gene therapy development prioritization? -- might be back to you, Sally, unless one of the KOLs want to jump on that as well.

Can you repeat that, Ben? Sorry.

Yes. So across all these IRDs that we're looking at, are certain mutations considered higher priority in terms of progression, like LCA versus RTE? And does this impact our prioritization of the pipeline?

So I think the prioritization of our pipeline is much led by our manufacturing efforts and when we're ready to take the various assets into the clinic. rather than the prevalence or the severity of the disease. So at the moment, as I said, we're expecting IDH12 to be in the clinic at the end of this year, with MerTK the beginning of next year and at the end of next year. And we'll be bringing these as quickly to the clinic as we can, dependent upon when we have availability of the drug and can push these forward.

Great. Makes sense. Dr. Bennett, anything you want to add to that?

I would agree with what Sally said. We plan to move forward with both -- with all of these candidates in a regimented time line and move as quickly as possible. But of course, there may be some factors which which would make one set of mutations, one disease target move faster than another. At this point, we can't predict.

Great. Thank you. All right. Great session for Part 1. Thanks to everyone for your participation. Thank you to all the speakers and all the great questions that came in. We're now going to move to Part 2 of our agenda. So I would now like to turn the call over to Dr. Bart Leroy to begin our clinical program discussion with LCA5.

Thank you, Ben, and thank you everyone -- to everyone for inviting me to be part of this beautiful series of presentations. So my brief is to talk on the LCA5 update. And can I have the next slide, please? So what is LCA5? It's actually an early onset severe inherited retinal disease with early onset visual loss as so many we've discussed previously in the first part of the meeting. Now the LCA5 is a particularly severe disease with very early onset loss of vision. It supposedly represents about 2% of all LCA cases. That would be globally 3,200-plus patients within the U.S., about 170 approximately thought to be there. a pigmentary retinopathy, which is typified by macular atrophy quite early, but preservation of photoreceptors in the pericentral area of the macula. The vision loss typically starts in infancy and patients often have just vision of hand movements or light perception. Thestagnus and hyperopia are things that are not only seen in this condition, but certainly also here or people with congenital bad disease or very early onset bad disease have nostatnus and hyperopia. But the photoreceptor cell loss also leads to the fact that it's very hard to obtain any visual fields in such patients, although there is potential because there's preservation of the pericenteral photoreceptors. Can I have the next slide, please? So the Opus Genetics LCA5 gene therapy, which is currently being used and tested is designed to restore a key protein of the visual cycle. And so basically, that protein is called liocillin. It's actually a ciliary protein that is critical for the function of photoreceptor outer segments mostly because it works in the connect in sum. All of the proteins that are involved in what is translation of light into electrical signals, the photo transduction are being produced around the nucleus and then have to travel all the way to the outer segment to do the phototransduction. Levoillin is very important in getting them there. The photoreceptors, as we said before, can actually survive quite long until the third decade of life, and that is suggestive again of as so many of the diseases we've been talking about of having a window of time during which treatment can happen. So on Opus genetics CCF5 is designed to address the mutations in this gene, and it's clinically a derisked AAV8 vector that delivers a functional copy of the LCA5 gene directly to the photoreceptor cells using similar promoter technology as it was used in Luxturna. It's a single subretinal injection. Next slide, please. So what is remarkable is that adults have been treated. And so what we're showing here is that the mean change from baseline in visual acuity in the adult cohort with 3 patients involved is continuing to be significant, as you can see on the left-hand side with the orange line, an improvement is upwards in this slide. On the right-hand side, you see for the first time until month 6, the results coming from the pediatric cohort, equally 3 patients. And you can certainly see that there's an improvement, a significant improvement of best corrected visual acuity. Next slide, please. So you can also continue to measure function. And in this slide, for example, we talk about cone function as measured using the FSD or full field stimulus test, actually full field sensitivity testing that is showing on the left-hand side, what we do with red light and with blue light in the adult cohort. And on the right-hand side, you see the pediatric cohort. And you can see a significant improvement again for both colors used in the cohorts, both adult and pediatric, the pediatric up to 6 months and 24 months for the adult cohort. Next slide. So you can also test sensitivity, if possible, that is if fixation is sufficient, using microperimetry. Microperimetry used separate protocols are available. And so here, for example, it's a 10-2 protocol that was used. This is a photopic test. And as you can tell, the sensitivity in one patient, adult participant 104 and pediatric participant 106, the 2 only patients who are capable of doing this test shows an absolutely significant increase in sensitivity in the central area of the macula and actually a little bit of a movement of the fixation of the patient towards the foveal area. So both patients show significant increase in function of the central area of the macula that is consistent with the treatment effect. Next slide, please. So one last thing that I just wanted to mention is what do people say -- and patients actually report changes in their daily life, activities of daily living are significantly improved. And for example, in the adult participants, 0101 reported being able to identify her children within a larger group of children 1 month after the surgery, which she couldn't do before, navigating urban environments independently and no longer requiring continuous use of a cane was reported by 0104. That's the patient -- the adult patient who was able to do the microperimetry. If we go to the pediatric patients, -- for example, the 0106 patient, also the one with a better fixation so that she could do the microperimetry reported a noticeable difference in the visual brightness between the treated and the untreated eyes. I said it was a girl, it's actually a boy, I'm sorry, and able to watch basketball, important for children, I think, and can see the players and follow the ball instead of watching the score ticker and listening to the commentary. So I think with that, I've shown that there is a real treatment effect of the Opus Genetics LCA5 program. And with this, I'd love to pass on to Ash again.

Thank you, Dr. Leroy. There are over 300 mutations associated with Best disease, which we'll talk about now. And there are several distinct phenotypes with both dominant and recessive modes of inheritance. The dominant forms include AVverC, which is autosomal dominant vitreoretinal choroidopathy. And then there is a highly prevalent phenotype, which is called BBMD or Best vitlloform macular dystrophy. It's named for the hallmark EggYoke or vitllaorm macular lesion in this disease. And then there's the recessive form, autosomal recessive bestrophinopathy. And disease onset and severity of BEST can vary. BEST1 is a calcium-activated chloride channel or CAC, and it is expressed in the retinal pigment epithelial cells, and it's responsible primarily for retinal ion and fluid homeostasis. So it follows that dysfunction in the BEST1 channel and its activity can result in a number of vision-threatening complications that you see here. As we discussed, there are several variants of BEST1 looking a little bit closer. The recessive form, BEST-ARB, lacks functional copies of BEST1 expression in the RPE. Now the more common dominant form of BEST, which is associated with BBMD, for example, has 2 different forms. It's a loss of function and gain of function variant type. And that's a critical distinction that we're making there because -- it's thought that gain of function dominant mutations are unlikely to be treatable with conventional AAV gene augmentation, which is the focus of the OPUS clinical trial with our candidate OPGXBest1. However, we and others have demonstrated that loss of function mutations in contrast are treatable with AAV gene therapy. And those happen to account for the majority of best 1 mutations, perhaps over 98% However, the genetic test in the clinic used to diagnose BEST1 IRDs may not report this detailed loss of function gain of function information. So OPUS has developed a paradigm to help predict treatment responses to BEST1 gene therapy and help ensure that the patient carries indeed a loss of function mutation, which is going to be amenable to gene therapy. So we're in the process now of testing every known BEST1 mutation for treatment response using tools such as iPSC-derived RPE cells and other engineered mammalian cell models. And in this case, we use technologies such as patch clamp electrophysiology and fluorescence reporter assays, which allow us to directly or indirectly measure the chloride conductance function of the TAC channel. And we've developed these in-house to understand, first, if the mutation is a loss of function or gain of function mutation and also whether or not it is amenable to VestT1 gene correction. So when we receive the genetic test, we can then look this mutation up in our test battery to see if this mutation has been tested for personalized responder, nonresponder type analysis by OPUS. And so we will be using this information in collaboration with our community of specialists to help select patients for clinical investigations of our candidate OPGXVest1. This is a single AAV2 vector for onetime subretinal administration and also features an RPE-specific promoter. And with that overview, I'm happy to hand the call over to George for a brief clinical review of VestT1.

Thank you, Ash. I'll provide a brief clinical update on BEST1 program. For reference, the data we have presented to date at Macula Society and ARVO are available on our website on the BEST1 page. We've completed enrollment in Cohort 1 of the Phase I/II study with 5 participants, including 2 autosomal recessive and 3 BDMD participants. You'll see that the BDMD participants are significantly better at baseline with participant 102, 102 being the least advanced participant from a visual acuity standpoint. What I'd like to really show you today is some of the phenotypes on the OCT that we're selecting for. Now this is being selected with a number of our colleagues in the field and has really been a a great process for ensuring that we get the right subjects into the trial. This participant is 101, 106, and this is a representative BBMD patient. You can see that the participant has a pretty intact foveal depression along with the retinal layers being intact in the periphery, both on the nasal and temporal side. Under the fovea and extending particularly to the temporal periphery of the retina, you can see the subretinal fluid that is part of the vllorm lesion. This fluid is low in diffuse and it's on the backside of the neurosensory retina, which is detached. Now importantly, for these patients, you can see the small areas of hyperreflective material, which are so-called shiny photoreceptors, which indicate the photoreceptor all segments may still be present. This is an important differentiation from the so-called faced backside of the neurosensory retina. So we do expect that the product, if it works, should be able to decrease the amount of fluid under the retina, under the fovea. And as that fluid decreases and the retina is repposed to the RPE and Brooke's membrane complex, there is a potential that there might be a functional benefit for this patient. We also may potentially see that the ellipsoid zone line, which is present in the periphery of this image, began to expand back out into the center of the macula, which would be fantastic for this patient. That would be expected to result in an increase in visual function. When we test visual function, we're testing really 4 different parameters. One of the most interesting to our team is the microperimetry. And what I'd like to see here is the overlay of microperimetry on the infrared image of the OCT that we've already shown on the prior slide. Essentially, the OCT and the infrared image on the prior slide can be directly overlaid onto a map similar to what you see here. So what you notice is that the areas of subretinal fluid that were present on the last slide on OCT are highly correlated with depression on sensitivity map on this slide. Therefore, in the areas where you see a 0 decibel sensitivity or a sensitivity of, say, less than 20 or so decibels on the heat map, you would expect the sensitivity of the retina to improve as the subretinal fluid in those areas goes away. That would be the hypothesis we're trying to prove in this study. The ability to overlay the pathology and the modification of the pathology with this functional endpoint is a very unique thing for this program, and it allows us to test functional improvement of the retina at a very high spatial resolution. This is an approval endpoint with the FDA, so the improvement in these phosal microperimetry treatment would be acceptable as a potential pivotal endpoint. Obviously, we're still collecting all the other functional data, but this is a very unique thing for this program that we're excited about. So this is why we're looking for patients with fluid that correlates with visual functional improvement. If we're successful in decreasing the fluid and there are photoreceptors present, then they should function better if they're in their native configuration. This should -- this we hypothesize should lead to an improvement in multiple functional endpoints. And most notably, as I've shown here today, potentially microperimetry. At this point, I'd like to turn the call over to Dr. -- I'm sorry, to Joe Schachle, our Chief Operating Officer, to discuss the patient journey and epidemiology of these IRDs.

Thank you, George. Good morning, everyone, and good afternoon to those in Europe and elsewhere. Two topics I'd like to touch base with you on. First is the IRD patient journey. I'll give you a brief overview of the patient journey. You heard a little bit of that this morning earlier. And then also talk about disease prevalence, global disease prevalence, which you've seen in each of the individual presentations, but we'd like to show you all together as well. So looking at the patient flow, as you heard, patients will often see an optometrist or a general ophthalmologist and then be referred to a retinal specialist. And that retinal specialist may make the diagnosis, may refer to a specialist that specializes in IRDs or a genetic counselor for genetic testing. And this is a very key step and something that we all need to support is the genetic testing aspect. If you look at the green bar, if you move to the left side of that, that's a patient that has a gene that we have a potential to treat and has been identified. Currently, RPE65 is the only one we have to treat and look forward to being able to add to that in the future. So that's kind of a general view of how patients may move from symptoms to diagnosis to ultimately treatment. So thinking about global estimates on prevalence. Originally, we look -- we use 2 primary sources for global incidence and prevalence. The first was the Stone paper, which is an excellent study. It's 1,000 I&D families being treated at one site from across 40 states. It's very helpful. The HA study is also very helpful. It's a global study looking at 6 markets outside of the U.S. and that was initial data that helped us estimate prevalence. Since then, we actually have asked Trimal Insights group to prepare analysis, a meta-analysis of studies and they completed that in the first quarter of this year, and that's what you're seeing data here in a moment. That meta-analysis originally looked at over 1,200 studies. And of those 1,200 studies, greater than 90 qualified for use in this study. They need to have genetic testing as a backbone to the actual study itself. And we looked at 5 geographies: the U.S., EU4 plus U.K., China, Japan and Middle East and North Africa. So just taking a look across the globe here, let's focus on the U.S. first. We kind of generalize that we have small, medium and large prevalence diseases we're focused on. If you look at LCA5 and MAT1, those are our smaller prevalence diseases at 170 and 1,200 -- if you think about the midsized disease, we're looking at RDH 12, MERTK and CNGB1, -- those are on the 2,000 range for prevalence. And then finally, we look at BEST1 and Re as the larger prevalence diseases at 8,400 and 8,800. And as you heard in some of the previous presentations, looking Middle East and North Africa, you can see RDH12 with a prevalence of 17,500, so a fairly large population and MERTK over 14,000 patients. Moving to China, you see Re has almost 15,000 patients and RDH12 has almost 10,000 patients. So you can see across the globe, there is substantial medical need for treatments for these diseases. One final slide here, and this is just -- this tags into some of the things you heard earlier is there may be underestimation of the actual prevalence of some of these diseases. If you look at our current best 1 prevalence, we're estimating about 8,400 patients with Bestung in the U.S. And that's based on studies that have confirmed genetic testing in the diagnosis. If you look at the right portion of this slide, we may be underreporting best disease, and there's 2 factors for that. First is, while most patients do get genetic testing, because of the vllongoest1, some patients may not get tested because they may be assumed to be best 1 and currently no treatment available. The flip side of that is actually the misdiagnosis of best 1. We're in the midst of a market research study right now, a large market research study, and we're hearing quite frequently about the misdiagnosis. And I'm going to read quickly this quote to you. Quite a few of my best patients have been seen by other physicians in my practice and did not get the diagnosis of Best disease. I think there are a lot of patients who are not diagnosed correctly, I would say, about 50%. So we are hearing this consistently across the study that there's a misdiagnosis and lack of diagnosis for best. So we may actually have some higher rates of prevalence that we have estimated currently. So thank you for your time. With that, I'll turn it back over to Ben.

Thanks, Joe. So now in addition to Dr. Bennett and Dr. Leroy, we are pleased to have joining us today Dr. Todd Durham, Senior Vice President of Clinical and Outcomes Research at the Foundation Planning Blindness. Todd is responsible for overseeing the Foundation's patient registry, natural history studies and other clinical programs. So let's go ahead and kick off this session. And I'll start with a question for Jean. Since Jean, you have such a unique perspective given your history in the field and the LUXTURNA development days. But if you could just kind of give us a perspective, what was the state of play with respect to genetic testing then versus now? And what were some of the biggest hurdles and unknowns?

When we first started getting ready to recruit patients in 2007, we had gotten everything all together and gotten all of the approvals, the institutional approvals, the FDA approvals. And then we looked out to try to find patients -- where were the patients? Nobody or very few patients in the United States had had genotyping because there was no reason to get genotype. There was no treatment, no clinical trial available. And it was thanks to our colleagues in the European Union that we were able to start. Our first 4 patients came from Italy, where they had made great progress in genotype phenotype correlations. And several of the next patients came from Bart Lois site in Belgium because he had also been genotyping patients. And so now the situation has changed dramatically. There are now numerous sites, physicians genotyping patients because there are treatments -- there is the LUXTURNA treatment available, and there are clinical trials available for many of the other forms of IRDs. And plus people are anticipating the clinical trials that are being developed by Opus Genetics.

Got it. Got it. Yes, it sounds like kind of a night and day difference. Well, that's great. Thanks, Jean. Todd, a question for you since the foundation offers free genetic testing program. Could you walk us through the history of the program, how it might differ from others? And what are some other resources available for doctors and patients?

Yes, sure. Thanks, Ben. Foundation Fighting Blindness has had a registry study, my Retina tracker registry since 2013. In 2017, we received a grant to try a pilot study to provide genetic testing and counseling to a small number of sites, really the centers of excellence at that time to see how -- what the uptake would be as a pilot study. And it turned into an amazing success. We now are able to offer at no cost genetic testing and counseling to patients with inherited retinal disease in the U.S. We have hundreds of eye care professionals, including optometrists, both vision specialists all over the country who are ordering through the program now. And at this point, we have tested over 32,000 individuals as of the end of March. And it's very -- it's a huge program, I would say, wildly successful. And I think from the foundation's perspective, we're opening access to patients all over the country, not just those who have access to a specialist center. And that makes a huge difference when it comes to recruiting for clinical trials. This program is just one of many that exists today. It has always been -- well, most recently has been an option in the clinical setting to access a test for those individuals who have insurance coverage or able to afford a cash pay. But there have been other programs over the years offered by commercial labs, the National Eye Institute had their own program for many years. I would say -- I would say -- I would estimate that at least half of the individuals in the U.S. with inherited retinal disease have had access to a genetic test by now. And I think this is going to be a program we will continue to need because not everyone will have access to a test at no cost or free.

That's great. I'm always astounded at how fast that registry is growing and how many tests you guys have provided. It's really remarkable and really moved the field forward. So great work. Bart, Dr. Leroy, since you sit in a different geography in Europe and Belgium, what's been your experience with genetic testing? How does that work in your part of the world? And what percentage of your IRD patients have confirmed genetic diagnosis...

Well, thanks, Ben. It is the culture of how to organize society is indeed very different from one side of the Atlantic to the other. Taxation is far less in the U.S. So more money is given for grants and so on and so on. That is certainly less in the EU where taxation is higher, but the tax is used, for example, for national health services. And so for example, in Belgium, but not only in Belgium, in many other countries, we have a fairly free or nearly free or if you're a clinical geneticist, which I also am, I can offer free genetic testing to our patients. Basically, everyone who walks into the door through the door with a genetic diagnosis gets genotyped. And so obviously, because of the constraints of what testing currently is, we don't do yet whole genome sequencing on everyone. But I would say we say about 70% of the patients get their genotype, but everyone gets the opportunity, and they generally don't pay a euro for it.