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

Good afternoon, and welcome to the Opus Genetics KOL event. [Operator Instructions] 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, and 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 Tomas 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 Vitreo Retinal 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 in 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 rightsized 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. But 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. And 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. And 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 going to 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 in 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's congenital amaurosis. This is one of the worst of the worst inherited retinal dystrophies. Worst 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 nondetectable visual fields. And 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 6 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. And then 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. And even -- you can even see these retained photoreceptors in individuals who only have light perception vision. So of course, with gene therapy, you need the cells to be present to be able to rescue them. So the structure function dissociation creates a favorable environment for AAV gene replacement. So lebercilin is a ciliary protein. It's critical for the function of photoreceptor inner and outer segments. And so in a normal healthy retina, one sees these elongated antenna-like structures, the rod and the cone photoreceptors in a retina with 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. And 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. So the Opus genetic OPGx-LCA5 reagent is designed to address mutations in this LCA5 gene. It uses a clinically derisked AAV8 serotype vector, which delivers a functional copy of the LCA5 gene directly to photoreceptor cells. And it uses the same promoter technology as was used in Luxturna. That has been derisked, obviously. It also uses a validated surgical delivery plan via -- 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 clinically -- the clinical outcome measures that have been used in addition to the multi-luminance orientation and mobility test. But 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 is -- uses a readily available virtual reality headset, one which has already been sold to 20 million people in the United States. So 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 past. That establishes a threshold of functional vision that may be used to address impact of disease and treatments. And it allows the device itself to assess the function of -- 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 corrected such as where the person is looking, if they step backwards, and how difficult it is to -- 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 luminants 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 5 log units typically over 3 log units. And 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 little amount of space. It's easy to deploy and duplicate at multiple sites. And of course, since the objects are virtual, there are no physical objects that could cause harm and a collision or cause the person to trip. Further, one can test one eye at a time or both eyes and adjust the view to the subjects height. This has been really attractive to a digital savvy pediatric population. And the data are obtained, as I mentioned, instantaneously and analyzed objectively. So we don't need reading centers. And there's no risk of personal identifiers being displayed. So I will now hand the microphone off to Dr. Tomas Aleman to tell you about the results of this study.

Hi, everybody. Thank you so much for your interest in our program. I'm Tomas Aleman from the University of Pennsylvania, and the PI for the study. We are presenting to you the results up to 6 months of a Phase I/II Opus Genetics sponsor gene augmentation trial for LCA5. So the studies designed as Phase I/II, as a uniocular treatment by subretinal injection against gene augmentation product, is a non-randomized, open-label, 3 dose ascending protocol. The study started about a year ago. Again, these are the results of 6 months. And I'm going to be presenting the results on 3 patients that we see 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, there were 3 subjects encompassing the spectrum of severity of these very bad disease. Ages, they were basically relatively young adult, 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 noncontact, noninvasive 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 one 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 injection. In terms of safety, which was the main objective of the trial. There were basically no surgical-related complications. And the adverse events were all expected. Were all mild. They were all resolved or recover. And most of them were actually the ocular ones were related to the surgical irritation that is expected to happen after the surgical procedure, 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 related to reading, which we all do, and we are very familiar on doing. And 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 of severe retinal degeneration, even though we recognize the potential for gains of acuity may be limited by neurodevelopmental issues. Nevertheless, in the LCA5 trials, we noted increases in acuity. They were variable among the patients, but nevertheless significant. So 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 6 months, the participants increased beyond 3 lines of acuity, which is recognized conventionally as the significant change in acuity that could be considered significant in a clinical trial. And at the same time, the difference in between the treated eye and the untreated eye as shown below, also shown that -- show that the treatment eye improved acuity significantly. Importantly, one of the patients actually our most severe patient who had never had formed vision was someone that we have known for 20 years or more. Had always had hand motion vision for the first time in his eye was able to use his vision to recognize objects and he is in the process of learning to use newly acquired ability. In this type of situations, we always wonder if -- so increasing acuity or modifying reading ability is important. But if there is no reconnection with the basic mechanism of disease, you would have to question whether the changes are just a random change just by even placebo effect. So it is important to measure mechanistic basically readouts that basically are related directly to the problem that the disease causes. In this case, ciliopathy is an impairment of -- the resulting problem is an impairment in the sensitivity of the photoreceptor, the light sensor to light. And in this plot here, we are basically comparing the control eye and the study eye compared to their baseline, the first bar to the left. And the height of the bars are the sensitivity of the retina to light measured by the ability of patients to see red light, red bars, or a bluish light, the blue bar. The reason we use 2 colors is to try to understand which photoreceptor mechanism in the back of the eye is mediating and the change in vision rods or night vision cells versus cones. And we can use the spectral differences in the response of the retina to figure that out. And as you can see here, at least 2 of the patients showed dramatic changes in sensitivity. I would say all 3 of them, but 2 dramatically, reaching the capacity of the retina, basically the changes are in the 2 patients, 03 and 04 at the range of 1 to 2 log units. And the changes are based by cone vision or daytime vision. And basically, the range that we have for improvement 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, why is the reason. The reason in this patient of a relatively smaller changes that the patient at baseline had still night vision and the improvement is basically at least in this group of patients mediated by cones. So to differentiate that, what we do is that we turn the lights on in the room, and do the same measures that I have shown in the previous slide in daytime conditions. And when we believe that all 3 patients actually improved significantly. Shown to the left are, again, changes from baseline in the sensitivity of the retina to light. Now that the scales are in log units. Again, on average, at least 1 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, it can be basically established by comparing the treated versus untreated eye, which is the plot on your right. Again, the vertical scale is in log units, and these are thresholds, sensitivity difference, the threshold of the response, and it's again in the same -- by the same magnitude. So changes compared to baseline and changes compared to the contralateral eye exceeding 1 log units all mediated by cones. Now you could -- even then, you can question, yes, you have a mechanistically related improvement in sensitivity but it's 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 and many, many years ago, we tried to solve that problem. And we did solve it by using chromatic dark adaptive pupillometry. Now what does that mean, we videotape the pupil reaction to light in night vision conditions using infrared cameras. And like we do with these other tests that we used to measure sensitivity, we use a spectral differences in the response of the people to light to gauge which photoreceptor mechanism is mediated in the response. And you can do that over a range of luminances. So you start very dim, you increase intensities of light and you can basically monitor what the pupil does when you do that. And it was very comforting to see that in every single eye -- treated eye of the patients, there was a shift in the sensitivity of the retina towards basically higher sensitivity. And that is basically the shift of the curve that are in green in the study eye compared to their baseline, which are the great functions. There is a shift again that is comparable to what we determined psychophysicaly by asking the patient to press a button. The shift is again at least a log unit or more towards a better sensitivity from 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 have 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. And one way of doing it is with a visual reality test, which again expands 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 patients to count objects after the treatment, and you can see compared to the red symbols that in the treated eye, there is an increase in the detection of the objects. So the count, the machine is actually counting the number of objects, automatically that the patients see when they are navigating that course. And 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 more severe disease, unfortunately, did not increase their behavior that much, whether there is a relation -- 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. And 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. About 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 -- that's the control eye and to right the treated eye. And the left most plot is basically the sensitivity of area of the retina in the center around the fovea, around the center of the vision. And as you can see, so black in the treated eye, meaning there is no sensitivity, the patient almost randomly pressed the bottom. In the left side, the patient, which is the 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 reducing sensitivity. And down below are actually the plot of where the patient is pointing their vision at or so-called fixation. That cloud of green point is telling you that the patient is actually radically looking around not fixating on anything. After treatment, and again, this is data to 6 months, so you can see already at 1 month post treatment, in the treated eye, there is now an island of vision around the fovea. And importantly, between 1 and 6 months that island not only was maintained, but the cloud of point went from a storm of point to a very small area of point, tight points, which are the yellow arrows located around the foveal center thus 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. So 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 thus supports 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 in a scenario that is actually very common in inherited retinal degeneration, where you have an active and severe neurodegeneration. So it demonstrates that it's possible to treat patients at a stage where you have actually tissue loss or neuronal loss. It can be a [ light ] experience to hundreds literally of retinal degenerations where this scenario is what clinicians find every day in the clinic. And 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 produce a successful clinical trial in a reasonable amount of time that, that can be used for other patients. And the next step is treating earlier disease stages to modify hopefully neurodevelopmental stages that we need to address. And with that in mind, we obtain support and are ready to basically enroll the first patients within the next few weeks or days, the first pediatric patient. And with that, I thank you, and leave the floor to questions.

Great. Thank you, Dr. Aleman. So I'd now like to turn the call over to Dr. Arshad Khanani, who will be the moderator for our panel discussion. So please go ahead, Dr. Khanani.

Thank you, Tara. Thank you, Dr. Jayagopal, Bennett and Aleman for excellent presentations and 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 IRD. So as a practicing retina specialist, I'm 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. So let's move on to the Q&A portion and the panel discussion. So our panel includes Dr. Ash Jayagopal with Opus, Dr. Jean Bennett, doesn't need any introduction, pioneer in gene therapy world. So is 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. Dr. Khanani. [Operator Instructions]

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. So 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. And then the second question is, based on the data you saw today, what gets you more excited about being -- this being a potential treatment for patients with LCA5.

Sure. Thank you, Arshad, an excellent job to all of the speakers. I think that was an excellent presentation. I'm a vitreo retinal 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. So 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. And then other times, we can just talk about updates in the field, and we can talk about trials in the landscape. And 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 and families are aware of that, and they're asking questions, are coming to clinic, they're making their yearly appointments. They're not missing these appointments. They have questions as they walk in the door. If my disease in a trial, what are the potential treatments. And now we have even optogenetics and other types of nongene agnostic therapies to talk to patients about. So this is a really exciting time, I feel, for the IRD field and the landscape. I think that 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 aware -- 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. So to answer the first question, I think that the conversation has become more optimistic in the last, say, 5 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 that's -- I'm counting at least 5 outcome metrics here that are positive, visual function, functional vision and objectives. So we have .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. But FST improvements in 1.5, 15 decibels, that's excellent. That's a huge improvement. It's always nice to see pupillometry because we heard that is an objective measurement that's able to kind of show an efficacy signal without any patient response, no subjective patient response. So we see this kind of confirmatory excellent data with pupillometry. And then, of course, the functional vision which was -- which was able to get the FDA approval for Spark Therapeutics voretigene neparvovec. Now we see this very interesting and optimized virtual maze or living in a 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 is a potential benefit. I think that will be very nice to be able to apply that to patients as being able to cover a larger spectrum of disease without a ceiling or a floor effect and automated all the things we heard about digital, virtual immediate response on -- rather than wait for a reading center. So I think that -- and then, of course, safety. Let's not forget about that as a surgeon seeing inflammation in previous trials, we didn't hear about that, the inflammatory profile looks excellent. Surgical profile looks excellent. So I am 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 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 time. And what I see the impact of the disease on the patients, but also on their family members. And 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 are seeing these patients in terms of how they present it to you and after receiving the treatment. 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?

I mean they are all optimistic and they are very happy with the outcomes. It has posed a few -- 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 doesn't -- did not present the typical relationship that we see in LCA or very preserved retinas with very abnormal vision. So some of these patients, like the first patients that were treated was really someone that had never been a visual individual, was basically totally independent, super smart person, super independent person, but not dependent on vision. So 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, 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. And the other patients, too, the ones are -- 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 mentioned in the questionnaires, which I didn't have the time to go over in the presentation is a shift in the eye preference. So from -- we always pick the worst eye to deliver this type of treatment to basically protect patients. And all of them, basically, recognize the treated eye is now the eye that is driving their day-to-day vision. And I hope that -- I'm hoping that will be the case in the further doses. So very optimistic. Usually not a very opportunistic guy. I'm very optimistic.

No, this is great, right? 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. So 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 have been 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. Aleman showed?

I was definitely surprised, particularly that first patient, I really thought would just be a safety data point. But this patient -- let me just tell you one of the challenges, okay, in doing this multi-luminance orientation test, this person had never seen an arrow before, had never seen a circle, had never seen a platform. And he learned how to find those platforms and to go through the test. Just we have assumptions about what people can see. But when he could first see a wine bottle on the table, actually reached for it and pour himself a glass of wine. That was a huge celebratory moment for him. So we're really excited about this. And notably, all 3 of these subjects have asked if their contralateral eye can be injected because now they're worst seeing eye is their best seeing eye. And they'd like to have it bilateral.

Wow, just listening to that is 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. And this correlates with the data that Dr. Aleman presented. So 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. So Christine, from your perspective, physical and virtual mobility assessments, the 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? And how does it relate to the endpoints required by the regulatory agencies?

Yes, great questions. And 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 sealing 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, the 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 ceiling effect and I think being able to have a virtual maze, no test is the same. The things we learned about from Jean of avoiding the learning effect, being able to have multiple different parameters that you can change, and I was learning quite a bit about this. I have not used at my sight 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 the luminance 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. And 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 going to be gone for 6 hours, if not 8 hours, and that's the day. And I have 2 staff that go and do physical maze with these patients, and it's a decent logistical consideration for a site to take the staff and train the staff to run some of these physical mazes. And then 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 so that might be transit for a patient to get to an offsite facility. Versus it sounds like this headset and then the first 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. So I think, of course, you had mentioned at the last end of the question, there are regulatory steps. Of course, we need to be able to educate the FDA and get to a validation and then be able to get these things validated and approved, but it sounds like that's underway. So I think that, that I think it's going to be an excellent solution to a problem of how to employ these types of functional vision mazes, which you 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. Tomas, 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 -- even from your site perspective?

The -- so 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 test, and they always have this problem of you design the test to deliver a measure being the minimum amount of light that the patient needs to see, the space around them and detect objects or to -- so they're very kind of custom build. Whereas in the visual reality space, you have the flexibility of basically with the touch of the 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. And so 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 visual reality space. We were -- I see a lot of children, I think patients at Children's Hospital of Philadelphia. And I always worry that we are totally focused on the adolescents and older patients and somewhat neglecting -- not me, in particular, but in general, in the field. And the visual 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 FST, I'm not saying that we're going to substitute the FST with a mobility test. But this is a friendly also way of delivering test. And 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. So it's I think -- I'm hoping that, that will be appreciated by others and that it would offer the possibility to adapt the testing algorithms to a specific questions in terms of the functioning of the retina in an easier way and expand the applicability of mobility and orientation test to not only the severity of spectrum of these diseases, but specific patient populations and dysfunctions.

No, 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, and 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. Aleman's adaptation of the MLOMT for the LCA5 trial. Because as we discussed, Opus has 7 different programs under development, all with a diverse genotype phenotypes and 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. So hope to work with Dr. Bennett and Dr. Aleman in the future.

Sounds very exciting. A couple of quick questions before we move to the audience Q&A. Jean, it seems like there's a renaissance of IRD gene therapies for companies, what excites you the most of our recent progress by Opus and others in the field?

I'm so excited about the entire field and of 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 cane and seeing a blind cane and seeing eye dog, learn how to told to -- learn how to read Braille. And 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. So 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. Starting with this one that you just heard about the LCA5 form of Leber's congenital amaurosis. As I mentioned, this is one of the worst forms of imperative blindness. And 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. And 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. And 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, very exciting. Just a quick question for Tomas. When are you expecting the 12-month data?

We just saw the last patient 12-month follow-up a week ago or so. So it's already -- we haven't had the time to -- 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.

Thank you so much, yes. Looking forward to it, we could stay for hours, but let's -- we are running short in time. So let's -- I'll pass it to the operator to have questions from the audience for our esteemed panelists here.

Great. Thank you, Dr. Khanani. So our first question comes from Matthew Caufield at H.C. Wainwright.

So really great discussion, very informative panel. I really appreciate everyone's time. So kind of 2 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? And then can you speak to any read-through for the AAV vectors themselves between the LCA5 and BEST1 programs?

I will ask Ash to get started on that. Ash, go ahead.

Sure. 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 vision -- of the visual function has changed such that the patient can do something visually that's meaningful that they couldn't do before. And 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. And so 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 AAV 2, 5, 8 and 9 throughout our portfolio, all of which have been clinically derisked. The LCA5 program is an AAV8 program, and the BEST1 program is a AAV2 program. Although the capsids differ, the BEST1 capsid is the same as the one used in the product, Luxturna. And so we rely on over a decade of clinical experience with these types of capsids, which informs our clinical trial execution.

So our next question comes from Laura Suriel at Alliance Global Partners.

Well, this is Laura on for Jim Molloy from AGP. So maybe a question for Dr. Aleman. So in regard to the safety of this therapy, you mentioned mild adverse events and no dose limiting toxicities among the patients treated. And in comparison to other gene therapy, especially Luxturna, 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 its clinical development?

Thank you, Laura. Thank you very much for the question. It's a relevant one especially when we are trying to treat children. I hope so. I hope we will continue to show the profile. It's very hard to extrapolate from just 3 patients. We have to see many more. In principle, we are expecting the same type of safety profile as 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 be always be an adult in each one of the dose escalation phases before we include children. And we are trying to do the same. So we're going to be careful with immunosuppression to try to prevent some other 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 in nonhuman primates. So we know about that a little bit better, but it has to be the risk as well. We cannot ignore that part of the equation. The development of cataract so far we haven't seen any, maybe because we're just lucky that these patients were basically are free at 12 months. But we have to just keep an eye open for toxicity as we move forward. And that's the main reason for the trial.

Maybe just one more question from us. So how exactly do you all see the potential adoption and integration of this gene therapy into the IRD space? And do you think there's any possibility for it to become the next standard of care for this patient population?

Christine, do you want to take that after Dr. Aleman. Go ahead, Dr. Aleman.

Yes. I hope so. I recognize the limitation. So we are dealing with infrequent diseases. But I always think of each one of these kind of experiments, I often tell patients, these are experiments and that's what they are. As experiments they have very valuable lessons for other diseases. So every success or every setback that we have in the trials should shape the way we do things in the future. And 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 kind of a better 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, there have to be a shift in thinking in the regulatory bodies to accept this as the next generation of treatment accepting also that every patient is not the same, accepting that every treatment is not the same. So the same way that we accept, I don't know, the antibiotic should not be effective in 100% of the patients. That should be the thought also in this type of situation. And 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, and there are now many more examples. They have seen example with GUCY2D, the CEP290 treatment that just happened, the X-linked retinoschisis. So there are many examples now of without a question, treatment efficacy, that are not by any mean 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?

Yes. 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 Tomas 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 Tomas mentioned with a subretinal approach, RPGR trials 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. But again, positive efficacy data from multiple different programs in the IRD space using subretinal injection. So 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 and -- but I would think at this point, I don't necessarily use the word novel. I use the word, 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 genetic therapy to patients which is at this point, subretinal for inherited retinal disease. And I think that patients are becoming more and more aware of this. So 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. So our final question comes from Debanjana Chatterjee at JonesTrading.

So I might have missed it, but did you mention how many patients you plan to enroll in the pediatric portion of the study?

Yes. I'll -- Ash, you want to take?

Dr. Aleman.

Dr. Aleman. Go ahead, Yes.

Sure . So 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. So 6 to 9 patients is the enrollment goal. And again, to test efficacy and safety at the same time and stay focused whether we expand that during the trial is to be seen.

So thanks for that. We expect the data on a rolling basis. So are we still on track for a third quarter readout? Or would it -- could we see some data even earlier?

Ash?

We'll be working closely with the investigators at University of Pennsylvania and look forward to sharing data, hopefully, throughout the year, but we'll definitely keep you posted on when to expect that.

Great. And maybe one last question. So regarding the efficacy, I know in pediatric population, we might see higher responses. So which particular efficacy end points will be the most interesting in the pediatric population?

So the -- we have explored the use of FST in the pediatric population already in our institution. So FST because it's, again, a mechanistically driven readout is going to be key. And I recognize that it's still not accepted by 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 3-year-old or 4-year-old, pediatric will be less than -- younger than 18 years of age. So 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. And -- but 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. But it's along the same lines with the same type of scheme.

Jean, anything from you to add on that?

In terms of readouts?

Yes.

Yes. Well, we have tested the MLOMT in some pediatric patients, and they seem to really like it. So we're hoping that, that will actually be a game like test that will be possible to use in this age group and time will tell.

Tara, any more questions or?

We actually -- so those are all the verbal questions. In the interest of time, we do have a bunch of written questions, but I just want to ask -- I'll read and ask one of them and then we'll close out the session. So the -- there are several questions just asking about the clinical endpoints for these studies. So to summarize the gist of these questions, it's 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 and their opinions on each of these other efficacy endpoints that are used.

Sure. Thanks for the question, Corey. Jean, Tomas and Christine have all discussed the value of FST pupillometry in MLOMT, the novel assay for assessing visual function. And as Tomas mentioned in his slides, the unexpected result was that was surprising is that was the microperimetry result. And 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 7-decibel change at 5 prespecified loci. So 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. But I'll let the others comment.

Can you hear me? Is my volume on?

Yes, go ahead Dr. Kay.

I think that it's really helpful for a company as a developer program, if you happen to be lucky enough to have not 1 or 2 or 3 or 4 or multiple metrics here that are potentially FDA approval. So 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. And the answer is that we're aware of at this point in the IRD field because we have conversations with the Foundation Fighting Blindness Consortium, FDA advisory panel, other Type C meetings with companies. We know that BCVA absolutely is an approvable outcome. The current standard in the U.S. as a 3-letter -- sorry, 3 line or 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 and a number of different programs is certainly something that's possible in the future hasn't been historically used yet. But microperimetry, we just talked about is absolutely an FDA approval outcome. Has been accepted in multiple different conversations with the FDA as that 7 decibels over 5 grid points as an approvable pivotal outcome, and we saw a signal already in this program. And then the functional vision. So the multi-luminance mobility test has been historically used. Of course, a virtual maze would go through its validation but could very similarly have -- be able to be a pivotal outcome. So I think that's really the question is what is a pivotal outcome of what could be used as an approvable endpoint. I think there are at least 3 options here of a path forward with the FDA with conversation. Pupillometry is, of course, very exciting and very useful, has not been yet historically accepted, although it is an objective measurement. But the FDA, of course, wants to know what is clinically significant, what is visually significant for a patient. So though that one is certainly extremely helpful objectively to corroborate, I think the other 3 would be a path forward, and it's really, again, a luxury to have potential 3 different options here of movement forward here with the FDA.

Any other opinions? And 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. And 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. And 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 3 patients. And we look forward to sharing the next set of results in 2025 from the pediatric cohort that we are about to enroll. So have a great afternoon, and thanks again for your interest in Opus Genetics.