KOL event

Dec 11, 2024

Good afternoon, and welcome to the Opus Genetics KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded and a replay will be made available on the Opus Genetics website following the conclusion of the event. I'd now like to turn the call over to Ash Jayagopal, Chief Scientific and Development Officer of Opus Genetics. Please go ahead, Ash. Thank you, Tara, and welcome to the Opus Genetics Key Opinion Leader event. We are excited to hear from pioneers in the development of gene therapies for the management of retinal diseases today. We're excited to discuss data from an ongoing phase I/II clinical trial for LCA5-associated inherited retinal disease, or IRDs. I'm pleased to briefly introduce you to Opus, starting off our session today, and discuss our vision for enabling transformative gene therapies for patients living with inherited retinal diseases. This presentation contains forward-looking statements, and so we encourage you to consult our website and SEC filings for further information. Following an introduction to Opus Genetics, we will devote the rest of today to discussion of clinical data from the ongoing LCA5 IRD trial and development of potential endpoints for assessment of therapeutic response in LCA5 IRDs, followed by a panel discussion and Q&A. It's my pleasure to introduce our distinguished speakers and panelists today, beginning with Doctors Jean Bennett and Tomás Aleman of the University of Pennsylvania, who will present on LCA5 clinical trial data and endpoints, and Dr. Arshad Khanani of Sierra Eye Associates and Dr. Christine Kay of Vitreoretinal Associates Florida, who will kick off our panel session. Very limited treatment options exist for patients with IRDs, which is truly unfortunate, as many of the genetic mutations attributable to these conditions may potentially be treatable by AAV-based gene augmentation strategies, as demonstrated by decades of strong preclinical research and recent promising data in IRD clinical trials. Opus was built from the ground up to advance more of these promising gene therapies to the clinic with the goal of saving sight. The field of IRD gene therapies is not without its challenges. First, the smaller addressable population associated with rare diseases can present obstacles for achieving commercial success and recruiting patients in clinical trials. Furthermore, traditional manufacturing of biologic medicines such as AAVs, or adeno-associated viruses, are geared towards higher prevalence diseases and isn't always right-sized for the smaller quantities of high-quality therapeutics needed for IRDs. In addition, translation of gene therapies from the laboratory to patients requires very strong expertise across multiple disciplines. The Opus approach is designed to address and overcome these challenges. We've built a robust pipeline of 7 programs in various stages of development to balance risk and create multiple shots on goal for treating IRDs. We are closely allied with patient organizations to enroll trials efficiently and help us locate patients if our treatments are approved. We have strategic manufacturing partnerships for bespoke manufacturing of IRD gene therapies at small scale and high quality. Furthermore, the programs have a number of synergies across them, which enable high efficiency translation of therapies to patients through shared endpoints and manufacturing processes, to name a few examples. We are proud of our IRD portfolio and are initially focused on clinical execution of LCA5-associated IRDs, which we will discuss today, followed by BEST1 associated IRDs. As we achieve clinical proof of concept for these programs, we will proceed on a gated path towards activating other programs in the pipeline further, with the goal of bringing these transformative therapies to more patients potentially. 2025 is gonna be a really important year for Opus and the patient community as we look forward to clinical data in the LCA5 and BEST1 phase I/II trials. We were pleased to have received orphan drug and Rare Pediatric Disease designations from the FDA for LCA5. We are well positioned to build a sustainable engine for the development of AAV-based IRD gene therapies. I'll now hand it over to Dr. Bennett to discuss LCA5 and a novel potential clinical endpoint for assessment of IRD gene therapies. Thank you. Jean? Thank you so much, Ash, and it's a pleasure to be here, and thanks to all of those who are attending. I'm really pleased to tell you about our program in LCA5, the LCA5 form of Leber congenital amaurosis. This is one of the worst of the worst inherited retinal dystrophies. Worse because it affects infants in their first year of life, and they begin life with terrible vision, with nystagmus and loss of visual fields, poor acuity, and what they have gets worse and worse. They have a severe and early photoreceptor loss, which results in severely abnormal or even non-detectable visual fields. Often the visual acuity is limited to only hand motion vision or light perception. If you look at the fundus photographs, you can see examples of patients who range from age six all the way through age 22, and you can see how early this begins. If one does fundus photography, one sees pigmentary retinopathy with areas of RPE and photoreceptors that are degenerating. OCT shows severe abnormalities. However, there are spared photoreceptors that one can see in the outer nuclear layer. If you look at that middle image on the right-hand side, you can see those photoreceptors and inner and outer segments, even at severe disease stage, such as a person in their 20s. You can even see these retained photoreceptors in individuals who only have light perception vision. Of course, with gene therapy, you need the cells to be present to be able to rescue them. The structure function dissociation creates a favorable environment for AAV gene replacement. Lebercilin is a ciliary protein. It's critical for the function of photoreceptor inner and outer segments. In a normal, healthy retina, one sees these elongated antennae-like structures, the rod and the cone photoreceptors. In a retina with a lebercilin deficit, those photoreceptors are stunted severely. As a ciliopathy, this condition forms a launching point for being able to demonstrate that it is possible to treat a ciliopathy that affects the retinal function. In this case, in LCA5 patients, the impairment is due to a lack of functioning lebercilin. However, since the photoreceptors can survive through the third decade, there may be a broader window of therapeutic intervention. The Opus Genetics OPGx-LCA5 reagent is designed to address mutations in this LCA5 gene. It uses a clinically de-risked AAV8 serotype vector, which delivers a functional copy of the LCA5 gene directly to photoreceptor cells. It uses the same promoter technology as was used in Luxturna. That has been de-risked, obviously. It also uses a validated surgical delivery plan via a method, via subretinal injection. Now, one of the questions that we have also worked on is to attempt to develop improved outcome measures. You will hear about all of the clinical outcome measures that have been used in addition to the multi-luminance orientation and mobility test. I'd like to tell you about this test briefly because it's novel and we're excited about its ability to provide information on clinically relevant aspects of vision. This uses a readily available virtual reality headset, one which has already been sold to 20 million people in the United States. It has a really good safety record, and it uses body trackers to navigate the person as they are walking through a virtual course. The virtual course contains household objects that are presented at increasing illumination while the subject follows a path of red arrows. The subject goes through the path, and when they see an object, they identify it and touch it with their handheld controllers while following the path. That establishes a threshold of functional vision that may be used to address impact of disease and treatments. It allows the device itself to assess the visual function of this individual in real time using objective data. In addition to the ability to touch these objects, there is an enormous amount of additional data that is automatically collected, such as where the person is looking, if they step backwards, and how difficult it is for them to actually touch and locate the object. Importantly, this readout measure appears to relate well with other clinical readouts, such as visual acuity and visual fields and visual sensitivity. I'd like to show you an example of one of our patients in this trial going through the course. This is colorized. This is actually a very low luminance, but you can see after intervention, this person goes around and identifies the objects, touches them, making them disappear, and that's tabulated automatically, and then they walk out of the maze, and an additional test is given. The subjects really seem to enjoy this game-like test, and it takes place in a very short amount of time. For those of you who are familiar with the standard physical multi-luminance mobility test, MLMT, that test can take hours to configure because it relies on test givers to physically place the objects, and it's limited in terms of their operating range. With our virtual test, we can go up to five log units, typically over three log units. We can also test the ability of people with extremely low vision to orient accurately, which cannot be done with the multi-luminance mobility test. The equipment and space is affordable. It occupies this low amount of space. It's easy to deploy and duplicate at multiple sites. Of course, since the objects are virtual, there are no physical objects that could cause harm in a collision or cause a person to trip. Further, one can test one eye at a time or both eyes and adjust the view to the subject's height. This has been really attractive to a digital-savvy pediatric population, and the data are obtained, as I mentioned, instantaneously and analyzed objectively. We don't need reading centers, and there's no risk of personal identifiers being displayed. I will now hand the microphone off to Dr. Tomás Aleman to tell you about the results of his study. Hi, everybody. Thank you so much for your interest in our program. I'm Tomás Aleman from the University of Pennsylvania. I'm the PI for the study. We are presenting to you the results up to six months of a phase I/II, Opus Genetics-sponsored gene augmentation trial for LCA5. The study is designed as a phase I/II, as a uniocular treatment by subretinal injection against a gene augmentation product. It's a non-randomized, open label, three dose ascending protocol. The study started about a year ago. Again, these are the results of six months, and I'm going to be presenting the results on three patients that received basically the lowest dose at 1E10 vector genomes. The patients, as Dr. Bennett had mentioned before, are extremely severe. These are typically severe among severe, even within the group of patients called Leber's or LCA. Hand motion vision, often from very early in life, before age 1, or very poor vision, from 20/200 to 20/400, in 3 subjects, encompassing the spectrum of severity of this very bad disease. Ages, they were basically relatively young adults, ages 19 to 34. Every one of them had very severe disease, with limited but detectable photoreceptors and disease that had already approached the central retina. The delivery of the vector was through classical subretinal injections after pars plana vitrectomy. For some time now, over a few years, we have been delivering a volume of about 300 milliliters divided in multiple injections to try to reduce mechanical damage to the retina and to try to approach the fovea in a more gentle way. The injections were all totally uneventful, without any surgical problems. These are examples of OCT cross-sections. For those of you who are not familiar with this, we do non-contact, non-invasive pictures of the back of the eye, where we do cross-section, pretty much like a histological cross-section. Shown are cross-sections through the fovea in each of the patients in the horizontal direction before and after treatment, showing that the histology of the retina in these areas were all involved by the injections, did not change significantly after the injections. In terms of safety, which was the main objective of the trial, there were basically no surgical-related complications. The adverse events were all expected, were all mild, they were all resolvable, recovered, and most of them were actually the ocular ones were related to the surgical irritation that is expected to happen after the surgical procedure. The systemic side effects had to do with the use of steroids, and again, all of them subsided after discontinuation of the steroids. One of the main things that we look at in clinical trials is visual acuity, mainly because it's widely understood. Visual acuity relates to reading, which we all do and we are very familiar with doing. It's a safe measure of safety. Visual acuity at least should not decline after an intervention like this, and that is the reason why we are using it in clinical trials for severe retinal degeneration, even though we recognize the potential for gains of acuity may be limited by neural developmental issues. Nevertheless, in the LCA5 trials, we noted increases in acuity that were variable among the patients, but nevertheless significant. Shown here are changes from baseline in something called logMAR acuity, which is basically a logarithmic scale of the change in acuity in reading ability over time. On average, at six months, the participants increased beyond three lines of acuity, which is recognized conventionally as the significant change in acuity that could be considered significant in a clinical trial. At the same time, the difference between the treated eye and the untreated eye, which is shown below, also shows that the treatment eye improved acuity significantly. Importantly, one of the patients, actually our most severe patient who had never had formed vision, it was someone that we have known for 20 years or more, had always had hand motion vision, for the first time in his life, was able to use his vision to recognize objects and is in the process of learning to use that newly acquired ability. In these type of situations, we always wonder if increasing acuity or modifying reading ability is important. If there is not a connection with the basic mechanism of disease, you would have to question whether the changes are just a random change, just by even placebo effects. It's important to measure mechanistic, basically readouts that basically are related directly to the problem that the disease causes. In this case, a ciliopathy is an impairment in the sensitivity of the photoreceptor, the light sensor to lights. In this plot here, we are basically comparing the control eye and the study eye compared to their baseline, the first bars to the left. The height of the bars are the sensitivity of the retina to lights, measured by the ability of patients who see a red light, the red bars, or a bluish light, the blue bar. The reason we use two colors is to try to understand which photoreceptor mechanism in the back of the eye is mediating the change in vision, rods or night vision cells versus cones. We can use the spectral differences in the response of the retina to figure that out. If you can see here, at least two of the patients showed dramatic changes in sensitivity. I would say all three of them, but two dramatically, reaching the capacity of the retina. Basically, the changes are in the two patients, O3 and O4, at the range of 1-2 log units. The changes are based by cone vision or daytime vision. Basically, the range that we have for improvements was achieved. We couldn't hope for a better result since this is basically the gap that we needed to fill with the therapy. The patient in the middle has less of a change, but you will see here in the next slide what is the reason. The reason in this patient of a relatively smaller change is that the patient at baseline had still night vision, and the improvement is basically, at least in this group of patients, mediated by cones. To differentiate that, what we do is that we turn the lights on in the room and do the same measures that I had shown in the previous slide in daytime conditions. When we did that, all three patients actually improved significantly. Shown to the left are, again, changes from baseline in the sensitivity of the retina to light. Note that the scales are in log units. Again, on average, at least one log unit of improvement in sensitivity, which is highly significant. This is at least twice the magnitude of change that you would be basically expecting in any other therapy. The same can be basically established by comparing the treated versus untreated eye, which is the plot on the right. Again, the vertical scale is in log units, and these are thresholds, sensitivity differences, the threshold of the response, and it's again by the same magnitude. Changes compared to baseline and changes compared to the contralateral eye exceeding one log unit, all mediated by cones. Now, even then, you can question, yes, you have a mechanistically related improvement in sensitivity, but it is always nice to have an objective measure of vision. In conditions like LCA, this is almost impossible to do by the traditional methods, which is electroretinography. Many, many years ago, we tried to solve that problem, and we did solve it by using chromatic dark-adapted pupillometry. What does that mean? We videotape the pupil reaction to light in night vision conditions using infrared cameras. Like we do with these other tests that we use to measure sensitivity, we use the spectral differences in the response of the pupil to light, to gauge which photoreceptor mechanism is mediating the response. You can do that over a range of luminances. You start very dim, and you increase intensities of light, and you can basically monitor what the pupil does when you do that. It was very comforting to see that in every single treated eye of the patients, there was a shift in the sensitivity of the retina towards basically higher sensitivity. That is basically the shift of the curve that are in green in the study eye compared to their baseline, which are the gray functions. There is a shift, again, that is comparable to what we determined psychophysically by asking the patient to press a button. The shift is, again, at least a log unit or more towards a better sensitivity for the retina, confirming objectively that there is biological efficacy. Dr. Bennett talked a little bit about the virtual reality test that we have devised to overcome some of the problems that we had with the earlier methods of doing these things. It is important to know, it's very nice to know that not only do we change the patient functionally using basically sophisticated readouts, but it's important to know if we have impacted behavior, if they can do with this newly gained vision better in a real world. One way of doing it is with a virtual reality test, which again extends the range of testing the behavior of patients over several log units, accommodating even patients with very severe disease, like in LCA5. What is shown here, again, is a comparison of the study eye and the control eye. The larger symbols are the ability of a patient to count objects after the treatment. You can see compared to the red symbols, that in the treated eye, there is an increase in the detection of the objects. The count, the machine is actually counting the number of objects automatically that the patient see when they are navigating that course. There is, again, a shift not only in the number of objects, but in the ability to detect objects at dimmer intensities, which is the shift to the left. The first patient, which was the one with the more severe disease, unfortunately did not increase their behavior that much. Whether that is in relationship with the severity of disease or the fact that this person had never used his vision is something to be explored down the road. Finally, this was something that was a little bit unanticipated. In a disease like LCA5, doing perimetry visual fields is very challenging. Let alone visual fields using something called fundus tracking perimetry or microperimetry, which is an accepted readout now for clinical trials in these type of diseases. One of the patients, the youngest at 19, we did not anticipate it, but did it nevertheless. At baseline, we measured microperimetry, and these are the plots of sensitivity to the left are the control. There's a control eye, and to the right, the treated eye, and the leftmost plot is basically the sensitivity of an area of the retina in the center around the fovea, around the center of the vision. As you can see, it's all black in the treated eye, meaning there is no sensitivity. The patient almost randomly press the button. In the left eye of the patient, which is a better eye, the eye that we didn't operate on because it was a little bit less severe, the island of vision is down to in space the size of your thumb and very reduced in sensitivity. Down below are actually the plots of where the patient is pointing their vision at, or so-called fixation. That cloud of green points is telling you that the patient is actually erratically looking around, not fixating on anything. After treatment, and again, this is data up to 6 months, and you can see already at 1 month post-treatment in the treated eye, there is now an island of vision around the fovea. Importantly, between 1 and 6 months, that island not only was maintained, but the cloud of points went from a storm of points to a very small area of points, tight points, which are the yellow arrows located around the foveal center, just supporting, like the other measures, that this is cone-mediated vision improvement affecting the fovea, thus supporting as well the fact that patients are improving visual acuity, which is mediated usually by the central retina. In conclusion, gene augmentation has demonstrated robust and durable, up to 6 months at least, efficacy in LCA5. The template that we use, I hope, demonstrate that across different modalities, there is consistency and in both magnitude and quality of the response to the treatment, and those support biological efficacy. Also very important in this disease, the disease departs from earlier experiences with Leber's, with Leber LCA trials, where we typically treat patients with retinas that look very nice, quite preserved. In this case, we are treating a scenario that is actually very common in inherited retinal degeneration, where you have an active and severe neurodegeneration. We demonstrate that it's possible to treat patients at a stage where you have actually tissue loss or neuronal loss. It can be a salutary experience to hundreds, literally, of retinal degenerations, where this scenario is what clinicians find every day in the clinic. Again, the template of the trial may be used to expand the experience to other diseases. We hope the same mechanism which has, in our case in LCA5, produced a successful clinical trial in a reasonable amount of time that can be used for other patients. The next step is treating earlier disease stages to modify, hopefully, neurodevelopmental stages that we need to address. With that in mind, we obtained support and are ready to basically enroll the first patients within the next few weeks or days, the first pediatric patient. With that, I thank you and leave the floor to questions. Thank you. Great. Thank you, Dr. Aleman. I'd now like to turn the call over to Dr. Arshad Khanani, who will be the moderator for our panel discussion. Please go ahead, Dr. Khanani. Thank you, Tara. Thank you, Dr. Jayagopal, Bennett, and Aleman for excellent presentations. Thanks for sharing the vision for Opus, as well as more exciting progress towards treatments of patients with LCA5 IRDs, as well as potential of this approach for other severe IRDs. As a practicing retina specialist, I am really thrilled to see the data you shared today. I think the data shows positive efficacy in multiple different endpoints, and I think it's very exciting to see that. Let's move on to the Q&A portion and the panel discussion. Our panel includes Dr. Ash Jayagopal with Opus, Dr. Jean Bennett, doesn't need any introduction, pioneer in gene therapy world. Dr. Aleman and Dr. Christine Kay, who also specializes in IRDs. Operator, can you tell everyone how to ask their questions before we move on to the panel? Yes. Thank you, Dr. Khanani. Just as a reminder to our audience, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. Thank you very much. While we gather questions, Christine, I want to start with you to get some thoughts. Number one, you treat a lot of IRDs, and you've been involved with many trials, and you've seen how different IRDs, including LCA, affect your patients. I think it would be nice for the audience to hear about the impact of this disease on the patients as well as their family members. The second question is, based on the data you saw today, what gets you more excited about this being a potential treatment for patients with LCA5? Sure. Thank you, Arshad, and excellent job to all of the speakers. I think that was an excellent presentation. I'm a vitreoretinal surgeon, and I'm an IRD specialist, and I've been involved in these subretinal gene therapy trials now for over a decade as an investigator and a surgeon in a number of these trials. I see these patients, I see these families. They come through my IRD clinic. Sometimes we have a clinical trial to offer them. Sometimes, rarely, we have an FDA-approved product to offer them or refer them to a center of excellence if it's RPE65. Other times, we can just talk about updates in the field, and we can talk about trials in the landscape. The thing I've been really excited about in the last couple of years, I think in the wake of Spark Therapeutics' voretigene neparvovec FDA approval in 2017, we've had an explosion of all of these gene therapy trials, and I think this is a very exciting time for the field. Families are aware of that. They're asking questions, they're coming to clinic, they're making their yearly appointments. They're not missing these appointments. They have questions as they walk in the door. "Is my disease in a trial? What are the potential treatments?" Now we have optogenetics and other types of non-gene-agnostic therapies to talk to patients about. This is a really exciting time, I feel, for the IRD field and the landscape. I think the FDA right now is in an interesting position of being potentially more supportive of trying to get some of these rare orphan diseases across the finish line and aware of that, and I think we're helping them as a collaborative scientific and clinical group of people, become more aware that we need to look at these outcome metrics when you think about outcome metrics in terms of what is approvable in these patient populations. To answer the first question, I think that the conversation has become more optimistic in the last, say, five years with my LCA families and my IRD families, and we have more to talk about and potential exciting therapies such as what we've heard about today. To answer your second question, what I'm most excited about with this presentation is the number of outcome metrics that are positive. I think that's kind of rare to see. I'm counting at least five outcome metrics here that are positive: visual function, functional vision, and objective. We have 0.3 logMAR improvement in visual acuity. That's excellent. We have FST improvements, and we're hoping, we're working with the FDA to kind of move that FST maybe closer to a finish line and potentially eventually becoming a pivotal outcome. We'll see. FST improvements in 1.5, 15 decibels, that's excellent. That's huge improvements. It's always nice to see pupillometry, because as we heard, that is an objective measurement that's able to show an efficacy signal without any patient response, no subjective patient response. We see this kind of confirmatory excellent data with pupillometry. Then, of course, the functional vision, which was able to get the FDA approval for Spark Therapeutics' voretigene neparvovec. Now we see this very interesting and optimized virtual maze, and we're living in an optimized world here, where we're understanding that there are some benefits to being able to have a virtual maze, and all of the things that were mentioned regarding this maze as a potential benefit. I think that will be very nice to be able to apply that to patients, being able to cover a larger spectrum of disease without a ceiling or a floor effect, automated, all of the things we heard about, digital, virtual, immediate response rather than wait for a reading center. I think that, and then, of course, safety. Let's not forget about that. As a surgeon and seeing inflammation in previous trials we didn't hear about, that the inflammatory profile looks excellent, surgical profile looks excellent. I'm very optimistic and very excited to hear about a platform that is showing, at this point, excellent safety data, which is important. We don't want to neglect thinking and talking to our patients about safety as well as multiple outcome metrics that are showing efficacy. No, that's a really good summary, and I completely agree with you. I think we all have these patients who are desperate, who have lost vision or are losing vision, and their family members, and the impact is huge. Multiple patients I have, my practice is broad retinal practice, so I do see IRDs at times, and what I see the impact of the disease on the patients, but also on their family members. I think giving them hope and sharing this positive data set with them, and then the excitement building up for different IRDs, I think this is a very important moment in our field, to have this data set to keep moving this program forward. Dr. Aleman, you treated these patients and obviously you have the most experience. Tell us from your perspective, before and after treatment, did you see an impact when you were seeing these patients, in terms of how they presented to you and after receiving the treatments? Because as you presented nicely, we have benefit in multiple different parameters, and I think, does that change how these patients are functioning in your clinic and also the response from their family members? They are all optimistic, and they are very happy with the outcomes. It has posed, like every single clinical trial that we have done in the past, they all bring questions, more questions than you have anticipated when you start them. One of which is, in some of these patients, you may require learning to use the newly acquired vision, and at least that happened in one of our patients, and that was semi-unanticipated. Again, when we started the trial, we were focused on safety, and more importantly in this disease, compared to other forms of LCA, because at least at the beginning of the trial, we were not as optimistic given that the disease did not present the typical relationship that we see in LCA or very preserved retinas with very abnormal vision. Some of these patients, like the first patient that we treated, was really someone that had never been a visual individual, was basically totally independent, a super smart person, super independent person, but not dependent on vision. To incorporate that, to see that day for the first time, I don't know. It's things that in the day-to-day basis we do every day, but seeing a cloud or seeing fireworks or seeing a bridge, for us may not be, if we don't think about it, a big deal. For the patients, it's a great change. The other patients, too, the ones that, again, we are talking very severe disease, even for LCA. They do appreciate that there is a change in vision. One of the things that they mention in the questionnaires, which I didn't have the time to go over in the presentation, is a shift in the eye preference. From, we always pick the worst eye to deliver this type of treatments to basically to protect patients and all of them basically recognize that the treated eye is now the eye that is driving their day-to-day vision. I'm hoping that will be the case for the doses. I'm very optimistic. Usually not a very optimistic guy. I'm very optimistic. No, this is great. This is a life-changing event for them. Just seeing things that we ignore because we see so well. I think you're making a huge difference in the lives of these patients. That is very exciting for me to see that you're actually able to see the benefit that you are seeing in these test results that you presented. Dr. Bennett, you being a pioneer in the field involved with so much innovation in our space. You did say that this is a disease that starts at an early age. Were you surprised that these advanced patients in their 20s and 30s had this level of functional improvement, as Dr. Alemán showed? I was definitely surprised. Particularly that first patient, I really thought would just be a safety data point. This patient, let me just tell you one of the challenges, okay, in doing this multi-luminance mobility test. This person had never seen an arrow before, had never seen a circle, had never seen a platform. He learned how to find those platforms and to go through the test. We have assumptions about what people can see, but when he could first see a wine bottle on a table and actually reach for it and pour himself a glass of wine, that was a huge celebratory moment for him. We're really excited about this. Notably, all three of these subjects have asked if their contralateral eye can be injected, because now their worst seeing eye is their best seeing eye, and they'd like to have it bilateral. Wow. Just listening to that, it brings excitement for me as a physician, that you're changing the lives of these patients, that we didn't expect it to work as good, but this is actually excellent. This correlates with the data that Dr. Aleman presented. This is great to hear. Now, the next question is, obviously, all of you have worked with the physical mobility testing. Obviously, Jean, you were involved with creating them. Christine, from your perspective, physical and virtual mobility assessments of visual function being part of all the trials, what do you think are the potential advantages of this digitized form of the MLMT, the MLOMT, which you were alluding to earlier, versus the physical? Do you think there are advantages, and is it changing how we are going to continue to evaluate these patients in the future? How does it relate to the endpoints required by the regulatory agencies? Yeah, great questions. I think there are certainly advantages. I think that the fact that it is virtual, the headset that's already been utilized in a number of patients, so we have good safety data on that, like Jean had mentioned. I think probably most importantly, the idea of being able to cover a spectrum of ceiling-floor patients and be able to potentially use this in a number of different types of LCA. There are certainly types of LCA where a physical MLMT might be perfect. Example, Spark Therapeutics with voretigene neparvovec, and I think that there are examples where that physical maze happens to be perfect for that LCA form. There are other forms of LCA where there may be a floor effect or a ceiling effect, and I think being able to have a virtual maze. No test is the same, or the things we learned about from Jean of avoiding the learning effect, being able to have multiple different parameters that you can change. I was learning quite a bit about this. I have not used, at my site, a virtual maze yet, but I'm excited if that happens in the future to be able to experience that and see that as my patients go through. Being able to alter things like the color and the shape and illuminance, to be able to alter that per test, have a different test each time, have an immediate response rather than wait for the reading center response, which I've experienced that. I think from my patient perspective, when I send them off, and I won't name the specific company and the specific trial, but when I send them off to a physical maze for a clinical trial that they've recently been doing right now at my site, they're gonna be gone for 6 hours, if not 8 hours, and that's the day. I have two staffs that go and do physical maze with these patients. It's a decent logistical consideration for a site to take the staff and train the staff to run some of these physical mazes. It's also a large room. It's actually an off-site facility because some of these larger mazes need to be in a relatively large room. That might be transit for a patient to get to an off-site facility. Versus, it sounds like this headset and then, of course, patients are still in a room moving around, but logistically might be easier to employ to a number of different sites, to a number of ex-U.S. sites as we get into other countries and try to use other countries. I know there are many countries where having a large room is a difficult problem to employ in some of these clinical trials. I think, of course, you had mentioned at your last end of the question there, regulatory steps. Of course, we need to be able to educate the FDA and get to a validation and be able to get these things validated and approved, but it sounds like that's underway. I think it's going to be an excellent solution to a problem of how to employ these types of functional vision mazes, which we know the FDA wants in clinical trials, and to have a more realistic option of what's potentially more logistically feasible for our patients. No, those are great comments. It sounds like it's a patient-friendly, site-friendly, efficient way to do this testing. Tomás, you used in these patients, this test, and you have used the physical one in the past. Were you able to tell that it was from your site perspective? The reason for designing the test was basically for ease of use, but also to do things that we cannot do, at least with the current mobility test that is FDA approved. We here at Penn, we had also done other physical kind of mobility tests, and they always have this problem of you design the test to deliver a measure of being the minimum amount of light that the patients needs to see the space around them and detect objects. They're very custom-built, whereas in the virtual reality space, you have the flexibility of basically with the touch of a button, not only change the conditions in which you're delivering the test, but changing the space itself, which would require an immense amount of time, and it would always have limitations. As Jean had mentioned before, scaling of the test, which is something that we have never been able to do in the physical space and what is obviously very relevant for the pediatric population, is very easily done on the virtual reality space. I see a lot of children. I see patients at Children's Hospital of Philadelphia, and I always worry that we are totally focused on the adolescents and older patients and are somewhat neglecting me, not me in particular, but in general, the field, and the virtual reality actually poses a friendly basically environment to them. Sometimes they are already familiar with using video games. And so instead of having them to sit in front of an FST, I'm not saying that we're going to substitute the FST with the mobility test, but this is a friendly also way of delivering tests. We were surprised when we initially tested the system years ago to see that kids will put it on and go about doing the test without complaining too much. I'm hoping that that will be appreciated by others and that it would offer the possibility to adapt the testing algorithms to specific questions in terms of the functioning of the retina in an easier way, and expand the applicability of the mobility and orientation test to not only the severity spectrum of these diseases, but to specific patient populations and dysfunctions. No, it sounds very exciting. Ash, from an Opus perspective in terms of implementing this test and continue implementing tests in your trials as well as regulatory endpoints, any comments on that? We're excited to work with the agency on the development of endpoints. At this early stage in the trial, it's very exciting to see initial preliminary, but compelling, safety and efficacy data. We'll be working closely with the agency to define and inform clinical trial design. I'll just add that it's really exciting to see Dr. Bennett, Dr. Alemán's adaptation of the MLOMT for the LCA5 trial because, as we discussed, Opus has seven different programs under development, all with diverse genotype/phenotypes. Developing an endlessly randomizable, customizable assay, which can be used to assess therapeutic interventions across many IRDs, is an enticing prospect. I believe that the MLOMT can benefit not just LCA5 patients in assessing treatment response, but also for other IRDs, hopefully. I hope to work with Dr. Bennett and Dr. Alemán on that in the future. No, it sounds very exciting. A couple of quick questions before we move to the audience Q&A. Jean, it seems like there is a renaissance of IRD gene therapies for companies. What excites you the most about recent progress by Opus and others in the field? Oh, I'm so excited about the entire field and Opus, of course. It was not long ago that people with inherited retinal degenerations did not even go to an ophthalmologist because there was nothing that could be done. They were basically given a blind cane and a seeing eye dog, told to learn how to read braille. Now, of course, the field has transformed with the ability to identify the genetic basis of these diseases and to look at the imaging and the outcome measures and actually do something to improve the vision of these individuals. I'm particularly excited about what Opus is doing because Opus is tackling these ultra-rare conditions as a platform to be able to treat conditions which afflict numerous individuals. Now, starting with this one that you just heard about with the LCA5 form of Leber congenital amaurosis. As I mentioned, this is one of the worst forms of inherited blindness. To be able to correct or improve vision in this patient group really offers hope to everybody else that it may be possible to tackle a diverse set of these conditions. Opus has plans for moving forward with, as Ash mentioned, a variety of other forms of inherited retinal degeneration, which affect many more people than this LCA5 form of disease. I think that has raised excitement in the community that people are just waiting for their disease to be addressed now, and indeed, everybody has a great deal of hope and optimism. Very exciting. Just quick question for Tomás. When are you expecting the 12-month data? We just saw the last patient 12-month follow-up a week ago or so. It's already, we are in the process of analyzing the data, but the data is in, and I'm expecting to see endurance of the treatment effect. That's my hope at 12 months and beyond. Time will tell. Thank you so much. Yeah. Looking forward to it. We could stay here for hours, but we are running short on time. I'll pass it to the operator to have questions from the audience for our esteemed panelists here. Great. Thank you, Dr. Kinani. Please hold for a brief moment while we pull for questions from the audience. Our first question comes from Matthew Caufield at H.C. Wainwright. Please go ahead. Hey, can you guys hear me okay? Yes, we can. Great, thank you. Really great discussion, very informative panel. I really appreciate everyone's time. Two high-level questions. What do you see as the greatest barriers to future approval for novel gene therapy in IRDs, specifically as we talk about LCA5? Then can you speak to any read-through for the AAV vectors themselves between the LCA5 and BEST1 programs? Thanks a lot. Thanks. I will ask Ash to get started on that. Ash, go ahead. Sure. Hi, Matthew. Thanks for the question. One of the key challenges to successful translation of ocular gene therapies, in my opinion, is the development of disease-tailored endpoints. The regulatory agencies generally want to know what aspect of the visual function has changed, such that the patient can do something visually that's meaningful that they couldn't do before. That's why I'm really excited about the MLOMT endpoint because it is a very objective, automated measure that's quantifiable of real-world visual function. We're excited to see the potential of that endpoint, potentially as the basis of approval in the future. I believe your second question was about read-through. Opus is built essentially to avoid risk on risk by using established AAV serotypes or capsids. In our clinical programs, we generally use AAV2, 5, 8, and 9 throughout our portfolio, all of which have been clinically de-risked. The LCA5 program is an AAV8 program, and the BEST1 program is an AAV2 program. Although the capsids differ, the BEST1 capsid is the same as the one used in the product Luxturna. We rely on over a decade of clinical experience with these types of capsids, which informs our clinical trial execution. Thanks. Thank you, Ash. Tara, let's go to the next question. Great. Our next question comes from Laura Suria at Alliance Global Partners. Please go ahead, Laura. Hello. This is Laura on for James Molloy from AGP. Thank you for the great presentation and for taking the questions as well. Maybe a question for Dr. Aleman. In regard to the safety of this therapy, you mentioned mild adverse events and no dose limiting toxicities among the patients treated. In comparison to other gene therapies, especially Luxturna, as it's known to cause side effects such as cataracts and retinal abnormalities. Do you anticipate this positive safety profile gathered to continue, especially as you start dosing pediatric patients and progress further into this clinical development? Thank you very much for the question. It's a relevant one, especially when we are trying to see children. I hope so. I hope it will continue to show the profile. It's very hard to extrapolate from just three patients. We have to see many more. In principle, we are expecting the same type of safety profile as the many other gene therapy trials. Whether we exceed or fail in achieving that, time will tell. The design of the next phase of the trial would maintain the design of including basically a sentinel patient, which is going to always be an adult, in each one of the dose escalation phases, before we include children. We are trying to do the same, so we're going to be careful with immunosuppression to try to prevent inflammatory reactions from occurring in the patients. From the surgical point of view, it's the same. The profile is a little bit more known, since we have done many of the other interventions as well, countless of experiments in NHP, non-human primates. We know about that a little bit better, but it has to be the risk as well. We cannot ignore that part of the question. The development of cataracts, so far we haven't seen any. Maybe it's because we're just lucky that these 3 patients were basically free at 12 months. We have to just keep an eye open for toxicity as we move forward. That's the main reason for the trial. Thank you. Maybe just one more question from us. How exactly do you all see the potential adoption and integration of this gene therapy into the IRD space? Do you think there's any possibility for it to become the next standard of care for this patient population? Thank you. Christine, you want to take that after Dr. Aleman? Go ahead, Dr. Aleman. Yeah. I hope so. I recognize the limitations. We are dealing with infrequent diseases. I always think of each one of these kind of experiments as experiments that have very valuable lessons for other diseases. I often tell patients these are experiments, and that's what they are. Every success or every setback that we have in the trials should shape the way we do things in the future. If anything, the field is moving at a speed that at least makes me a little bit uncomfortable. If anything, I'm hoping that that speed would remain reasonable, but remain with a kind of a vector direction, to end up in the clinic at some point. We would have failed the patients if all of this stays in the clinical trial space, and that's one of my main concerns. There has to be a shift, I think, in the pharma community, and there has to be a shift in thinking in the regulatory bodies to accept this as a next generation of treatment, accepting also that every patient is not the same, accepting that every treatment is not the same. The same way that we accept, I don't know, the antibiotics should not be effective in 100% of the patients. That should be the thought also in this type of situation. If we kind of change our mindset, I think that would increase the likelihood that these therapies are going to be accepted as the next standard of care, hopefully. As it happened with Luxturna, it should not stay there. There are now many more examples. There are Atsena example with XLRS, 2D, the CEP290 treatment that just happened, the X-linked retinoschisis. There are many examples now of, without question, treatment efficacy that are not by any means universal, but that should be enough to move the field into accepting these technologies as a standard of care for our patients. Makes sense. Christine, any follow-ups from you? Yeah. I would echo that from a surgical perspective and from an IRD specialist having treated these patients surgically. I think we have learned that subretinal delivery for inherited retinal disease is really the standard of care, and it's tried and true at this point. The safety profile and the efficacy profile, as Tomás gave a few examples, has not only been shown with an FDA approval in 2017 for Luxturna, but now with multiple phase I, II trials, the Atsena Therapeutics X-linked retinoschisis with a subretinal approach, the Atsena Therapeutics LCA1 trial, the GUCY2D that Tomás mentioned with a subretinal approach, RPGR trials on a number of different companies, X-linked RP, hoping to be moving in a direction towards an FDA approval. We shall see in the near future. Again, positive efficacy data from multiple different programs in the IRD space using subretinal injection. I would argue, and when I talk to my patients about this, I don't necessarily use the word novel anymore when I talk about gene therapy. It's exciting, but I would think at this point, I don't necessarily use the word novel. I explain that this is how we deliver gene therapy to patients, and that we have a new standard of care of genetic testing to identify the genotype, and we have a new standard of care of how we deliver gene therapy to patients, which is, at this point, subretinal for inherited retinal disease. I think that patients are becoming more and more aware of this. It's an exciting time, and I do think that this is moving in a very positive direction. I'm excited to be a part of it. Thank you, Christine. Tara, let's move on to another question, if you have any. Yes. Thank you. Our final question comes from Debanjana Chatterjee at JonesTrading. Please go ahead. Hi. Thanks for taking my question. Do you guys hear me well? Yes. Yes. I might have missed it, but did you mention how many patients you plan to enroll in the pediatric portion of the study? Yeah. Ash, you want to take that? Dr. Aleman. Dr. Aleman, go ahead. Yeah. Sure. For now, we are planning to enroll 6 patients. It could be expanded, so we are trying to be cognizant on the fact that this is a low-frequency disease. 6-9 patients is the enrollment goal. Again, to test efficacy and safety at the same time and stay focused, whether we expand that during the trial is to be seen. Thanks for that. We expect the data on a rolling basis. Are we still on track for a sneak third quarter readout, or could we see some data even earlier? Ash? We'll be working closely with the investigators at the University of Pennsylvania and look forward to sharing data, hopefully, throughout the year. We'll definitely keep you posted on when to expect that. Great. Maybe one last question. Regarding the efficacy, I know in pediatric population, we might see higher responses. Which particular efficacy endpoints will be the most interesting in the pediatric population? We have explored the use of FST in the pediatric population already in our institution. FST, because it's, again, a mechanistically driven readout, is going to be key, and I recognize that it's still not accepted by the regulatory bodies, but it's something that we know pediatric patients can and will use. The plan is to, of course, we won't start treating three-year-olds or four-year-olds. Pediatric will be younger than 18 years of age. The plan is to, initially at least, address the population that is able to do things that they would do in the adult population, such as FST and all of the readouts that I presented to you a few minutes ago, and then overlap a little bit with readouts that we have been exploring for younger patients, basically preschoolers. For now, it's basically bridging the plan of the trial is to bridge readouts that are used by this kind of younger population that can do both adult type readouts and pediatric readouts. It's along the same lines with the same type of scheme that I gave. Jean, anything from you to add on that? In terms of readouts? Yeah. Yeah. Well, we have tested the MLOMT in some pediatric patients, and they seem to really like it. We're hoping that will actually be a game-like test that will be possible to use in this age group, and time will tell. Okay. Thanks for that. Thank you. Tara, any more questions or? Those are all the verbal questions. In the interest of time, we do have a bunch of written questions. I just want to ask, I'll read and ask one of them, and then we'll close out this session. There are several questions just asking about the clinical endpoints for these studies. To summarize the gist of these questions is, aside from the mobility test, the one that was used similar to the approval basis for Luxturna, which of the other clinical endpoints are most important to regulators? Why don't we have Ash, start with that answer and then ask some of the others to chime in on their opinions on each of these other efficacy endpoints that are used. Sure. Thanks for the question, Corey. Jean, Tomás, and Christine have all discussed the value of FST pupillometry and MLOMT as the novel assay for assessing visual function. As Tomás mentioned in his slides, the unexpected result that was surprising is the microperimetry result. That's a very interesting result to us because regulators in retinitis, with respect to XLRP and other forms of retinitis pigmentosa, have had a favorable opinion of microperimetry as a potential registrational endpoint, specifically demonstrating, for example, a greater than or equal to seven decibel change at five pre-specified loci. The fact that that test was relevant in this population could be interesting because the regulators have had a favorable opinion of microperimetry as a clinically meaningful endpoint in other IRDs. I'll let the others comment. Yeah. Can you hear me? Is my volume on? Yep. Go ahead, Christine Kay. I think that it's really helpful for a company as they develop a program, if you happen to be lucky enough to have not one or two or three or four or multiple metrics here that are potentially FDA approvable. Let's just talk about what we know historically, the FDA, at least at this point, has historically and will approve as a pivotal outcome. The answers that we're aware of at this point in the IRD field, because we have conversations with the Foundation Fighting Blindness Consortium, FDA advisory panels, other type C meetings with companies. We know that BCVA absolutely is an approvable outcome. That the current standard in the U.S. is a 3-line or a 0.3 logMAR. Although there is a lot of work being done to look at low vision patients and how that logMAR conversion scale might be adaptable to low vision populations, which might be applicable to multiple LCA programs and other OPUS programs. FST is not something that we are having conversations with the FDA about in a number of different programs. It's certainly something that's possible in the future, hasn't been historically used yet. Microperimetry, we just talked about, is absolutely an FDA approvable outcome, has been accepted, in multiple different conversations with the FDA as that 7 decibels over 5 grid points as an approvable pivotal outcome. We saw a signal already in this program. The functional vision. The multi-luminance mobility test has been historically used. Of course, a virtual maze would go through its validation, but could very similarly be able to be a pivotal outcome. I think that's really the question is, what is a pivotal outcome and what could be used as an approvable endpoint? I think there are at least three options here of a path forward with the FDA conversation. Pupillometry is, of course, very exciting and very useful, has not been yet historically accepted, although it is an objective measurement. The FDA, of course, wants to know what is clinically significant, what is visually significant for a patient. Although that one is certainly extremely helpful objectively to corroborate, I think the other three would be a path forward, and it's really, again, a luxury to have potential three different options here of movement forward here with the FDA. Any other opinions? If not, I think that covered it. Why don't we turn it back to Ash to wrap things up. Thank you, Corey. To close out this session, on behalf of Opus Genetics, we'd like to thank our panelists for their insights and the audience for your great questions and interest in Opus. We're especially grateful to the patients, their families and caregivers, and our investigators for their tremendous support on our journey. Without them, we wouldn't be able to move this technology forward. Hopefully, you can tell from the event today that everyone involved is really excited about these programs. We're really encouraged by the compelling initial safety and efficacy data we have on our first three patients. We look forward to sharing the next set of results in 2025 from the pediatric cohort that we are about to enroll. Have a great afternoon, and thanks again for your interest in Opus Genetics.