Ocuphire Pharma Inc Aktie

Good morning, and thank you for joining us today to delve into our gene therapy pipeline with a focus on our earlier-stage programs. As a reminder, this event is being recorded.

Before we begin, I'd like to remind you that during today's call, we will be making certain forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements. Please refer to our annual and quarterly reports and our other SEC filings available on our website.

Any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to these go even if our views change.

Recording of this event and the accompanying slides will be available in the Events section of the Opus Genetics Investor Relations website later today. So we have a really terrific lineup of speakers and are really grateful for all the key opinion leaders joining us today to share their expertise on the treatment of inherited retinal diseases, including targeted indications for Opus. For reference, you can access speaker bios on the right side of your screen or via the button in the top right corner.

Today's agenda is divided in 2 parts. In part 1, we will provide a brief company introduction and scientific overview. Then one of our KOL guest speakers will discuss each disease followed by a summary of our scientific approach for the corresponding indication. We will review our clinical development strategy and approach followed by our first Q&A session on these programs that will be entering the clinic later this year and into 2027. Please note that any time during our presentation today, you can submit a question using the Ask a Question button on the top right corner of the screen.

In part 2, we will provide a brief summary of the clinical trial data from our lead programs, LCA 5 and BEST 1. We will highlight the recent epidemiology work we commissioned to better inform the disease prevalence of our 7 current indications. And finally, we are excited to host a panel discussion with several industry experts to discuss patient recruitment and retention in inherited retinal diseases. We will then open the call back up for questions. So I'd now like to turn the call over to Dr. George McGrath, Opus' CEO, to kick off our program.

Thank you, Ben, and good morning, everyone. At Opus Genetics, we're focused on accelerating groundbreaking gene therapies for inherited retinal diseases. We're advancing a portfolio of 7 AAV gene therapy assets built on validated science and a proven delivery approach pioneered by our co-founder and guest speaker today, Dr. Jean Bennett, whose work led to the first approved IRD gene therapy. We hold first-mover advantage across multiple indications supported by broad IP protection, orphan drug exclusivity potential and rare disease regulatory pathways that offer flexibility and potentially accelerated approval.

Our approach emphasizes streamlined time lines, capital-efficient development and the ability to progress multiple clinical programs in parallel. We're fortunate to collaborate with leading scientific and clinical innovators in gene therapy, many of whom are here with us today. By building a portfolio that spans multiple rare retinal diseases, we believe we can capture meaningful share in a multibillion-dollar market and deliver multiple approved therapies for patients with severe genetic eye disorders.

As you will hear today, our validated scientific approach and early clinical success give us strong momentum as we expand into our next group of promising programs. We're currently targeting 7 inherited retinal diseases caused by genetic mutations. As you think about the indications we're focused on, there are 3 primary buckets of IRDs, the bestrophinopathies, bleber's congenital amaurosis and retinis pigmentosa. We have chosen these programs specifically since they have common approaches that we can leverage, including cell biology, delivery method and clinical trial design. Then we can differentiate as needed for each disease.

For example, LCA mutations are typically earlier onset conditions in children, and they are also more macular focused, while the retina pigmentosa mutations have a more concentric loss of peripheral vision. All of these programs are fairly straightforward subretinal IRD gene therapy programs. And one of the reasons we pick these indications is because we can potentially see a rapid proof of concept in clinic. We will go through much of this today as we look towards several clinical trial initiations and data readout in the next 12 to 18 months.

We really are building a differentiated gene therapy pipeline. Our company is essentially built as a platform to develop these gene therapies and advance them in a very capital-efficient and time-efficient manner. For LSA-5, we are currently enrolling participants in the run-in portion of our Phase III clinical program. This program has received multiple regulatory designations, including the Regenerative Medicine Advanced Therapy, or RMAT, -- and most recently, we were accepted into the new Rare Disease Evidence Principles, or RDEB program focused on ultra-rare diseases.

For BEST1, Dr. Mark Panesi presented our data on the Sentinel patient at the Macula Society in February, and we look forward to presenting our first full cohort of data in September. Our key focus today is to provide you with the disease profile and scientific rationale for our next 3 programs. RO, RDH12 and MerTK that are all progressing into the clinic.

Here on Slide 10, we've laid out our planned time lines. And importantly, current cash runway into 2029 will support 5 clinical development programs through multiple inflection points. We are really entering a pivotal time for the company. Based on early success we've had with LC5 and BEST1 and our recent fundraising activities, we are now in a position to accelerate RDH12, MERTK and R in the clinic. This increases our total addressable market in a significant way and gives us multiple shots on goal. We are now funded to achieve readouts in our BEST1 and LC5 programs and also generate clinical data from these additional programs coming online.

Currently, we expect as many as 4 clinical trial readouts in 2027. It is important to note that all of our programs treat various forms of rare pediatric diseases with the potential to receive priority review vouchers if approved.

It's my honor to introduce our first guest speaker, Dr. Jean Bennett. She is the inventor of Luxturna, which is the first gene therapy approved in the U.S. to treat inherited retinal diseases. She is one of our -- the scientific co-founders of Opus Genetics and remains a key member of our Board of Directors.

Today, Dr. Bennett will provide an overview of IRD drug development and discuss the concept of structure function association that underlies all of our programs.

Thank you so much, George. It's my pleasure to be here. I thought to set the stage for the next set of talks, I'd give you a little bit of background about the rationale for selecting the various targets that we've selected. Obviously, the optimal targets have to affect -- have to target the affected cells before they've degenerated. Otherwise, you can't treat them.

Ideally, lack of function disease is optimal since one can then reactivate the function and rescue the disease. We want transgene cassettes that will fit within the small cargo capacity of the adeno-associated virus or AAV, and that AAV must transduce the target cells efficiently. The disease has to be severe enough to be able to detect improvement and ideally in a fairly rapid time frame so that we can see this improvement quickly.

We need the relevant animal or cell models to be able to develop proof of concept to be able to go forward and ideally select diseases which are relatively prevalent, so we can find enough patients to be enrolled in the clinical trials. The more challenging diseases are those that are developmental conditions, for example, those that begin the whole process -- degenerative process in utero, those would be very difficult to treat.

And there are also some technical challenges with large genes fitting them into the small cargo capacity of the AAV. -- ideally, we want disease that progresses fairly quickly because we don't want the trials to have to take 10 years or longer. And it's more challenging if we don't know much about the natural history of the disease or if there's asymmetric disease or if it's extraordinarily rare. So shown in this graph is a diagram of the numbers of genes which when mutated cause retinal degeneration.

Over time, the first ones were identified in around 1990, choroideremia and rhodopsin were some of the earliest. And as you can see now, the number has expanded to more than 348 identified genes, and that's in large part, thanks to the human genome project. When we first started and others first started considering gene therapy, gene augmentation therapy, the only 2 genes that were known were rhodopsin and choroideremia. RPE65 or retinal pigment epithelium 65 kilodalton protein encoding gene were some of the earliest ones identified, and those have been targets of clinical trials, choroideremia and RPE65 were targets of Spark Therapeutics and other people, including those that you'll hear later today have been involved in trials for choroideremia.

But shown here are additional diseases, which have been identified over the course of this progress in the gene identification. And these are targets that OCU has selected that fit the characteristics that are listed in this slide in terms of optimal targets.

In the next slide, we -- obviously, if the retinal structure is relatively preserved, even though visual function is already impaired, it becomes possible to deliver the gene to rescue the function in a therapeutic window when these are still -- the cells are still viable enough to be able to function.

And if one can pick the right patients and choose the meaningful endpoints for clinical trials, one can potentially demonstrate benefit. And that's exactly what has happened with Luxturna, which was the reagent that was developed to treat RP65 deficiency. In the next slide, I'd like to show you 2 of the targets that Opus has initiated studies on. One is -- they're both forms of labor's congenital amaurosis. This is a severe early onset form of retinal degeneration, one of the most severe forms of retinal degeneration because it affects children and infants. LCA 5 and RDH12 are both diseases which are first manifest in photoreceptor cells, unlike RP65, which is the gene target of Luxturna. And these are both sillyopathies. They're very rare.

But by imaging, we know that there are photoreceptors that are still available and treatable in childhood and young adults. And so that satisfies one of the requirements. There are animal and cell models that can be used to demonstrate proof of concept. However, compared to RPE65, these are more severe and earlier onset. And so we hypothesized that by treating children, we could actually intervene well with the disease and potentially even prevent the disease. And shown to the right are some of the children who are the first to be identified with these diseases.

The top one is one with LCA 5 and underneath our EH12 children when they came to visit my laboratory. In the next slide, one of the reasons why these 2 diseases are so dear to my heart is because of the patient and family partnerships that have been made over decades. And starting with LCA 5, a labor's congenital amaurosis conference was held in 1998 that was developed and formulated by parents of a child with LCA.

At that point, they didn't know what the cause of his disease was. And they fueled the efforts of academics and really an international consortium to try to figure out what was the cause of this and other forms of LCA. And their child's gene was identified in 1997 -- well, the child was born in 1997. But after this conference, his gene was identified some 10 years later in 2007. That picture on the lower left shows the team at Nyagan in the Netherlands who had discovered this gene. And that fueled a consortium to try to develop a treatment for this particular disease. The family continued to fund projects, including generation of a mouse model of this disease, which was made at Jackson Labs by Patty Nina, sent to my lab. And together, we all developed a reagent, which we showed could actually ameliorate the disease in this mouse model.

In our lab, we set up a GMP facility to generate AAV. And then we were lucky enough to partner with Opus Genetics and develop a clinical trial. And shown in the lower right is the team that delivered the first gene therapy for LCA5 in 2023.

In the next slide, I'd just like to close by telling you what I think the status of retinal gene therapy is. There's abundant safety data. There are more than 140 different retinal gene therapy clinical trials that have been initiated.

There are gene therapy centers around the world and thousands of eyes have been injected. We have a lot of safety data -- there are numerous disease targets that have been tested and are in the process of being tested in the clinic with a variety of strategies, excellent safety data. And now there's familiarity with gene therapy surgical techniques, vector handling and storage, genotype, phenotype correlations, development of outcome measures all over the world. And it's a very exciting time.

There are more than half a dozen retinal gene therapy clinical trials, which will read out within the next year, hopefully giving us additional approved gene therapy products besides Luxturna. Now where are we with Luxturna, also known as voretigene, the neparvovec rizzzle. This is the treatment for RPE65, which is now approved not only in the United States and the European Union, but in numerous countries and continents around the world.

There is a great deal of long-term durability data that stems from the clinical trial that was run to approve this drug. It's more than 9 years in counting of this durability data. And the real-world efficacy is very similar to that reported in clinical trials. So we're really optimistic that Opus is going to contribute further to development of treatments for these currently untreatable conditions.

So I'd like to hand off the next session to Dr. -- actually, let me give this slide. There are numerous obstacles to retinal gene therapy that have been overcome, just as a continuation of where we are. In the 2000s, when we began with LUXTURNA, there was no path. There were no regulatory guidelines. Everything had to be derisked, including the safety of subretinal delivery of AAV and dosing of AAV.

There was a lack of genotype patients because there was no reason to genotype them. There was no treatment, no clinical trials in progress. No one had enrolled pediatric subjects for gene therapy clinical trials. We didn't know the status of immune response, whether this would cause rejection or inflammation. And we had no guidelines from the FDA, including whether or not it was going to be necessary to inject the second eye, the contralateral eye, what we needed in terms of control groups, et cetera.

There was no natural history data and no relevant outcome measures and certainly no potency assays with which to measure the quality of the product. In 2007, when we began our first retinal gene therapy clinical trial, there was only one approved outcome measure, and that was reading the eye chart.

Now there are numerous potential outcome measures, including the outcome measure that was developed during the process of testing Luxturna. That's the multi-luminance mobility test. And they're now virtual reality tests -- there's perimetry, there are anatomical features and also changes in disease progression. So it's a very bright future for retinal gene therapy.

And now I'd like to turn the table over to Dr. Fan, who will tell you about RDH12. Thank you very much.

Thanks, Dr. Bennett. That was such a great overview of how far we've come with gene therapy and IRDs, of course, you've been so pivotal to all of that. Let's get into the slides in the interest of time. I'm just going to start reviewing this disease, RDH12, which is truly one of the most devastating forms of early onset retinal dystrophies or degenerations that I see in my clinic. D12 is interesting because it draws a lot of parallels to the severity and intensity of vision loss to RPE65. We know RDH12 accounts for up to 10% of all LCA cases. That makes the global prevalence over 30,000 with a high concentration in the Middle East and North Africa.

There are still quite a few patients in the U.S., probably underestimating it at about 2,500 patients. But surely, as we know about all IRDs, the true prevalence is probably a little bit higher. These are images of a patient I see of my clinic, a young patient. As you can see on the images on the right, that you have essentially severe peripheral retinal atrophy. But what's unique about this retinal degeneration as opposed to a disease like retinitis pigmentosa is that you have more macular atrophy, which is central involvement early on in life.

And so what you often see in these patients is they'll present in childhood with a diagnosis of retinitis pigmentosa, but then you kind of watch them progress very quickly into losing central vision in addition to peripheral vision, and that can be truly devastating for this patient population.

Let's go to the next slide. Not to bore you with the scientific mechanism of action of RDH12, but essentially, as Dr. Bennett was saying, this enzyme and this gene has its function in the photoreceptors as opposed to the retinal pigmented epithelium. So you can see that the job of the photoreceptors, the outer segments is to process light and clear toxic byproducts like alltansretinol, which then can be recycled into the visual cycle. But if you're unable to clear those byproducts, what happens is that the byproducts will build up, they'll dimerize, they'll create oxidative stress and damage to the photoreceptors in forms of entities like A2E, lipofusion and that kind of thing.

And so we know in RDH12, this process is very severe and will damage photoreceptors if left unchecked, leading to early vision loss in the disease that we call liver's congenital amaurosis or LCA.

Let's go to the next slide. One of the most interesting things that we have found about RDH12 is, in some ways, it is parallel to RPE65, but in other ways, it is not. So the way that it is similar is that it has profound vision loss early on in life.

We know that maybe in your teens or childhood, you're about 2,200, but it can steeply decline very quickly thereafter hitting counting fingers or even hand motions or life perception in your 30s and 40s, which is truly devastating and much more severe than a lot of other inherited retinal diseases.

Drawing your attention to the diagram on the right, you can see that the OCT image of the patient of RDH12 has more disorganized anatomical layers of the retina as compared to the image of the OCT of R65. However, we have found on electrophysiology that there is better co-mediated sensitivity in patients with RDH12 despite the anatomical disorganization of layers as compared to RPE65, which may suggest because the pathobiology is relatively similar that perhaps these cones are rescuable because they still maintain pretty good sensitivity despite what we see on exam and also on imaging to be more severe retinal disorganization or potentially retinal atrophy.

And so there is a therapeutic window here for us to produce a therapy that may mimic that of Luxturna that may be able to treat patients similar in some ways to RPC35 and maybe optimistically be able to rescue in maybe a more efficient way or better way this co-mediate sensitivity before it causes damage to the central vision.

I'm going to pass it over to Ash now so we can review the scientific overview. Ash is the Chief Scientific Officer of Opus. Thanks.

Thanks, Dr. Fan. OPGX-RDH12 is an AAV8 vector designed for a onetime subretinal administration to deliver functional copies of the RDH12 enzyme to photoreceptors in order to restore visual function using a photoreceptor-specific promoter. And in our studies, mouse model of RDH12 deficiency was used to test OPGX-RDH12 to test for expression as well as function of RDH12 in the mouse retina.

And we demonstrated with Dr. Bennett that OPGX-RDH12AAV restores RDH12 enzyme expression in the mouse retina as shown on the right panel, and in a dose-dependent manner, also restores enzymatic activity and function approaching that of wild-type mouse retina levels. And the RDH12 deficient or as we call it, a knockout mouse model is also highly susceptible to light damage due likely to acceleration of phototoxic stress and subsequent photoreceptor apoptosis.

So left untreated, these RDH12 knockout mice treated with high-intensity light exposure to the retina degenerate as shown by thinning outer nuclear layers where the photoreceptor nuclei reside, and you can see that on the top panel. However, AAV8 encoding for RDH12 expression in this published study was capable of preventing this retinal degeneration.

And furthermore, mouse behavioral testing used to assess visual function also improved with AAV gene therapy for RDH12 as shown on the bottom half of the panel. And we, therefore, are well poised to now investigate OPGX-RDH12 safety and efficacy in clinical studies.

And so with that, I would now like to turn the call over to Professor Robert McLaren to discuss MERTKRDs.

Thanks very much, Ash. And also thank you to Jean for a very helpful summary of the history of the retinal gene therapy, which I've been following myself for over 20 years now. So I'm Robert MacLaren, Professor of Ophthalmology in Oxford, and I've been involved in gene therapy trials for a number of conditions, choroideremia, X-linked retinitis pigmentosa, which take a lot of my time at the moment and also the work we've been doing with age-related macular degeneration.

Now MERTK is one of those inherited retinal diseases that can be very severe in early onset and cause what we refer to as labor congenital amaurosis and others very, very poor vision from birth. But more often, what we see is missense changes where patients have a disease that is clearly causing the vision impairment, but still some ability to see things and read the chart. And this particular condition is caused by a mutation in the gene that encodes a protein that is involved with the phagocytosis of photoreceptor disks. And most significantly, the MERTK gene is expressed in the retinal pigment epithelium. And we know this cell, in particular, is readily transducible with low levels of AAV compared to photoreceptor transduction, again, which helps us in terms of predicting the clinical trial outcomes in terms of safety.

The prevalence worldwide, I have patients in my clinic and oxate,' particularly high in the Middle East. And my colleague, Alan Alka originally did a MERTK gene therapy trial at the Kingollyye Hospital in Riyadh. And the reason for that was that it was funded by a family, the Aldi family, who unfortunately have MERTK in the family and was really done almost like as an off-label treatment. I was very much hoping that Fazan would continue the program. And in fact, I invited him to Oxford to come and speak about the results of the trial, but it's sort of faded away, unfortunately, at that stage.

But we do have some very good examples from that paper that he published on the safety and in some case, efficacy of the treatment administered to a small cohort of 6 patients. So the phenotype, very, very similar to all of these inherited retinal diseases. If you look at the picture on the bottom right, kindly provided by Ken, again, I'm going to comment on your image, I hope you don't mind. But there is some debate about whether we can see subretinal clumps in the subretinal space. And you can see in the bottom right, the retina, the subretinal space.

There is certainly good data from the models, the animal models that these are photoreceptor allogments of clump there. And it's one of those things that we look for potentially as a phenotype to identify patients and try and narrow down the genetic testing. So the ability to phagocytose the other segments is all part of the visual cycle indirectly. And so not surprisingly, these patients have night vision loss, peripheral vision loss. And indeed, the actual clinical features are very similar to those seen in many of the other inherited retinal diseases. So if we could go to the next slide, please. So this just shows a little bit more about the mechanism.

And you can see that the MERTK receptor is on the surface of the retinal pigment epithelium. So we can translate a lot from the luxtoma program, which is also targeting retinal pigment epithelium to MERTK. And we might expect to see, as indeed we have seen with other inherineases is when you put back a protein that has a critical role in maintaining the structure of the photoreceptor, particularly the outer segment, then you can expect to see an improvement in the outer segment structure. And we've seen that with OCT scans as well. And if you improve the outer segment structure by liamans, you can also expect to improve the retinal sensitivity, which is very important because that gives you a functional endpoint.

And functional endpoints are much easier to achieve with a small number of patients than anatomical endpoints in which one would have to wait quite a long time to see a difference in slowing degeneration in a treated eyes compared to untreated eyes. We know that the functional endpoints are well established. I mean it's going to be low lumous visual acuity, best corrected visual acuity, microperimetry. These are the tests we do all the time on our patients, and they're all recognized as being useful tests by the regulators for clinical trial approval. And ideally, we'd like to see something within 1 year improvements, which would justify approval of the treatment. So if we could go to -- so the failure of the MERTK results in accumulation of this outer segment debris in the subretinal space. And there is undoubtedly a window where the function is impaired, but the cells are still there, potentially could be reversed with a clinical trial outcome measure seen very quickly after gene therapy. And that is seen in the animal models.

Next slide, please. So again, this just explains a little bit about what I said, the functional loss, okay? So any disease in which there's a loss of function before you get degeneration has a potential opportunity for reversal of functional loss by gene therapy, which gives us a nice clinical trial outcome measure. The reduction in vision, as I said, in most cases, we see it in childhood teenage years. Most patients manage reasonably well. But they do lose vision, and we do have a large cohort of patients who are treatable. And these patients will, in general, have had relatively normal development.

They may have problems with in childhood with night vision, but they will be able to use a visual system and gives us an opportunity, a relatively large window in their lifespan where we could perform the intervention, as I said, because primarily of the preserved structure as well. And the phenotype on the right-hand side, again, I mean, to be honest with you, it's very, very similar to all retinal degenerations. But what you have to look at, if you're familiar with the structures of the OCT scan is the bottom scan. And you can see the black line, which is basically the outonuclear layer in contact with the reflected line, which is the retinal pigment epithelium. And this outonuclear layer is relatively well preserved.

In other words, the photoreceptors are still there. They're probably largely nonfunctional because the other segments cannot grow. They're not being properly fanocytos. There's debris in the subretinal space, but the cells are there. And when the cells are there, there's a capability of regeneration following gene therapy. And by the way, the reference we've got at the bottom there is the guarding reference, which is the clinical trial led by Cal's a geneticist when he was working in Saudi Arabia. So I think just check. That's pretty much all from me.

So I'll hang around for questions afterwards, and I'll gladly hand over to Ash to go through the molecular biology of the treatment. Thank you.

Thank you, Dr. McLaren. Our clinical candidate, OPGX-MERTK is an AAV2 vector designed also for onetime subretinal administration to deliver MERTK gene within RPE cells. And in this case, it uses an RPE-specific promoter. The capsid used AAV2 is the same as that used in the approved product for digene neparvovec or Luxturna, which as Dr. Bennett elegantly described, has now had a long track record of improving clinical outcomes in patients with RPE65 associated IRDs.

So the MERTK deficient mouse model, which has been published and established for some time now, allows us to study the efficacy of MERTK gene therapies in a relevant context. This mouse model rapidly loses photoreceptors and concurrently loses visual function, but this decline can be prevented through subretinal injection of AAV and coding for MERTK.

Specifically here, gene therapy-treated mice exhibited improved outer nuclear layer thickness as shown on the top right panel and improved electroretinogram or ERG functional responses as shown on the bottom right panel. And furthermore, using another model, this case, a rat model of MERTK deficiency called the RCS or World College of Surgeons rat model of retinal degeneration, we demonstrated that the clinical candidate, OPGX-MERTK was capable of dose-dependently reducing photoreceptor degeneration in this model when compared to a control injection, which had no therapeutic response as outlined by the blue dash line on measures of outer nuclear layer thickness. So with that, we look forward to investigating the safety and preliminary efficacy of OPGX-MERTK in clinical studies.

And with that, I would now like to turn the call over to Dr. Lejla Vajzovic to discuss ADRPRO IRDs.

Thank you. Thank you very much, Ash. Good morning to you all. It's truly a pleasure to be here with all of you. It's really a pleasure to be included with such an outstanding, really world-renowned experts and clinicians, scientists and industry leaders. It's super excited to be here because the future of, I think, care of IRD patients is looking really bright. And I commend the Opus Genetics team for working so hard to provide more options for our patients in the future.

As mentioned, my name is Lejla Vajzovic, I'm Professor of Ophthalmology, Pediatrics and Biomedical Engineering with tenure at Duke University. As a clinician and surgeon who has been taking care of pediatric and adult retinal patients with IRDs and who has been delivering the gene therapy surgeries for the last 15 years at Duke, I'd like to provide some more perspective on RO specifically associated retinitis pigmentosa, what I see in my clinic, how these patients progress over time and what's really the essence of the disease and why this may be a great therapeutic approach to treating these patients.

So let's dive into RO-associated retinitis pigmentosa and one of the most common inherited retinal degeneration that we encounter in our practice. There has been more than 290 disease-causing mutations that have been identified and RO variations account for approximately 20% to 30% of autosomal dominant retinitis pigmentosa cases that we see. Importantly, this is not an ultra-rare disease. Currently, estimates suggest approximately 8,800 affected individuals in the United States and more than 30,000 across the global markets.

From a clinical perspective, these patients often first present with night blindness and difficulties in dim environment. So this is really the first complaint we will hear very much from our patients. Over time, they experience progressive peripheral vision loss while maintaining the useful central vision for years to come. I think this combination of meaningful patient population, prolonged disease course, I think, makes an especially attractive target for therapeutic delivery.

Next slide, please. Well, let's dive into biology itself. Well one of the aspects that makes RO particularly compelling is that we understand the disease biology exceptionally well. Row encodes rhodopsin, the critical photopigment with the rod photoreceptors that really enables vision in the low light conditions. When mutation does appear, the resulting protein can misfold or function abnormally, triggering cellular stress and progressive photoreceptor degeneration. Importantly, many dominant role mutations act through toxic gain of function or dominant negative mechanism.

As a result, these therapeutic approaches most address the mutant protein itself rather than really adding another copy of the gene. So we really want to address that mutant protein than just kind of multiplying and adding new copies. So deep understanding of this disease biology really provides us with stronger scientific rationale for targeting gene therapy approaches for certain.

Next slide, please. I think one of the most encouraging aspects of R-associated disease, it's often relatively slow progression. This disease typically begins with raw destruction during the childhood. As I mentioned earlier, it presents with night blindness and peripheral visual field construction over time. But the cone, the central vision degeneration is typically the last one to occur in this disease course. We do understand that there are 2 classes, 2 broad phenotypes that have been described here. Class A patient experience is more of a severe disease with early functional loss, while Class B patients often maintain broad function and preserve retinal structure well into the adulthood.

I think this distinction is important because many patients, again, retain viable photoreceptors for years, creating meaningful opportunity for us to intervene therapeutically and hopefully stop their degeneration or at least slow it down. I think the structural and functional data shows that there is definitely room for intervention and the disease progression can very much, as mentioned earlier, in other diseases can be measured as such with imaging and functional testing, providing us now tools to really understand and how to develop clinical trial designs, follow the patients and ultimately report on outcomes.

I think before I transition back to Ash, I just want to summarize. I believe Rove represents one of the most compelling opportunities in inherited retinal diseases because it truly combines 3 key characteristics for me. First, we have well-understood disease mechanism; second, meaningful and identified patient population that we can treat. And third, we have a therapeutic window where the photoreceptors remain present and potentially are amenable to interventions. Those characteristics, I think, make RO an attractive target for gene therapy, especially in development.

And with that, I'm going to turn it back to Ash to discuss really their OpusRO program. Thank you so much.

Thank you, Dr. Vajzovic. In this case, we're talking about the clinical candidate, OPGX-RO. This is an AAV5 vector. And like the others, it's for onetime subretinal administration for patients with autosomal dominant retinitis pigmentosa associated with RO mutations. OPGX-RO is a mutation-independent single AAV construct for silence and replacement. And this is designed to replace mutated rhodopsin proteins with a functional nontoxic copy, and the vector targets rod photoreceptors using selective promoter technology.

We've been fortunate to have demonstrated preclinical safety and efficacy in 2 large animal models of ADRPRw as previously reported. Here, in the canine model in collaboration with Dr. William Beltran of the University of Pennsylvania, we have tested safety and efficacy of the clinical candidate in this model of ADRPRO mutations. The canine model is a mastive, English mastive with a naturally occurring point mutation in row and expresses nearly equal amounts of wild-type and mutated row proteins and captures well, we think the structural degeneration observed in Class B human ADRP patients, as you see on the top right.

Within the first 2 years of life in this model, there is a substantial loss of photoreceptors. However, this time course can be accelerated even further with light exposure to enable the study of therapeutic interventions within an efficient window. In fact, with a 1-minute light exposure protocol, rapid photoreceptor loss down to even a single row of outer nuclear layer nuclei can be observed as early as 2 weeks post light exposure in the ADRP row, but not the wild-type canines. And you can see that on the bottom right panel. So this accelerated degeneration model has been useful for us to test our clinical candidate.

So here, on the left panel, we can see that the retinas post injection of subretinal AAV and light exposure treatment have exhibited significant outer nuclear layer retention in the treated areas. So the dash lines are actually showing demarcating the subretinal blood boundaries here. And immunofluorescence on the right panel shows rhodopsin and cone staining with conarstin in green and red, respectively. That histology and immunofluorescence confirms our observations in vivo. And what we're seeing here is photoreceptor cell body retention with observation of rod outer segments as well, which was only observed in the subretinally treated areas, not the proximal untreated areas.

So in the addition to the canine model, we have also tested on the next slide, OPGX-RO safety and efficacy, in this case, in a humanized swine model of ADRPRow, and this was in collaboration with Dr. Maureen McCall of the University of Louisville. This model exhibits a human p23HR variant, which is highly prevalent in North America. And the retina in this model rapidly degenerates by postnatal day 60, such as there is only residual rod structure and function followed by subsequent cone degeneration. And thus, this also, we believe, accurately models the structural and functional degenerative time course that we see in ADRPR patients.

We observed that OPGX-RO here, as shown on the right, preserves rod photoreceptor structure and reduces the aforementioned degeneration. And specifically, if you look in the untreated panel on the bottom left, untreated rods are sparse. They are dysmorphic and rhodopsin is mislocalized in these retinas. However, when we treat with OPGX-RO, we see that it's capable of dose-dependent preservation of rods as shown in the upper right panels -- and in this case, you're starting to see proper localization of rhodopsin and preserved cell morphology.

Not shown here, but also previously presented was preservation of the rod isolated full field ERG in treated animals, but not untreated animals. We also have observed preservation of cone structure throughout the study as shown on the upper right panels. And this is also correlated with preserved cone ERGs, again, not shown here, but previously presented. And so with that, we look forward to investigation of OPGX-RO in clinical studies.

And on that topic, I will turn the call over to Dr. Sally Tucker, our Chief Medical Officer.

Thanks so much, Ash, and good morning, everybody. As Ash said, I'm Sally Tucker, Chief Medical Officer. If we go to the next slide. As mentioned earlier, when we consider the IRDs we're targeting, that fall into 3 separate buckets. We have the vestroonopatpies, which includes both ARB and BVMD. These patients with ARD generally occurred much earlier on than BBMD. And the progression can be slow and often variable.

It results in a defective calcium chloride channel that results in functionality dysfunction of the RPE that results in cone loss, patients often complain metyphoxia, decreased central vision and photophobia. And then in the other 2 buckets, we have LCA and retinitis pigmentosa. LCA, which we have touched upon already, generally occurs from a much earlier onset. Patients are born with the LCA and it affects vision much earlier on and in many cases, from 1 to 2 years with many patients being blind early on. Whereas in retinitis pigmentosa, the vision loss can occur in the adolescents to adulthood.

So there can be progression over years. However, regardless, with these patients, they have abnormal red cone functionality, decreased central vision, night blindness, visual field loss that results in tunnel vision and for many patients, niceness. And as we indicated previously, our goal is to reinstate the functionality of the retina in those patients that have structure so that we can then see vision improvements in a relatively short time period.

We go to the next slide. This indicates the signs and symptoms of the various IRDs that we're targeting. And what you can see here is that the signs and symptoms really key in the development and design of the protocols for all of our IRD programs with us addressing either structural endpoints or key functional endpoints. So you can see here with many of the signs, we're really focusing in on fuunalystography, funder autofluorescence and SVOCT. -- as Dr. MacLaren indicated, it can be that these changes occur over a longer time period. However, with the symptoms, we're focusing in on better corrected visual acuity, low luminance visual acuity, FSP, microperimetry, contrast sensitivity, virtual reality, MLMT, perimetry, static perimetry and kinetic visual field testing.

And then in addition, we also can look at pupilometry and quality of life parameters as well, which are important to consider in those symptoms that might be more hard to quantitatively assess. Our clinical designs follow a data-driven dose exploration approach. So what does that mean? Well, with any Phase I/II study, the primary purpose is to determine safety.

We want to ensure that the drug delivery is safe and is well accepted by the patients that it is administered to. But we're also wanting to see an efficacy, and we're wanting to see as maximum efficacy as possible. So what we will do is we take a data-driven approach. We utilize an independent data monitoring committee, and we will present the data to the committee. We're looking for safety. And if the -- there is some efficacy there, but it doesn't represent a maximal approach, then we will dose escalate into higher doses. However, if there is evidence to suggest that a maximal efficacy signal has been reached, we would then progress into a pivotal trial without any further dose escalation. We go to the next slide.

We have 3 programs that we are entering the clinic over the next 12 months. So it's an incredibly exciting time. We're expecting RDH 12 to be initiated later this year, MERTK in Abu Dhabi in the first quarter of 2027 and Row utilizing global locations in the second half of 2027.

As such, if we go to the next slide, we do have a number of strategic partnerships, one of which is with the RDH12 Alliance. This encompasses the fund for site in the U.S. and eyes on the future in the U.K. And I see the RDH12 is a co-developer in our IDH12 program. We have received funding from the alliance to support the progression of this clinical trial. And we have regular calls to discuss the trial design, providing updates to the patient community. And we are actually at the Family Day, the RDH 12 Family Day that's being held in London this weekend where we'll be providing updates of our current RDH12 program. In addition, we have a partnership with the Abu Dhabi Department of Health.

As indicated earlier on, MERTK has a higher prevalence in the UAE and Middle East. and we have received funding to support the execution of the clinical trial there. And we also have other partnerships with Hope and Focus, Foundation Fighting Blindness and other organizations that really help to elevate awareness of the clinical development programs we are running, support our patient enrollments and optimize recruitment to the studies that we run. Moving on to patient recruitment and retention strategies, which are key in the overall success of any clinical development program. It's true that globally, more than 80% of clinical trials fail to enroll in time.

So how can we overcome that? Well, we're developing patient education videos -- we want to increase awareness of the IRDs that we are focusing in on, but also help to provide more education to the patients that are considering participation. So we're interviewing patients that have been involved in prior clinical trials, what were the questions that they had, what was the thought process that they went through, how can we provide more material to the patients in a mentorship capacity to support the decision-making that they might have. Where possible, we'll initiate observational studies before moving to the interventional study, which will help to identify IRD patients in a proactive way. And as I said previously, we optimize patient engagement. So where possible, we'll work with patient alliance groups such as the IDH12 group, be involved in family days -- we also have a newsletter that patients can sign up to through our website. And we also reach out across patient databases, utilizing many of the databases from Foundation Fighting Blindness, SyoGenetics, Invitae and others.

The other thing that we need to consider is that there is an 88% clinical trial dropout rate in long-standing studies. And with our studies, they have a 5-year follow-up. So it's important to collaborate and consult with patient advisory boards, giving their inputs to our protocol design, making sure that we're selecting the right endpoints and also making sure that we're considering the burden on the patients being involved in the study.

And finally, what we are also piloting as part of a way to improve retention in our clinical trials that goes above and beyond the traditional step end that you see in the U.S.-based trials. is that we also want to give something back to the patients. So making sure that we continually educate them throughout the course of the trial, reminding them why they're in the trial and what we're hoping to achieve through the trial, but also providing a coaching initiative to these patients so that they're getting something back in return for their time, which is not insignificant over a 5-year period.

And then lastly, we are all about increasing the patient's voice. So this is one of our patients that was recruited to LCA 5 and was actually featured on -- good Morning America. We're not only wanting to increase awareness amongst the IRD community, but more broad than that. What does it mean to a patient living with blindness, the impact that it has on them and the impact that being in a trial can have on them and the treatment and what it means to them. So we're very proud of this initiative and how we've supported Linzay in increasing awareness of LCA 5 in this way.

I'm now going to hand over to our President, Ben Yerxa.

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

I can briefly take some of those questions. I would say, obviously, they're very rare diseases, but patient identification for an IRD specialist typically comes naturally. You get a lot of referrals, not just from the retina community, but also the optometric community and fellow ophthalmologists, general ophthalmologists. So typically, if you're in a referral center, they do come. And oftentimes, you can see multiple rare diseases of the same gene mutation in the same day.

I think a lot of a lot of patients are incredibly motivated despite the fact that there may not be an approved therapy just because there's other implications beyond just clinical trial and FDA-approved treatment, including family planning, protecting future generations, genetic counseling, all those things are major factors and perhaps sometimes the primary motivation for genetic testing.

And with efforts from OPI and collaborations with FSB, there's been increased availability, at least in the United States to get low-cost genetic testing universally for all patients. I've had no issues testing these patients and almost 100% of them will do it because they're motivated for sure.

Thank you. Dr. MacLaren?

Yes. I mean in the U.K. and I think in Europe as well, virtually everyone will have genetic testing. It's an essential part of the workup of any patient with an inherited retinal degeneration. And indeed, if anything, the electrophysiology is what's gone out window. We tend not to do that very much anymore because we can tell very well from the imaging how advanced the patient is and monitor progression.

But I think it's important to think about this as a lot more globally, okay? So I agree that there are individual genes, which are very rare, but the strategy is the same. It involves measurements of OCT measures of visual function. It involves an AAV vector. We know now exactly what the dose is. There will be differences in the requirements of different vector. The shipping manufacturing, don't forget, manufacturing is a key part of regulatory approval that should not be underestimated. It might be sometimes manufacturing is more complicated than the actual clinical trial.

And then you've got the administration, the surgery, the subretinal injection, all the technology that's developed quite a lot, followed by the monitoring, the checking for inflammation and all the rest of it. So if you look at all the diseases together, then it becomes quite common. And we're talking about young people as well.

So I always say, since we've been better at managing diabetic retinopathy, the inherited retinal les collectively are now probably in the U.K., the most common cause of untreatable sight loss in people of working age. So if that's not an unmet need, where is it? And I think what we've got quite nicely here is like a platform technology that overlaps on many different genes and therefore, has much more -- many more patients just for one single gene disorder.

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

And just to add to those amazing answers really from Dr. Fan and Dr. MacLaren, I would say, in the U.S., everybody that steps into retinal clinic that has any hint of IRD will get genetically test tested. So I think that has been really the crucial change for all of us in taking care of these patients. And not only will the patient result, but really we're discussing the effects of the entire family.

And I feel like as a result, due to genetic testing, now we're diagnosing siblings and other family members earlier than we might have done before. So that has been really the big change. And lastly, we have amazing technology to image these patients in clinic these days. So I completely agree that we're relying on imaging more than ever to help us understand the disease and in clinical trials to help us understand responses.

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

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

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

Well, it wasn't really done as a proper clinical trial in terms of particularly having a natural history beforehand, which you normally have like a just getting baseline data to the tests are. And then the patients were selected with some very, very end stage because they're part of the family. So I think there's limited data we can get across the cohort. But there was one patient who did particularly well with the vision.

And these patients have not had any major side effects and the effects we've seen following the gene therapy with are very, very similar to that seen elsewhere. So I think if I were writing the investigator brochure or preparing the work for the regulators, I'd certainly be citing this trial as a good example of having used the vector before in humans. And I think that would make the process a bit smoother and probably even less requirement for doing NHP work in order to gain regulatory approval.

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

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

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

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

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

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

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

Can you repeat that, Ben? Sorry.

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

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

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

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

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

Thank you, Ben, and thank you everyone -- to everyone for inviting me to be part of this beautiful series of presentations. So my brief is to talk on the LCA5 update. And can I have the next slide, please? So what is LCA5? It's actually an early onset severe inherited retinal disease with early onset visual loss as so many we've discussed previously in the first part of the meeting.

Now the LCA5 is a particularly severe disease with very early onset loss of vision. It supposedly represents about 2% of all LCA cases. That would be globally 3,200-plus patients within the U.S., about 170 approximately thought to be there. a pigmentary retinopathy, which is typified by macular atrophy quite early, but preservation of photoreceptors in the pericentral area of the macula. The vision loss typically starts in infancy and patients often have just vision of hand movements or light perception. Thestagnus and hyperopia are things that are not only seen in this condition, but certainly also here or people with congenital bad disease or very early onset bad disease have nostatnus and hyperopia.

But the photoreceptor cell loss also leads to the fact that it's very hard to obtain any visual fields in such patients, although there is potential because there's preservation of the pericenteral photoreceptors. Can I have the next slide, please? So the Opus Genetics LCA5 gene therapy, which is currently being used and tested is designed to restore a key protein of the visual cycle. And so basically, that protein is called liocillin.

It's actually a ciliary protein that is critical for the function of photoreceptor outer segments mostly because it works in the connect in sum. All of the proteins that are involved in what is translation of light into electrical signals, the photo transduction are being produced around the nucleus and then have to travel all the way to the outer segment to do the phototransduction. Levoillin is very important in getting them there.

The photoreceptors, as we said before, can actually survive quite long until the third decade of life, and that is suggestive again of as so many of the diseases we've been talking about of having a window of time during which treatment can happen. So on Opus genetics CCF5 is designed to address the mutations in this gene, and it's clinically a derisked AAV8 vector that delivers a functional copy of the LCA5 gene directly to the photoreceptor cells using similar promoter technology as it was used in Luxturna. It's a single subretinal injection.

Next slide, please. So what is remarkable is that adults have been treated. And so what we're showing here is that the mean change from baseline in visual acuity in the adult cohort with 3 patients involved is continuing to be significant, as you can see on the left-hand side with the orange line, an improvement is upwards in this slide. On the right-hand side, you see for the first time until month 6, the results coming from the pediatric cohort, equally 3 patients. And you can certainly see that there's an improvement, a significant improvement of best corrected visual acuity.

Next slide, please. So you can also continue to measure function. And in this slide, for example, we talk about cone function as measured using the FSD or full field stimulus test, actually full field sensitivity testing that is showing on the left-hand side, what we do with red light and with blue light in the adult cohort. And on the right-hand side, you see the pediatric cohort. And you can see a significant improvement again for both colors used in the cohorts, both adult and pediatric, the pediatric up to 6 months and 24 months for the adult cohort.

Next slide. So you can also test sensitivity, if possible, that is if fixation is sufficient, using microperimetry. Microperimetry used separate protocols are available. And so here, for example, it's a 10-2 protocol that was used. This is a photopic test. And as you can tell, the sensitivity in one patient, adult participant 104 and pediatric participant 106, the 2 only patients who are capable of doing this test shows an absolutely significant increase in sensitivity in the central area of the macula and actually a little bit of a movement of the fixation of the patient towards the foveal area. So both patients show significant increase in function of the central area of the macula that is consistent with the treatment effect.

Next slide, please. So one last thing that I just wanted to mention is what do people say -- and patients actually report changes in their daily life, activities of daily living are significantly improved. And for example, in the adult participants, 0101 reported being able to identify her children within a larger group of children 1 month after the surgery, which she couldn't do before, navigating urban environments independently and no longer requiring continuous use of a cane was reported by 0104. That's the patient -- the adult patient who was able to do the microperimetry.

If we go to the pediatric patients, -- for example, the 0106 patient, also the one with a better fixation so that she could do the microperimetry reported a noticeable difference in the visual brightness between the treated and the untreated eyes. I said it was a girl, it's actually a boy, I'm sorry, and able to watch basketball, important for children, I think, and can see the players and follow the ball instead of watching the score ticker and listening to the commentary. So I think with that, I've shown that there is a real treatment effect of the Opus Genetics LCA5 program.

And with this, I'd love to pass on to Ash again.

Thank you, Dr. Leroy. There are over 300 mutations associated with Best disease, which we'll talk about now. And there are several distinct phenotypes with both dominant and recessive modes of inheritance. The dominant forms include AVverC, which is autosomal dominant vitreoretinal choroidopathy. And then there is a highly prevalent phenotype, which is called BBMD or Best vitlloform macular dystrophy. It's named for the hallmark EggYoke or vitllaorm macular lesion in this disease.

And then there's the recessive form, autosomal recessive bestrophinopathy. And disease onset and severity of BEST can vary. BEST1 is a calcium-activated chloride channel or CAC, and it is expressed in the retinal pigment epithelial cells, and it's responsible primarily for retinal ion and fluid homeostasis. So it follows that dysfunction in the BEST1 channel and its activity can result in a number of vision-threatening complications that you see here. As we discussed, there are several variants of BEST1 looking a little bit closer.

The recessive form, BEST-ARB, lacks functional copies of BEST1 expression in the RPE. Now the more common dominant form of BEST, which is associated with BBMD, for example, has 2 different forms. It's a loss of function and gain of function variant type. And that's a critical distinction that we're making there because -- it's thought that gain of function dominant mutations are unlikely to be treatable with conventional AAV gene augmentation, which is the focus of the OPUS clinical trial with our candidate OPGXBest1. However, we and others have demonstrated that loss of function mutations in contrast are treatable with AAV gene therapy.

And those happen to account for the majority of best 1 mutations, perhaps over 98% However, the genetic test in the clinic used to diagnose BEST1 IRDs may not report this detailed loss of function gain of function information. So OPUS has developed a paradigm to help predict treatment responses to BEST1 gene therapy and help ensure that the patient carries indeed a loss of function mutation, which is going to be amenable to gene therapy.

So we're in the process now of testing every known BEST1 mutation for treatment response using tools such as iPSC-derived RPE cells and other engineered mammalian cell models. And in this case, we use technologies such as patch clamp electrophysiology and fluorescence reporter assays, which allow us to directly or indirectly measure the chloride conductance function of the TAC channel. And we've developed these in-house to understand, first, if the mutation is a loss of function or gain of function mutation and also whether or not it is amenable to VestT1 gene correction.

So when we receive the genetic test, we can then look this mutation up in our test battery to see if this mutation has been tested for personalized responder, nonresponder type analysis by OPUS. And so we will be using this information in collaboration with our community of specialists to help select patients for clinical investigations of our candidate OPGXVest1. This is a single AAV2 vector for onetime subretinal administration and also features an RPE-specific promoter.

And with that overview, I'm happy to hand the call over to George for a brief clinical review of VestT1.

Thank you, Ash. I'll provide a brief clinical update on BEST1 program. For reference, the data we have presented to date at Macula Society and ARVO are available on our website on the BEST1 page. We've completed enrollment in Cohort 1 of the Phase I/II study with 5 participants, including 2 autosomal recessive and 3 BDMD participants. You'll see that the BDMD participants are significantly better at baseline with participant 102, 102 being the least advanced participant from a visual acuity standpoint.

What I'd like to really show you today is some of the phenotypes on the OCT that we're selecting for. Now this is being selected with a number of our colleagues in the field and has really been a a great process for ensuring that we get the right subjects into the trial. This participant is 101, 106, and this is a representative BBMD patient. You can see that the participant has a pretty intact foveal depression along with the retinal layers being intact in the periphery, both on the nasal and temporal side. Under the fovea and extending particularly to the temporal periphery of the retina, you can see the subretinal fluid that is part of the vllorm lesion. This fluid is low in diffuse and it's on the backside of the neurosensory retina, which is detached.

Now importantly, for these patients, you can see the small areas of hyperreflective material, which are so-called shiny photoreceptors, which indicate the photoreceptor all segments may still be present. This is an important differentiation from the so-called faced backside of the neurosensory retina. So we do expect that the product, if it works, should be able to decrease the amount of fluid under the retina, under the fovea. And as that fluid decreases and the retina is repposed to the RPE and Brooke's membrane complex, there is a potential that there might be a functional benefit for this patient. We also may potentially see that the ellipsoid zone line, which is present in the periphery of this image, began to expand back out into the center of the macula, which would be fantastic for this patient. That would be expected to result in an increase in visual function.

When we test visual function, we're testing really 4 different parameters. One of the most interesting to our team is the microperimetry. And what I'd like to see here is the overlay of microperimetry on the infrared image of the OCT that we've already shown on the prior slide. Essentially, the OCT and the infrared image on the prior slide can be directly overlaid onto a map similar to what you see here. So what you notice is that the areas of subretinal fluid that were present on the last slide on OCT are highly correlated with depression on sensitivity map on this slide.

Therefore, in the areas where you see a 0 decibel sensitivity or a sensitivity of, say, less than 20 or so decibels on the heat map, you would expect the sensitivity of the retina to improve as the subretinal fluid in those areas goes away. That would be the hypothesis we're trying to prove in this study. The ability to overlay the pathology and the modification of the pathology with this functional endpoint is a very unique thing for this program, and it allows us to test functional improvement of the retina at a very high spatial resolution. This is an approval endpoint with the FDA, so the improvement in these phosal microperimetry treatment would be acceptable as a potential pivotal endpoint.

Obviously, we're still collecting all the other functional data, but this is a very unique thing for this program that we're excited about. So this is why we're looking for patients with fluid that correlates with visual functional improvement. If we're successful in decreasing the fluid and there are photoreceptors present, then they should function better if they're in their native configuration. This should -- this we hypothesize should lead to an improvement in multiple functional endpoints. And most notably, as I've shown here today, potentially microperimetry.

At this point, I'd like to turn the call over to Dr. -- I'm sorry, to Joe Schachle, our Chief Operating Officer, to discuss the patient journey and epidemiology of these IRDs.

Thank you, George. Good morning, everyone, and good afternoon to those in Europe and elsewhere. Two topics I'd like to touch base with you on. First is the IRD patient journey. I'll give you a brief overview of the patient journey. You heard a little bit of that this morning earlier.

And then also talk about disease prevalence, global disease prevalence, which you've seen in each of the individual presentations, but we'd like to show you all together as well. So looking at the patient flow, as you heard, patients will often see an optometrist or a general ophthalmologist and then be referred to a retinal specialist. And that retinal specialist may make the diagnosis, may refer to a specialist that specializes in IRDs or a genetic counselor for genetic testing. And this is a very key step and something that we all need to support is the genetic testing aspect.

If you look at the green bar, if you move to the left side of that, that's a patient that has a gene that we have a potential to treat and has been identified. Currently, RPE65 is the only one we have to treat and look forward to being able to add to that in the future. So that's kind of a general view of how patients may move from symptoms to diagnosis to ultimately treatment. So thinking about global estimates on prevalence.

Originally, we look -- we use 2 primary sources for global incidence and prevalence. The first was the Stone paper, which is an excellent study. It's 1,000 I&D families being treated at one site from across 40 states. It's very helpful. The HA study is also very helpful. It's a global study looking at 6 markets outside of the U.S. and that was initial data that helped us estimate prevalence. Since then, we actually have asked Trimal Insights group to prepare analysis, a meta-analysis of studies and they completed that in the first quarter of this year, and that's what you're seeing data here in a moment. That meta-analysis originally looked at over 1,200 studies.

And of those 1,200 studies, greater than 90 qualified for use in this study. They need to have genetic testing as a backbone to the actual study itself. And we looked at 5 geographies: the U.S., EU4 plus U.K., China, Japan and Middle East and North Africa. So just taking a look across the globe here, let's focus on the U.S. first. We kind of generalize that we have small, medium and large prevalence diseases we're focused on.

If you look at LCA5 and MAT1, those are our smaller prevalence diseases at 170 and 1,200 -- if you think about the midsized disease, we're looking at RDH 12, MERTK and CNGB1, -- those are on the 2,000 range for prevalence. And then finally, we look at BEST1 and Re as the larger prevalence diseases at 8,400 and 8,800. And as you heard in some of the previous presentations, looking Middle East and North Africa, you can see RDH12 with a prevalence of 17,500, so a fairly large population and MERTK over 14,000 patients.

Moving to China, you see Re has almost 15,000 patients and RDH12 has almost 10,000 patients. So you can see across the globe, there is substantial medical need for treatments for these diseases. One final slide here, and this is just -- this tags into some of the things you heard earlier is there may be underestimation of the actual prevalence of some of these diseases. If you look at our current best 1 prevalence, we're estimating about 8,400 patients with Bestung in the U.S. And that's based on studies that have confirmed genetic testing in the diagnosis.

If you look at the right portion of this slide, we may be underreporting best disease, and there's 2 factors for that. First is, while most patients do get genetic testing, because of the vllongoest1, some patients may not get tested because they may be assumed to be best 1 and currently no treatment available. The flip side of that is actually the misdiagnosis of best 1. We're in the midst of a market research study right now, a large market research study, and we're hearing quite frequently about the misdiagnosis. And I'm going to read quickly this quote to you. Quite a few of my best patients have been seen by other physicians in my practice and did not get the diagnosis of Best disease.

I think there are a lot of patients who are not diagnosed correctly, I would say, about 50%. So we are hearing this consistently across the study that there's a misdiagnosis and lack of diagnosis for best. So we may actually have some higher rates of prevalence that we have estimated currently. So thank you for your time.

With that, I'll turn it back over to Ben.

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

When we first started getting ready to recruit patients in 2007, we had gotten everything all together and gotten all of the approvals, the institutional approvals, the FDA approvals. And then we looked out to try to find patients -- where were the patients? Nobody or very few patients in the United States had had genotyping because there was no reason to get genotype. There was no treatment, no clinical trial available. And it was thanks to our colleagues in the European Union that we were able to start.

Our first 4 patients came from Italy, where they had made great progress in genotype phenotype correlations. And several of the next patients came from Bart Lois site in Belgium because he had also been genotyping patients. And so now the situation has changed dramatically. There are now numerous sites, physicians genotyping patients because there are treatments -- there is the LUXTURNA treatment available, and there are clinical trials available for many of the other forms of IRDs. And plus people are anticipating the clinical trials that are being developed by Opus Genetics.

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

Yes, sure. Thanks, Ben. Foundation Fighting Blindness has had a registry study, my Retina tracker registry since 2013. In 2017, we received a grant to try a pilot study to provide genetic testing and counseling to a small number of sites, really the centers of excellence at that time to see how -- what the uptake would be as a pilot study. And it turned into an amazing success.

We now are able to offer at no cost genetic testing and counseling to patients with inherited retinal disease in the U.S. We have hundreds of eye care professionals, including optometrists, both vision specialists all over the country who are ordering through the program now. And at this point, we have tested over 32,000 individuals as of the end of March. And it's very -- it's a huge program, I would say, wildly successful. And I think from the foundation's perspective, we're opening access to patients all over the country, not just those who have access to a specialist center.

And that makes a huge difference when it comes to recruiting for clinical trials. This program is just one of many that exists today. It has always been -- well, most recently has been an option in the clinical setting to access a test for those individuals who have insurance coverage or able to afford a cash pay. But there have been other programs over the years offered by commercial labs, the National Eye Institute had their own program for many years. I would say -- I would say -- I would estimate that at least half of the individuals in the U.S. with inherited retinal disease have had access to a genetic test by now. And I think this is going to be a program we will continue to need because not everyone will have access to a test at no cost or free.

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

Well, thanks, Ben. It is the culture of how to organize society is indeed very different from one side of the Atlantic to the other. Taxation is far less in the U.S. So more money is given for grants and so on and so on. That is certainly less in the EU where taxation is higher, but the tax is used, for example, for national health services. And so for example, in Belgium, but not only in Belgium, in many other countries, we have a fairly free or nearly free or if you're a clinical geneticist, which I also am, I can offer free genetic testing to our patients.

Basically, everyone who walks into the door through the door with a genetic diagnosis gets genotyped. And so obviously, because of the constraints of what testing currently is, we don't do yet whole genome sequencing on everyone. But I would say we say about 70% of the patients get their genotype, but everyone gets the opportunity, and they generally don't pay a euro for it.

Got it. That's great. So it sounds like basically everyone in your practice with an IRD has at least had access to a test.

It's true. And I'd love to actually add to what Joe is saying because if you look at, for example, the bigger European countries, I mean, don't forget if you take the U.K. plus the EU currently because the U.K. left us, Together, it's 550 million people. I think that in the U.S., there are 335 million people. So I think if you look at the whole of the EU and certainly the Western part of the EU, they have really good molecular programs. So for example, for bestophinopathies, I would certainly say that there are many more patients in the EU than there are in the U.S. And as he was rightfully saying, there are many underdiagnosed.

Yes. Yes, great point. All right. Let's transition over to natural history studies and thinking about how it affects clinical trials because as we know, every IRD has its own clinical natural history and there's even genotype, phenotype correlations or noncorrelations that can complicate the picture here. So Maybe, Jean, starting with you, how do you see how an understanding of clinical natural history affects clinical development plans and for example, how that helped in the development of LUXTURNA?

Well, when we started planning towards a clinical trial for LUXTURNA, we started doing a retrospective natural history study for RPE65 because there was no information and it would have taken too long to do a forward planned study. And that natural history study was run by Dan Chung, who went to numerous centers, including Dr. Luz and and other centers around the world to collect this data. And the data was extraordinarily helpful.

It demonstrated that contrary to some people's hypotheses, this disease is not stable, that it does progress in the photoreceptors degenerate and retinal pigment epithelium degenerates over time and it's relentless. And it confirmed that the various outcome measures that are used to monitor retinal degeneration, standard clinical measures such as visual acuity, visual fields, et cetera, light sensitivity decrease over time.

And that data has been really important, not just in the early stages of the trial, but also in following the durability of the treatment. We're now looking at long-term durability and comparing that to what one would normally see in an untreated patient and seeing big differences.

Right. Great. So like deviation from natural history is a clear sign of efficacy, I guess. Yes.

Todd, at the foundation, you guys have been running these really large multicenter longitudinal studies. I mean some would say these are the gold standard in the field now. And can you talk about the clinical consortium that you guys are running, your approach and some of the benefits of like a multicenter versus single center study?

Sure. Yes, the Foundation Fighting Blindness clinical Consortium is a collaborative network of inherited retinal disease specialists, reading centers and geneticists to help us better understand inherited retinal disease.

And I would say from the foundation's perspective, the primary purpose there is to better inform better clinical trial design, selection of outcome measures, length of follow-up that's required. finding the best opportunity for therapeutic intervention for various modalities.

The largest of these that we've completed to date is the RUSH 2A study in non-syndromic and syndromic SS2A retinal degeneration, and we've had numerous papers about that. I think what makes it unique is the investigators, this is intended to be collaborative. And I think the benefit here is we share the learnings across the centers. And I think from a data perspective, A single center offers one advantage when it comes to clinical development, especially for subretinal injections, things like that.

But many of the larger IRD trials and programs will require multiple centers to recruit sufficient participants for rare disease. And so we need to know how to run those studies so they can be generalizable and maintain the quality. So that's a big focus of ours is to use standard protocols, same images and equipment, reading center methodologies and to develop and to publish those results. We have lessons to learn to share with the whole community.

Super helpful for any sponsor in the space wanting to run a trial, that's really, really helpful. Real quick, could you also just talk a little bit about the UNyARE study? I know OPUS is sponsoring a couple of arms of that study for RDH12 and BEST1. Any updates there?

Yes. Just briefly, the UnyE study was our answer to trying to streamline the start-up process for natural history studies, where we already launched a study in EYS-associated RP that essentially using same protocol and procedures as did the RUSH2A study. So Dr. Shell from UPMC said, why do we keep doing the same start-up process? Let's develop a protocol that -- where we can do a plug and play, so bring in gene-specific cohorts and run with those rather than having to put the sites and all of us through all the pain and hassle of having to do all the protocol review and IRB submissions. So UnyRE was intended to target the most rare of the IRDs because it got relatively little attention in other studies.

And as you mentioned, Ben, we are partnering with Opus Genetics on a BEST one cohort of UNyRARE and one for RDH12. And these 2 cohorts illustrate the unique design of UNyRARE, which is a very large cross-sectional study. We're calling the registry component of the study, where we have planned enrollment of 1,500 individuals. And this is really just an opportunity to get a good phenotypic characterization and cross-sectional look, including images that we can then send to the reading center. So that's in the case of OPUS, the BEST1 cohort.

And then as we receive funding interest and prioritization for cohorts to follow longitudinally, we can then plug those into the longitudinal protocol and follow people annually up to 4 years. In the case of OPUS, that's the RDH12 cohort. And the latest update on those is we have 65 enrolled in the BEST 1 cohort with OPUS and 19 enrolled in RDH 12, and we're beginning to bring in the RDH 12 participants to year 2.

Great. Great. Thank you, Todd, for the update. We're really excited about that work. We are real quick lightning round, one last sort of question for each of you, starting with Jean. What's one actionable step you think sponsors and sites can take together tomorrow to improve recruitment and retention in IRD trials?

I think one possibility would be to make genetic testing available on commercial platforms or patient-oriented platforms such as 23andMe and not just patients, but people who are interested in looking at their own genetics might make it more available.

Got it. All right.

Yes. I think certainly, there's a difference. I think having genetic testing, like Jean was saying in the U.S., a little bit more accessible despite the unbelievable actions of FFB. I'm a real big fan of FFB, and you can see that initiative from large organizations like this help enormously. I think patient retention is not as bad as I think the numbers that were shown in the sense that it's not my experience across 13 different gene therapy trials that we're currently running in GE that we lose many patients.

It's actually by all means, just here and there, maybe one individual. So I basically think that getting them in will be better, as Jean was saying with what she mentioned. Maybe if you want to do even better is really helping sponsor the activities of what FFB is doing because I think the Unilever study is the way to go for the future.

Thank you. Todd bring us up.

Yes. I think the -- in addition to those comments, I would say, hyper focus on the needs of patients and their families regarding trial participation, communication about what clinical trials are, making sure they have assistance with any translation or interpretation that they may need when they visit the site. And I think this is all pretty standard in the IRD field now, but really focus on that experience for them. It's a tough decision for people to decide to participate in the clinical trial.

Yes. Great. Perfect. Thank you very much to all of our panels for sharing your thoughts on this important topic.

Now we will transition to our final Q&A session, where we will be joined by the rest of our speakers. So the we will get ready for our first question. That is -- I think I'll send this to you, Jean, actually. So can you comment on the expected duration of effect of a single treatment?

The best information I have goes to LUXTURNA, where we started out studying dogs and the longest -- we followed was the life of a dog, which was 10 years. We showed that, that rescued the photoreceptors in the treated area of the retina only. We're now following patients in long-term studies. In fact, the LUXTURNA studies go for 15 years of follow-up. That's a long time, and we are at the 10-year mark. That data will be -- has been submitted for publication and so should be out shortly. But it looks very promising in that the durability data is excellent.

Got it. A quick follow-up to this for Ash. It's a question about the MerTK animal model slide, where it looks like the effect is waning at the latest time point at 71 days. Is there something you could comment there?

This was a preliminary proof-of-concept study and further dose optimization, further readouts are necessary to confirm kind of the true window of treatment and durability. So that's an effort that's ongoing right now.

All right. So are the other IRDs beside BEST1 also likely to be underreported? How are the general dynamics in genetic testing and diagnosis for IRDs? I'll take a volunteer for this one.

And I'm happy to talk about the best one or the question on IRD frequency. I think we -- others may be underreported. So that may be the case with some of the IRDs because there are so few treatments. However, we really have the most data on BET one because of our quantitative market research. So I really can't speak to as much as the other ones, maybe some of our key opinion leaders have an opinion on that.

Got it. Anyone want to chime in on that?

I can do so if you want to. So I think Joe is right. So bestrophinopathies are probably highly underreported -- some of them have been seen from clinics that treat uveitis patients, et cetera, et cetera, even patients who are just not aware that they have anything. I think that other ILDs are underreported, but probably at lower numbers. I'm pretty certain there are patients even in developed countries like the EU countries and the U.S., where still patients even with night blindness and some visual field issues roam around without understanding that their disease is actually a retinal degeneration. So there's an underreporting certainly ongoing. I think many people will still not get to a specialist, but I think the numbers are particularly high for bestrophinopathies.

Question for Ash. For best for BE1 gain-of-function mutations, would it be possible in the future to test a silence and replace strategy similar to R.

Sure. So why that's not in scope for OPUS now, silence and replace and editing could be possible for gain-of-function mutations in the future.

All right. So regarding the 24-month update for LCA 5, did improvements in BCVA translate to benefit observed in the virtual reality mobility test at month 24? Probably a question for Sally.

Yes, it did. So with all 3 patients, they all had a meaningful improvement in the virtual object recognition.

Great.

All right. What is the proportion of LCA 5 patients would be candidates for treatment? And how long is the treatment window for most patients? Do you want to take that one also, Sally, or maybe one of the KOLs...

It's down to the O&L preservation. So a lot of these patients have preserved ONL quite late on in the disease. I mean up to in their 40s and 50s. So I would say that it's a large amount of the population. Bart might be better to comment. However, that's -- those are the patients that we'd be targeting. We'd be targeting those that have preserved ONL.

And Sally, I can just comment what you just said. In the interest of briefness, you're absolutely right. I think a large chunk of the patients would be treatable because they have preservation of some meaningful cells that can be targeted until fairly late in life.

This one is probably good for George. In BEST1, how do you think about treating patients whose lesions do not yet involve the fovea? How can benefit be assessed in these patients?

This is one of the beautiful things about the microperimetry. It's kind of the key point of the microperimetry is that the grid overlay can identify the retinal sensitivity directly over where the lesion is present. And so for patients with extrafoveal or paraphoveal, the tellform lesions, you can look at the microperimetry grid points that are overlying the area of the teleform material and our natural history studies and our initial patients enrolled in this trial -- inform us that those should be depressed compared to retina without nurositry detachment.

A question for ASH. Will the disease and the dish be part of the clinical workup -- and how much time cost does that add? How can you determine that the expression of wild-type BES will be sufficiently high for any given mutation?

Sure. We're currently testing all mutations now. So we don't wait for the patient information or genetic testing to come in. We are testing all annotated mutations in this disease in a dish model to understand which mutations are loss of function and which are likely candidates for gene therapy.

And in those tests, we're able to directly interrogate using in vitro cell models that resemble B1 disease pathology, whether we can restore BS1 channel activity to that of wild-type best expression. So that is a proxy for expression, but also directly measures function. And we think that's a decent predictor of what could happen clinically and then which patients are going to likely be responders.

Great. Thank yo. Next one is, given the recessive ARB subtype is mechanistically cleaner than the dominant BVMD subtype, would you consider splitting the 2 into separate time lines, so the ARB program can keep moving even if BVMD optimization takes longer. Someone from the OPUS team, George or Sally.

Sally, why don't you take that one?

So I think that it will be down to -- like I said earlier on, we take a data-driven approach. So we'll be looking at the data, seeing how the patients respond following treatment. And then that will scope our strategy as to whether we continue with BBMD and ALD together or if we split out into 2 separate studies. So it's something that we might consider. But again, it will be down to the data and what we're seeing.

All right. I think we're here at our last question, just about our last question. So based on manufacturing, how many patients can you treat once approved in initial 3 indications? First question on manufacturing. Who wants to take that?

So I can take that. So the manufacturing has been a really productive discussion with the FDA. So just like we've been having the clinical discussions on trial size and endpoints for ultrarare, we're also having the same type of discussion on the manufacturing processes. For some of -- for the smaller programs, certainly for LC5, a single 50-liter batch will treat a majority of the world's population, right? So we're delivering 300 microliters through the subretinal injection LCA5, the manufacturing is quite modest. For RDH12,erckyK R, those programs are a little bit bigger, but still should be well covered by 50-liter batches.

As will best disease, if the upside of best disease that Joe talked about, it turns out to be true, then certainly, we will start to get up to a -- to needing more than batch and having to make multiple batches, which in our experience with best one should be very doable. It's important to remember -- a big part of the thesis of OPUS is not just clinical efficiency, but it's also on the manufacturing side.

And I think Dr. MacLaren mentioned this earlier. This is one of the reasons why we're using pretty well-known vectors well-known gene augmentation techniques is because these things can be readily manufactured. And now the world has now a couple of decades of experience, thanks to some of the pioneering work by Dr. Bennett and the University of Pennsylvania team years ago.

Great. Thanks, George. So I'll do one more quick question and then George will make some closing remarks. So this is to Todd Durham. Can you just talk a little bit about how Foundation Play and Blindness as a patient advocacy group works with the FDA to help move the field forward.

Yes, sure. Happy to, Ben. So I guess the best example is from our RUSH 2A study. We had several meetings involving the FDA and the European Medicines Authority to share our learnings from that. One of those things, I would say, resulted in a Duke Margolis meeting in September 2025, primarily about our findings and recommendations about the FST.

I think where we ended up with that is the FDA currently is not ready to accept that as a primary outcome measure for inherited retinal disease trials. That has, I think, informed our decision to develop a strategic plan to provide the missing evidence around clinically meaningfulness for that outcome measure and others for inherited retinal disease, and that's work we're undertaking now, having gotten a lot of input from our key opinion leaders and experts on that.

So we intend to continue our dialogue with the FDA and EMA and other regulators as we learn about novel endpoints. And we are also advocating for patients through patient-focused drug development meetings as we go through time. So it's an active engagement, and we're pleased to collaborate with them.

Great. Thanks, Todd. Appreciate that. Thanks, everyone, for that Q&A session. I'll now like to turn the call over to George for some closing remarks.

Thanks, Ben. And so let me just summarize what's special about Opus. Number one is it's proven science. Number two is that we're uniquely well capitalized to execute against multiple programs. Number three is that we do have multiple shots on goal. And number four is that there are real near-term significant value inflection points, multiple within our current runway.

And I'd like to thank everyone for your time and attention this morning, especially a big thank you to our guest speakers. What an amazing panel, I mean, really honored to be a part of for adding -- thank you for adding your insights and your expertise. We look forward to updating everyone on our progress as we continue to advance our gene therapy pipeline and continue to hopefully bring these innovative therapies to patients. Have a great day.

Good morning, everyone. My name is Susmita Roy, and I'm an associate on the JPMorgan Healthcare Investment Banking team. On behalf of JPMorgan, I would like to thank everyone for attending the Healthcare Conference this year. And I'm pleased and honored to introduce Opus Genetics for the company presentation today.

A bit about Opus Genetics. It is a clinical stage biopharmaceutical company developing gene therapies for inherited retinal diseases, trading under the ticker symbol IRD. They have a multi-asset pipeline with near-term data readouts with many milestones in 2026.

It's my pleasure to introduce the CEO, George Magrath, for the company presentation. I'll hand it off to him, and we'll take Q&A right after. Thank you.

So thank you, and thank you to the JPMorgan team for inviting us, and it's great to see a full room here. That's wonderful.

So I'd like to take a minute to talk to you about Opus Genetics and what we're up to. So this year is going to be a pivotal year for us. We have a readout in our biggest indication, which is BEST1 disease, which will happen in the midyear. We've got the ongoing pivotal trial in the LCA5 program. That was the program that was featured on Good Morning America a few months ago, and that's going to have additional data coming in the not distant future as well. And then we're looking forward to multiple additional assets hitting the clinic. So it really is a good year.

The Opus Genetics story is really interesting. It's very unique. It is a story that's based on Dr. Jean Bennett from University of Pennsylvania, along with a number of other collaborators of hers. And we're looking at what we consider sort of low-hanging fruits. So we're looking for diseases where the structure of the eye is normal, but the function is not, and it's not because a single gene is missing. And that lends itself very well to straightforward gene augmentation, very similar to what Luxturna did as the first approved genetic medicine in 2017, also invented by Dr. Jean Bennett.

So in these AAVs, you're delivering a small dose directly under the retina, very localized, very precise and looking at diseases where we're not trying to do long studies where you bend curves. These are studies where you should see an improvement of function, a reversal of the pathology pretty quickly, 3 to 6 months. So it lends itself to efficient development. There are a number of these in our pipeline. You can see we refer to as a string of pearls. The seven of them are at the bottom of this slide. And each of these is a very efficient, quick program that's been hand-selected for these reasons.

When you think about this delivery system, it is, I think, the most precise drug delivery in all of medicine. We're delivering a 300-microliter bleb under the retina, really like in our BEST1 program, we're really only trying to transfect 5,000 or 10,000 cells in the retina. The exposure outside of the eye is negligible. The side effects are -- the systemic side effects are negligible and the ocular AEs are very well characterized. These are all AAV2s, AAV8s, AAV9s. These things have been used in the eye before our company is really more of a development company, not a discovery company. We pick things that we think are going to have high probability of success and are reasonable to show efficacy in efficient, quick trials.

Now the important key underlying factor to what we're doing is the concept of structure function dissociation. So in these patients, in these diseases, we're looking for patients that have almost normal anatomy, right? So the photoreceptors are there, the bipolar cells are there, the Muller cells are there, the ganglion cells are there, the RPE cells are present, the retina structure is there and the machinery is turned off for some reason. And so that is the structure function dissociation, lends itself very well to gene augmentation. It's almost like you're baking a cake and you're missing one ingredient. You put that ingredient in and all of a sudden, you're off to the races.

So the structure function dissociation is important because it gives you a high probability of making a biologic impact. It also gives you a quick readout. And so when you reverse pathology, when you take these profoundly blind people and give them vision back, you see it pretty quickly. So in these studies, we know whether or not we have a drug pretty quickly.

Now the pipeline is broad with these. So there are 7 of them. The key thing to focus in on is the fact that we typically use equity dollars to concentrate on clinical programs. Right now, those are LCA5 and BEST1. This year, it's going to be multiple others that are in this pipeline. The preclinical assets all have additional support to get them through the clinical -- preclinical pipeline. So the team led by Ash and others has been incredibly efficient at getting grant funding, getting partnerships with different patient alliances such as the RDH12 group that are bringing these things forward. So it really is an interesting business model that is taking these things from the lab into the clinic.

We have another unique aspect to the company is which we have a commercial asset that's partnered with Viatris for sales. So this asset is a topical eye drop called Phentolamine Ophthalmic Solution. The brand name is Ryzumvi. It's on the market for the first indication, which is that it reverses dilation after an eye exam. And then it's -- we just submitted the sNDA for presbyopia, which is the need for reading glasses.

So if you put this eye drop in once at night, if you look at our Phase III studies, people can then read without glasses for about 24 hours. So a very, very interesting value proposition for people. So this has been partnered with Viatris. We have a double-digit royalty that tiers into the 20s, and we have around $120 million in milestones on it. Viatris is a great partner. They have a large sales force, and we're very excited for presbyopia to potentially be approved this year.

So we're going to have a readout in BEST1, which is our biggest wholly owned indication. We're going to have a potential approval for presbyopia, and we're going to have an ongoing pivotal trial for LCA5, and we're going to have multiple of these preclinical assets entering the clinic this year. So the team is busy. It's a lot of fun.

Let's talk about 2 of the lead programs here and the upcoming milestones that we have for these. So BEST1 is a disease I'll talk about in some detail in a minute, but it's a large indication in the rare space. It's 9,000 patients in the United States. When you think about that epidemiology, there are around 5 or so epidemiological studies. The bookends of that are somewhere between 5,000 and 19,000. Using our methodologies, we're honing in on around 9,000 patients in the United States.

This disease is a loss of a calcium chloride channel where you get a blister of fluid under the retina. If you replace that calcium chloride channel, then the fluid should go away and the vision improves. This trial -- the Phase I/II trial is ongoing. And in the midyear, we'll report data. And the things to look at in the data are an improvement in the electrophysiology, so the ability to have a calcium chloride gradient, a voltage gradient across the RPE, you can actually measure that. So that will tell you about cellular target engagement. If the fluid on OCT goes away, then that will tell you about the macro structure. And then if vision improves, that will tell you about the function. So it's a really nice logical walk of endpoints that we'll be able to read out in the midyear.

LCA5 is a program where we have already treated 6 patients. All 6 of those patients have had clinically meaningful improvements in vision. One of those patients was featured on Good Morning America because of how profound her vision restoration was. And after an RMAT meeting in October, we have begun enrolling into the pivotal trial. And so the first 2 patients have been enrolled in a pivotal trial, and we're going to continue that this year, looking for data readout -- not this year, but probably in 2027.

These are actually big indications. And the reason I say that is because a first principle is that you get reimbursed for the improvement in patients' lives that you create. And when you have a dramatic improvement like taking a blind child and restoring vision, you can command reasonable pricing to make it worth your while. So you can see here that the market opportunity is actually really good as long as the string of pearls stays intact. And these are -- this is a very important slide because a lot of the preconceptions that gene therapy development is long, expensive and with limited return is just fundamentally not true for Opus Genetics. We're going after very well-characterized AAVs, very well-characterized diseases, quick endpoints, small trials, meaningful impact that should be reimbursed in a reasonable manner.

So let's talk a little bit about -- more about BEST1. So BEST1 disease is one of the most common IRDs that's out there. There are about 350 of these inherited retinal degenerations. 3.5% of those have BEST disease. It's typically seen in regular retina clinics. So the way the patient's journey goes with this is that they -- it's in the first -- in the midlife years, second to fourth decade of life or so, the patient will have mildly distorted vision, and they'll typically go to their optometrist. The optometrists will see the clinical exam, which is almost pathognomonic for BEST disease. They'll send them to a retina specialist to confirm that diagnosis.

A lot of times, in my practice, I didn't even genotype these patients. because you could tell -- you can make a clinical diagnosis of BEST disease and there was nothing you could do for these patients. So you would tell them to follow up once a year. Eventually, those photoreceptors will atrophy and they will end up with a large area of geographic atrophy. It looks exactly like the geographic atrophy associated with macular degeneration. That's profound vision loss. So you end up with this multiyear window of potentially intervening for these patients where they're mildly symptomatic, the photoreceptors are still present, but they're detached from the retina, so they're kind of floating in this fluid. If you can resolve that fluid, the photoreceptors won't atrophy, they'll be back in their native place and they can potentially see again. It's a really nice pathology to be able to intervene with, large therapeutic window, not much of the channel is needed to impact the disease, and it's a very precisely delivered directly to the lesion.

So the cellular biology is really interesting with this. So the bestrophin channel is a pentamer that creates a calcium chloride channel. The purpose is to put calcium on one side of the cell, chloride on the other side; doing that creates a gradient, which pulls fluid from the photoreceptors into the choroid, into the systemic circulation for disposal. So as those photoreceptors, which are incredibly metabolically active, are continually to produce byproducts, that osmotic gradient causes those byproducts to be pulled out of the retina into the circulation.

In BEST disease, you lose that channel. That gradient goes away and the fluid just accumulates under the retina. And that's exactly what you see on these scans. So on the right of this slide, where you see OCT, that is a cross-sectional view through the retina. And at the top, on a Stage I, that is essentially normal looking. And what you see is as the fluid accumulates, as the patients go from Stage II to III to IV, you get more and more fluid. So the photoreceptors now are on the backside of that fluid detached from the wall of the eye. So if you look at the bleb of fluid, you've got photoreceptors, you've got RPE, you've got fluid in between them.

That fundamentally takes the photoreceptors away from their support system, from their nourishment. So they are kind of hanging out in the wind there. And if they do that for long enough, they will atrophy. As they atrophy, they stop producing metabolic byproduct. The fluid goes away and you start to see that in Stage IV, and you see the conclusion of that in Stage V, where you have atrophy where the photoreceptors are gone and you have total vision loss in that image where the black circle is in the middle of the autofluorescence image.

There are 2 types of BEST disease that are important for us to talk about. The first is BVMD, the second is Autosomal Recessive. So Autosomal Recessive is a very clear-cut gene augmentation target. There's no bestrophin channel that's being made. Gene augmentation can restore that. In autosomal dominant disease, this is still a good augmentation target without the need to silence the mutant protein because this is -- the stoichiometry allows you to outcompete the mutant, which is nontoxic in most cases. and formed that pentamer.

So we've actually done a lot of in vivo disease in the dish type models at a patient level basis where we can show restoration of the function of that channel with dominant mutations. So the one part of this disease, one genotype of this disease where we will not work is gain of function. In a recent publication by GeneScape, that accounts for around 2% of the BEST population.

The AAV is very straightforward. So it is a construct in an AAV2 that has the normal BEST promoter. So not only are we delivering it directly to the RPE cells in a very targeted fashion, the promoter won't even be turned on unless it is in an RPE cell. So it's like a second line of safety for off-target effects.

In a dog model, which is the data is shown here on this slide, what you can see, this is a naturally occurring dog model that was done at the University of Pennsylvania published in PNAS on the citation that's listed. You can see that, that blister of fluid on the cross-sectional image, which is the image right below the picture, you see the pocket of fluid in a control animal, that pocket just gets bigger. In a treated animal, that pocket literally goes away. So you're looking at reversal of pathology in this disease. It's a wonderful endpoint. It's a wonderful view of target engagement.

The retina specialists in the United States, every one of them does this scan on every patient that comes through their door. This is going to be very important to us as we try to show target engagement and modification of biology.

On the histopathology right underneath that, you can see that the photoreceptors not only lay back down on the RPE, but they restore normal interdigitation with the RPE. It's almost like a handshake. So it goes literally back to a normal configuration.

So right now, we're doing a Phase I/II trial. We've -- we're enrolling these patients in 2 cohorts, 1.5E9, 4.5E9, 5 per cohort, and we're going to be reporting the data in midyear. We do think that the -- that even at the lowest dose, we should see target engagement. And that target engagement, we would know through electrophysiology at the cellular level, OCT at the macro structural level and microperimetry and visual acuity at the functional level. BEST disease is incredibly exciting.

I'll talk a little bit about LCA5. It's a much smaller indication, but we have amazing data in this. So this is a really, really impactful medicine. This disease is a type of childhood blindness where the typical patient journey is that these children are born with the mutation. They usually -- mom or dad notices that the kid at age 1 or 2 can't really pick up a toy, can't see to pick up their cheerios to eat, things like that, take them into the doctor's office. The fundus looks pretty nondescript.

And so these patients all get genotyped. They all end up at tertiary care centers. Honestly, most of them end up at the University of Pennsylvania. So of the 200 patients, I think 50 or so are seen at the University of Pennsylvania by [ Dr. Tomas Solomon ], who's the world's expert in this. So this is a profound blinding disease from early in childhood.

However, for the first few decades of life, the structure remains normal. So as in the nondescript fundus findings, when you look at these patients, typically, the fundus looks pretty normal, the OCT has all the structure there. Everything looks good, patient can't see. They have a defect in a protein called lebercilin, which is a structural protein in the photoreceptors that causes them to be in their normal configuration. So the loss of lebercilin causes the photoreceptors to still be present, but not to be able to sense light.

So the rest of -- so what we're doing is very simple. We're using an AAV8 with the same promoter technology as Luxturna to replace lebercilin in photoreceptors. The reason this is AAV8, BEST1 is AAV2 is because of the target cells. BEST1 is targeted to RPE. This one is targeted to photoreceptors.

So we've -- at this point, we've treated 6 patients. All 6 have had clinically meaningful endpoints and profoundly blind patients, you need to look at the endpoints across different types of modalities to be able to evaluate them. The first and actually, honestly, the most unexpected was that 5 out of 6 had a clinically meaningful improvement in actual visual acuity.

The first patient that I'll show you in a minute, went from -- this is an example, went from being able to just see shadows like a hand maybe in front of their face to being able to see the biggy on the eye chart. So very profound type improvements. And these gains were seen as early as 1 month. And so it's pretty fast to turn on the machinery.

The durability that we've seen in the adults that we've treated so far is out to 18 months. And really, you sort of see a peak in efficacy at 3 to 6 months with a duration at least out to 18 months at this point.

FST is an incredibly important endpoint. This was the first statistically significant endpoint in the Luxturna trials in the 2010s. FST is a way to measure the overall sensitivity of the retina to light. It's a very good test. What we've seen here is a logarithmic scale improvement in FST and an improvement to what the investigators and the FDA consider to be sort of a theoretical maximum for this disease. The improvements in FST in these patients is the reason why we worked with the FDA to -- even at the lowest dose to stop dose escalation and go immediately into a pivotal trial. It's really remarkable on FST.

MLoMT, this is a virtual reality maze. So this is a test where the patient puts on a headset like a meta headset, and they have the 2 little joysticks or whether the controllers, whatever you call them. And they are presented a course that they follow in virtual reality world through the headset with objects that they tag. And so it's a very simple elegant test, mostly of their peripheral vision. So if visual acuity measures sort of your central vision, then MLoMT is more of a peripheral vision test.

And so what you'll see reported here is the number of objects that they could identify. And you do it at multiple luminances, which are all clinically significant. You kind of start at like a starry night lumens and you go to like a full moon to a normal conference room to a bright conference room type lighting. And you'll see that this was pretty meaningful. Safety was as expected. So there were no ocular treatment-related serious adverse events.

So the 6 patients we've treated, you can see here. The main things to see on this, we started with adult patients, right? So these are adults literally like the 34-year-old patient, 0101 is the one that was on Good Morning America. She's 34. She's been blind since she was a little child. And what you can see is with the logMAR visual acuity, it's pretty severe. Now we are going into pediatric patients because we believe as you treat younger and younger patients, you have more of an ability to intervene and restore vision. And so we think that the results are probably going to be amplified in the pediatric population, and that's exactly what I'm going to show you in the coming data slides.

The first is visual acuity. We measure visual acuity in logMAR because these patients are off of typical eye charts. And actually, they jump between charts, and it's a little bit more nuanced to measure this low of vision. But you measure in logMAR and a kind of rule of thumb for the people in the audience that are familiar with ophthalmic trials is that for every 0.1 logMAR improvement is about the equivalent, approximately the equivalent of 5 letters on an eye chart or 1 line on an eye chart. So what you can see here in the adults is the orange line is the treated eye. The untreated eye is the more teal line, and you see a nice separation there that is seen pretty early in disease and is maintained out to 18 months.

In the children, on the right of the slide, we have much less follow-up. We only have 3 months of follow-up, but you see a more profound separation from the fellow eye, and you see a really remarkable 0.4 improvement in logMAR visual acuity. It's really great vision. Patient level data is available on our website, if anybody is interested in seeing actually all 6 patients.

FST is really interesting. So FST, again, this is a logarithmic scale. So when you look at the separation, you have to put this into a logarithmic type framework, not a linear framework. And red and blue is both -- is different wavelengths of light, obviously, measuring different types of photoreceptors. Again, you see a separation that is clear, consistent and durable.

MLoMT, this is the virtual reality mobility test. Again, this is the number of objects a patient could identify through the meta headset. On the Y-axis, you see the number of objects. On the X-axis, you see time. And again, you see the adult cohort on slide left and the pediatric cohort on slide right. And what we think is noise in this based on some work done at Penn on the validation of this test is that approximately a difference of about 2 or 3 objects is going to be the standard error.

Microperimetry is really interesting. Microperimetry is a test where you can actually do a point-wise testing of the -- it's almost like probing the retina to see the light sensitivity. So on this image that you see here on this slide, you see a grid overlaid on the patient's retina. And then in every one of those black points, you test the sensitivity of light at that point. And so only this requires fixation at baseline. Only 2 of our patients could actually complete the test, but these patients had a remarkable improvement in the area of the retina that could sense light.

So the thing to concentrate on this is really sort of the heat map. So if you look, for example, in the second column, that's the study eye, if you look under sensitivity, you see baseline is the first image with maybe 3 little red marks at 1 month and then at 12 months, you see something that looks like the continent of Australia, I think, something like that, much, much better. You see this also in one of our pediatric patients who could do this. Really remarkable test that shows not only target engagement, but also shows functional improvement in these patients.

So at this point, we have excellent safety data. We have robust biological activity across every endpoint that we've tested. We've received Rare Pediatric Orphan Regenerative RMAT, all the things. And we have talked to the FDA, and we flipped this trial into an adaptive Phase III trial that we're currently enrolling.

We do have that partnership with phentolamine. I'll go very quickly through this. We're very excited about the sNDA for presbyopia. I'll tell you the differentiation here is that currently, the approved version of phentolamine, Ryzumvi does not carry a warning label for retinal detachment or for issues with dim light vision. And so we think that this will be very well received for patients and a great product. So we're looking forward to potentially having this approved this year.

At this point, I'll go through a little bit of just the expected catalyst one more time, and then we'll open it up for questions. So again, the main thing to concentrate on is the BEST1 readout in the second half of -- or I'm sorry, in the midyear of '26. Initial data will be at a medical conference in Q1, but that will be very limited data.

LCA5, we're going to continue dose in the Phase III, and we'll provide updates on that. We think that at least 2 additional gene therapy programs will enter the clinic this year, and we're very excited about both of those. And then Phentolamine, the second indication of presbyopia, we hope for an approval sometime this year.

With that, we'll open it up for questions. And I'll also ask the President of the company and Co-Founder of the company, Ben Yerxa, to come up along with Ash Jayagopal, the Chief Regulatory Development Scientific Officer.

I'll kick off questions that we have here. You slightly touched on it during the presentation, but if we could just double-click on what you think is the differentiation on Opus' approach to gene therapy, in particular, in the diseases that you mentioned.

Yes. Ben, I'll let you take that since you founded the company.

I mean in terms of the differentiation of approach, I think it's a really unique opportunity to take assets that have a very straightforward material set. So known capsids, known promoters, very well-understood method of delivery. So it kind of derisks our approach as we go into the clinic. I think that we rely on Jean Bennett for her expertise so that we really know the right starting doses to go into. So that translational moment from animals to man is a really important moment. And I think just kind of nailing that program after program is a pretty big differentiator for us. Did that answer your question?

Yes. I appreciate it. As a quick follow-up to that, I think a lot of the presentation focused on the mechanism of action and the delivery to the back of the eye. Could you just double-click a bit more on not only the -- I guess, more on the safety benefits of that, kind of just double-clicking on that would be appreciated.

Ash, do you want to take that? Talk a little bit about safety of the product.

Sure. To date, the drug products in both BEST1 and LCA5 trials has been well tolerated with no serious adverse effects. And we're not surprised that's based on a very well-established subretinal delivery technique. We use very low doses of vector compared to approved gene therapies on the market. And we have -- these clinical programs are backed by an extensive nonclinical safety package. So this helps to derisk our approach.

Awesome. That's great to hear. Kind of going along the lines of that with the upcoming milestones that you mentioned and the data readout expected later this year, what readouts are you expecting to be able to talk about with the voice later on?

Yes. Well, the one that we would index most people to the biggest value inflection for the company will be the BEST1 readout in the midyear. And our goal for that readout will be to show in the first cohort, a full cohort of data, obviously focused on safety first. And then on target engagement. We think we should be able to show meaningful target engagement.

And again, to reiterate, the things to look at are, it's really beautiful because we can study this disease at a cellular level in humans using electrophysiology that should translate to a macro imaging endpoint with OCT, which then should cross over into multiple different types of functional improvement, either with different types of visual acuity or with microperimetry. So I'd index to that, I think that's going to be the most important thing for the company this year.

Awesome. That's very exciting, and we look forward to it. Briefly moving on to the LCA5 program, not knowing much about it myself. I would love to hear a bit more about what does the therapeutic window look like for a patient with this. Could you talk a bit more about the rate of degeneration and exactly how OPGx, the program, how does it fit into the window that the patients are provided and the options that they have?

Yes, totally. Ash, do you want to talk about that one?

Sure. In LCA5 inherited retinal degenerations. -- this program was selected as the first in the Opus portfolio really because of our conviction and confidence in the treatment potential for gene augmentation. In LCA5, although the visual function declines severely, in the first decade of life. Most patients are diagnosed as legally blind within those first few years of life.

There persists a viable photoreceptor structure that we observed in natural history studies going into the third and fourth decade of life. So these patients have poorly functioning photoreceptors, but they are viable, and we believe that they can be restored by a low-dose restoration of a ciliary structural protein that they're missing. And early results indicate that it is indeed possible even in patients in their 30s to restore what we believe to be clinically meaningful real-world visual function. So hopefully proving out Dr. Bennett's hypothesis.

Awesome. Thank you. I appreciate that. Last question before I turn it over to audience or any closing remarks. I think this is a question all biotech and pharmaceutical companies have with so many great programs and all the diseases that the team is studying. What are -- how is the team thinking about prioritization? Obviously, with the data releases that makes it a bit easy to do, but would love to hear given the extensive pipeline the team has.

It's a great question. And it's something that is unique to us, but we think a whole lot about, and we think it actually is very interesting for patients and for stakeholders in the company. We pick programs that fundamentally have high probability of success with efficient development pathways. So what you're going to see here is manufacturing costs and time lines are reasonable because we're not trying to invent new manufacturing techniques or anything like that. We're doing straightforward AAV augmentation.

We're picking diseases where the pathology can be reversed, which allows you to see an improvement and as we saw in LCA5 as early as a month. And so we're picking diseases. We're picking manufacturing techniques. We're picking science that really -- I think the first principle way to think about it is this is more of a development company, less of a discovery company. Our goal is just to get approved products. I mean that we're going as fast and as quickly as we can towards that.

Truly cool. But thank you so much. I'll leave it. Any other questions from the audience or any closing remarks?

I have a quick question about the presbyopia asset. Is it expected to be a long duration treatment option like last more than 8 hours, a day or?

Yes. So it's -- one of the unique aspects about this presbyopia asset is that you dose it at night and it lasts for up to 24 hours. The reason that we can do that is because you don't -- you fundamentally don't have the issue with dimming that you get with some of the other presbyopia assets out there. The reason for that is fundamental biology. Our target pupil diameter is 2.5 millimeters. The target pupil diameter for the pilocarpine or pilocarpine-like products that are available in the market is more like 1 millimeter. And so if you don't dim the patient's vision, then you can dose at night and you can dose with longer durability. It's a great question. Yes.

So I was just curious about whether you intend to commercialize the approved products when approved or your focus on being a development company. So just how to think about that.

So this is a really great question. So a couple of sort of first principle considerations here. Number one is that in the United States, these are small populations. The call point for a sales team for BEST1, the biggest indication would be around 2,000 doctors. So it's very reasonable. You could do this as opposed to phentolamine, which we partnered with Viatris on because that is a mass -- like the presbyopia market is 140 million Americans or so. So they're very different profiles in the United States. So you certainly could commercialize this in the United States.

One critical -- the second critical sort of first principle thought here is that these inherited retinal degenerations have different founder effects in different regions of the world. So some of these, for example, LCA5 is very common in Germany. MERTK, very common in the Middle East; CNGB1, very common in Asia. So I do think that there's a need for a global type commercialization, which is going to be tricky, but it's something that Luxturna has been succeeding with and that we're looking at different avenues for how to do.

But we see this as -- we see these gene therapies, not just as U.S. products, but as global products. And we think that you will get reimbursed globally. If fundamentally back to what I said earlier, if truly these results kind of hold and are replicated in the other programs, then I think that people will want these for their children.

Any other questions? All right. If there's no further questions, we'll wrap up the presentation. Thank you so much all for attending, and thank you all for presenting. Appreciate it. Any closing remarks, please go ahead.

No. Just thank you for everybody that came. This is great to see the room, and thank you to JPMorgan for the invitation and for all the support.

Greetings, and welcome to the Opus Genetics LCA5 Data Conference Call.

[Operator Instructions] Please note that the webcast participants will be able to see and hear the video. However, teleconference participants dialed-in by phone will need to view the video in the Event Replay in the Investors section of the company's website. As a reminder, this conference call is being recorded.

I will now turn the conference over to your host, Jenny Kobin, Opus Investor Relations. Ma'am, please go ahead.

Good morning, and thank you for joining us today for our call to discuss recent results from the Opus Genetics LCA5 Clinical Development Program.

Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. Various remarks that we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our annual report on Form 10-K for the year ended December 31, 2024, our quarterly reports on Form 10-Q for the quarters ended March 31, 2025 and June 30, 2025, and our other SEC filings available on our website.

In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so even if our views change.

Presenting on the call today, we have Dr. George Magrath, Chief Executive Officer; and Dr. Sally Tucker, Senior Vice President of Clinical Development. They will summarize our LCA5 clinical study data. In addition, Dr. Ben Yerxa, President; Dr. Ash Jayagopal, Chief Scientific and Development Officer; and Rob Gagnon, Chief Financial Officer, are with us today and will participate in the Q&A portion of our call.

The remarks on today's call will be accompanied by a slide presentation, which is available in the Events section of Opus Genetics Investor Relations website at opusgtx.com. A recording of this call will be available on the website later today.

I would now like to turn the call over to Dr. Magrath.

Thank you, Jenny, and thank you all for joining us this morning. We're extremely excited to present the recent results of our LCA5 gene therapy clinical development program targeting Leber congenital amaurosis. Notably, our safety and efficacy data for all 3 pediatric participants is positive with observed improvement at 3 months. We will also provide new data on our adult participants supporting durability out to 18 months.

Before I turn the call over to Sally to review the clinical data in detail, I will spend a few minutes providing a snapshot of our gene therapy programs targeting inherited retinal diseases and provide a brief overview of our LC5 program.

At Opus Genetics, we are focused on accelerating groundbreaking gene therapies for inherited retinal diseases, drawing on robust preclinical validation from leaders in the gene therapy innovation field. By building a portfolio that spans multiple indications targeting inherited retinal diseases, we believe we are strategically positioned to capture a significant share of a multibillion-dollar market, offering numerous opportunities for approved therapies to address rare genetic eye disorders. We have delivered on several critical milestones this year with additional catalysts anticipated in the fourth quarter, particularly driven by progress in our OPGx-BEST1 program.

Our portfolio of assets features AAV-based gene therapies, utilizing validated scientific, clinical and regulatory processes and endpoints. These indications have an established regulatory pathway, and we have received rare pediatric orphan drug and regenerative medicine designations. The advancement of our pipeline has been bolstered by non-dilutive funding from the NIH, FDA and patient advocacy groups.

Our lead candidate, OPGx-LCA5 is a Phase I/II trial for Leber's congenital amaurosis, and the trial is co-funded by the FDA. OPGx-BEST1, which targets bestrophinopathies and affects a much larger patient population, has cleared its IND, and we expect to initiate a clinical trial in the fourth quarter with our first data expected in the first quarter of 2026.

To put our data in context for you, I'd like to provide a summary background on LCA5 and related outcome measures. Despite recent advances in gene therapy, treatment options for inherited retinal diseases remain limited. More than 350 genes are known to cause IRDs, affecting the vision of over 180,000 individuals in the United States alone. Nearly all IRD patients still lack therapies to slow disease progression or restore sight, with Luxturna as the only FDA-approved gene therapy to treat RPE65 mutations.

LCA5 is an ultra-rare disease that affects approximately 200 patients in the U.S. and generally presents in the first year of life. LCA5 was selected as our first clinical program due to the significant unmet medical need, the severe early onset nature of the disease and the preserved retinal structure these participants exhibit throughout the first 3 decades of life. This structure-function disassociation creates a favorable pathobiology for AAV gene replacement and presents an opportunity for gene therapies aimed at partial restoration of visual function, making LCA5 both a strategic and high-impact target as our lead program.

OPGx-LCA5 is an AAV8-based gene therapy, designed to restore production of the lebercilin protein in the retina. Lebercilin is a ciliary protein critical for the function of photoreceptors in the eye. And in LCA5 patients, this photoreceptor function is severely impaired due to a lack of functioning lebercilin. OPGx-LCA5 is a onetime treatment administered via subretinal injection, which is a validated surgical delivery method for many ophthalmic therapies. By delivering a functional copy of the gene to the retinal photoreceptors, we aim to enable these cells to regain their role in supporting vision, offering new hope to these individuals affected by the severe disorder.

Before I turn the call over to Sally to walk through the data, I want to take a moment to describe the secondary efficacy endpoints we are evaluating. It is important to remember that LCA5 patients have extremely low vision with little-to-no formative vision to be able to see or identify an object. Because of this impairment, the tools used to evaluate improvement are not the same as those used for cited individuals.

For our visual acuity and other outcomes, we will measure improvement utilizing a scale known as the logarithm of minimal angle of resolution, or logMAR scale. It assesses the ability of individuals spatial resolution or the ability to see black on white. This is assessed in normal-sighted individuals by asking them to read letters on the chart, but with people with extremely low levels of vision, gratings or patterns are used since their vision is so impaired. LogMAR is used to assess visual acuity in a standardized fashion because it is a logarithmic. It means that equal distances on the scale represent multiplicative changes rather than additive ones. This isn't jumping from 0 to 1. It's an exponential improvement.

The Full-Field Stimulus Test, or FST, measures the cone or photoreceptor sensitivity. In the eye, you have cones that have peak sensitivities to different wavelengths of light. This includes cones that are more sensitive to long wavelengths or red light, the red cones, or those that are more sensitive to shorter wavelengths of light, the blue cones. FST uses red and blue light to target these different photoreceptors to determine changes in sensitivity of these photoreceptors. As you may recall, FST was the first endpoint that showcased significance in the Luxturna trials as a marker of retinal sensitivity.

The Multiple Luminescence (sic) [ Multi-Luminance ] Orientation and Mobility Test, or MLoMT, is a virtual reality mobility course. It assesses what luminance or brightness the individuals can navigate through the course and measures how many objects they can recognize. This is a very sensitive test that actually requires a lot of perception. Users have to follow arrows that are on the floor to navigate the course, while also looking around to identify objects such as a cover, a ceiling fan, a skateboard and a number of other round objects or orbs, some of which are static and some that move.

Microperimetry is a detailed eye tracking assisted visual field test that creates a retinal sensitivity map with the macula, the center part of the retina, by testing a patient's response to light at specific points. Many of the participants in our trial could not conduct this test due to poor visual acuity and nystagmus or abnormal eye movements at screening.

I will now turn the call over to Dr. Sally Tucker, who leads our clinical development programs, to walk through the results to date of our LCA5 Phase I/II study.

Thank you, George. I am pleased to walk you through the data today, which will showcase the vision improvements for the participants treated to date with OPGx-LCA5.

In today's data presentation, we are going to provide 2 important updates: release of the 3-month pediatric data and the 18-month adult data. To date, we have treated 6 participants, 3 adults and 3 pediatric participants, whose demographics are depicted here. One item I will point to on this slide is the baseline visual acuity. As we go through the data, the baseline vision for these participants is important as we are seeing a pattern develop with some of the efficacy outcomes. Of note, in all cases, the participant's eye with the worst vision was treated.

The primary endpoint for our Phase I/II study was safety. OPGx-LCA5 was well tolerated by all the participants treated, including the pediatric cohort at 3 months and the adults who we have followed out to 18 months. No ocular serious adverse events and no dose-limiting toxicities have been observed in any of the treated participants to date. All ocular adverse events were mild and were anticipated, and there were no events related to the study drug itself. One pediatric patient, 01-05, presented with a cataract at screening that worsened at 3 months, which was deemed related to the surgical procedure and not to the drug.

On durability and visual acuity outcomes, first, we will provide combined data and then provide the individual pediatric participant data. When you are looking at these charts, the negative logMAR values going up the scale indicate improved visual acuity, while the higher logMAR values indicate worse visual acuity. You can see that visual acuity for the combined adult data was maintained out to 18 months when we look at both the mean change from baseline and the mean intraocular difference. This supports the potential for lasting durable responses from this cohort.

For the pediatric cohort, similarly to the adult data, there was improved spatial resolution for these individuals. On average, this was slightly greater in the pediatric cohort when compared to the adult cohort with there being a 0.3 logMAR improvement. This is perhaps indicative of the potential for greater changes being possible when younger, more viable photoreceptor cells are treated. When we look at the pediatric participants individually, it is clear that all 3 saw improvements in vision. I'd like to walk you through the visual acuity data for each participant, along with their personal outcome anecdotes that they shared following treatment with OPGx-LCA5.

Participant 01-05 had a baseline visual acuity of 2.2 and at 1 month had an improvement of 0.5 logMAR visual acuity. This was the participant that had a worsening of their cataract observed at the 3-month visit, which could be contributing to a more muted visual acuity response at this time point, albeit they still showed an improvement from baseline in their visual acuity. This participant reported being able to walk and cook without the assistance from others and how treatment has helped them in their writing capabilities. The participant's mother described how their daughter's eyes moved and rotated independently of one another prior to surgery, but that now that they seem to be much more coordinated in their movements.

Participant 01-06 had baseline visual acuity of 0.96 and is the pediatric participant who had the best vision at baseline. They had a 0.2 logMAR improvement in visual acuity at 3 months and reported a noticeable difference in their visual brightness between their treated and untreated eyes.

Participant 01-07 had a baseline score of 2.3 and following treatment had a 0.7 logMAR improvement in visual acuity at 1 month. This improvement was maintained to the 3-month visit, and I will share the anecdote in just a moment.

Now moving on to our data related to FST, MLoMT and microperimetry. As a reminder, FST uses red and blue light to target different photoreceptors to determine changes in sensitivity of these photoreceptors. We are pleased to report that we observed overall improvement in all participants. 5 out of the 6 participants improved in dark-adapted FST and 1 participant improved in light-adapted FST. In the adult participants, these gains have been seen out to 18 months. We are really excited about the FST data observed in the pediatric participants. As you can see, these 3-month results have shown FST improvements in all 3 individuals. These 3 participants had large log scale improvements, which were consistent across them all and overall superior to those seen in the adult participants. This is a true indication of the potential improvement in photoreceptor functionality.

These next 2 slides will review the MLoMT data from the virtual reality mobility course. When you are looking at these charts, the X-axis represents 4 different light levels, which go from dimmest to brightest. The 0.02 is the dimmest light level and is equivalent to seen outside on a moonless night. 0.07 is similar to a moonlit night. The 0.22 represents being a normally lit room and 0.47 is the brightest light level, similar to a brightly lit office. The colors of each line represent the time points from baseline, month 1, month 3 and for the adults at months 6, 12 and 18.

In looking at the MLoMT data for the adults, all participants identified more objects through 18 months compared to baseline. Participant 01-01 had significant improvements in their functionality as observed using the MLoMT. They went from not being able to see any objects at baseline to being able to see 6 out of the 9 objects at 3 of the lighting levels out to 18 months. This is an impressive reflection of the gains this participant was seeing, which she so eloquently describes in the video we will show you at the close of this presentation.

As I mentioned earlier, the baseline visual acuity seems to be an important measure when it comes to results using MLoMT. Participant 01-03 was our first sentinel patient, who had no formative vision at screening. This participant went from being unable to navigate through the course prior to treatment to being able to successfully complete the course following treatment. Another anecdote this participant shared with the study team is that following treatment, they were able to navigate through the work corridors without bumping into colleagues, demonstrating the real-world impact reflected in the ability to navigate through the course post treatment. The last adult participant, 01-04, who like 01-01 had better vision at baseline had similar impressive improvements, but across all luminances.

In looking at the MLoMT data for the pediatrics, all participants identified more objects through 3 months compared to baseline. The second participant 01-06 showed gains observed at all of the light levels and had a more similar starting visual acuity to the adult participant 01-04. Participant 01-05 and 01-07 had superior visual acuity in FST gains, though the fact that they had no formative vision at screening translated to more subtle MLoMT scores. However, even a minimal score on the virtual test appears to have a real impact in everyday life.

Participant 01-07 was mostly nonvisual prior to treatment, but reported taking a visit to a local zoo following treatment where they were able to recognize an owl for the first time. When considering the level of vision observed at screening, it appears that better vision at screening is correlated to more significant improvements in object recognition in the MLoMT test. This makes sense as the better vision could be indicative of the ability to identify objects because they have had the ability to see these objects in the past and have learned how they look. For example, they know what these objects are and have confidence in tapping them when navigating the course, whereas when vision is non-formative, the focus will be head down to follow the arrows to just get through the course safely.

Microperimetry is an assessment to measure foveal sensitivity. Participants 01-04 and 01-06 were able to conduct this test with there being positive results. We were not able to conduct the test on the other 4 participants due to their poor visual acuity and nystagmus at screening.

Participant 01-04 had both increased sensitivity and movement of fixation toward the fovea post treatment. Sensitivities were barely detected at baseline, but improved and were then detected over the central area of spared photoreceptors. Further, the fixation area was tighter and shifted towards the center. Interocular differences revealed trends towards improvement with the control eye remaining unchanged. Participant 01-06 had gains in sensitivity by area and degree at just 1 month, and we are excited to see how this progresses over time.

In summary, we are encouraged by the results seen in the pediatric participants across multiple endpoints. We saw improvements in visual acuity with initial gains being observed as early as 1 month in all 3 participants. On FST, there was evidence of improvement in all 3 participants with increased sensitivity in treated eyes and measurable photoreceptor function. For MLoMT, improvements from baseline was also observed in all 3 participants out to 3 months. And importantly, OPGx-LCA5 was well tolerated in all 3 pediatric participants with there being no ocular serious adverse events or dose-limiting toxicity. All of the ocular adverse events were mild, anticipated and unrelated to the study drug.

Similarly, when we look at the totality of the combined data, on visual acuity, we observed improvement in 5 out of 6 participants with initial gains observed as early as 1 month and duration out to 18 months in the adult participants. On dark-adapted FST, we observed improvement in 5 out of 6 participants. And in all 6 participants, we saw increased sensitivity in the treated eyes and measurable photoreceptor function. On MLoMT, we observed significant improvements in object recognition in participants with formative vision at baseline, which we will continue to monitor over time.

That concludes the summary of our results, and I will now pass the call over to George to review our next steps.

Thank you, Sally, for walking us through the data. That was excellent. We're thrilled with our results to date with OPGx-LCA5 in both our 3 adults and 3 pediatric participants. We believe the totality of this data supports the impactful vision restoring potential and durability of our gene therapy. LCA5 was well tolerated in all participants with no ocular serious adverse events. We were pleased to see that our treatment provided data supporting potential biologic activity as early as 1 month and also was observed to be durable out to 18 months in the adult participants. We saw robust biologic activity corroborated through multiple functional outcomes. On visual acuity and FST, the improvement suggests potential enhanced visual perception and clarity. And the improvement we saw in MLoMT translates to a potential improved ability to navigate the environment and perform daily activities, which are critical for these participants.

We have benefited from having the FDA as a positive partner as LCA5 has been granted multiple key regulatory and operational milestones. A grant from the FDA Office of Orphan Drug Products is supporting the ongoing Phase I/II trial. We have also secured rare pediatric disease, orphan drug and RMAT designations from the FDA. We are potentially eligible to receive a priority review voucher if our Biologics License Application, or BLA approval is granted and the FDA determines the BLA satisfies the criteria for eligibility for priority review.

In parallel with clinical progress, we are advancing our manufacturing capabilities, focusing on scaling up both clinical and commercial production and testing to ensure a sufficient supply of cGMP-compliant material. We expect to review the OPGx-LCA5 results and discuss the path forward in this ultra-rare disease with the FDA in the fourth quarter of 2025. We are also on track to begin enrolling participants in our BEST1 Phase I/II clinical trial in the fourth quarter with initial data anticipated in the first quarter of 2026.

In closing, I would like to recognize and thank our team, the clinical investigators and staff at the University of Pennsylvania, who are running the study and especially the 6 participants and their families who made the commitment to be part of this groundbreaking research. As Sally described, it is extremely inspirational to hear the real-life impact that these participants have experienced following their treatment. We have shared quotes from each participant on this slide, and we will close our formal remarks with a video clip from one of our adult participants. Listening to Lindsay's experience helps solidify what we do every day and highlights the impact of OPGx-LCA5.

Operator, once the video ends, you can open the call for questions.

[Presentation]

We hope you have enjoyed the video. Operator, you may now open the line for questions.

[Operator Instructions] Our first question is coming from Debanjana Chatterjee with JonesTrading.

Congrats. So now that you have the early vision trends at hand, are you still considering MLoMT as the ideal registrational endpoint? Or do you think visual acuity or FST could be a more sensitive measurement? And even if it is MLoMT, are you still considering 0.7 to be the best luminance or perhaps something brighter would be a better way to assess the visual improvements?

Yes, Deb, this is George. Great question, and thank you for that. And before I answer your question, it's just -- it's -- I'm just impressed by how much the team has really done this year. Like this is the third clinical trial we've read out this year. And in these results, we were extremely excited about the visual acuity. We were not expecting to see this dramatic of an improvement in the actual visual acuity we saw. And so kind of obviously, if visual acuity is a great -- is an achievable endpoint for the drug product, then we would prefer to use that because it's the most standard traditional method of measuring functional impact of a treatment on a patient. And so we'll have to discuss this with the FDA. We'll show them all the data, and then come up with the right plan going forward.

When we think about MLoMT, to answer your question further on that, I think we need to think with the agency about how do we truly get at the most clinically relevant endpoint on the MLoMT. And we were -- I think we've got multiple paths on that based on this data set. So we're pretty reassured by this. And it's exciting when we look at these endpoints that we have a number of great endpoints to choose from, which is a great problem to have.

Thank you, Deb.

And if I may, I have a quick follow-up. So this one patient who had the cataract, had muted response at month 3. I'm wondering for a registrational trial, would you consider having an exclusion criteria for patients who have this kind of predisposition at baseline and if that would give you higher results and potentially like higher doses as well?

Yes, potentially. We're sort of working through that right now internally and with the FDA. And so cataract is certainly a known side effect of all vitrectomy surgery, for any indication, whether it's retinal detachment, epiretinal membranes or subretinal delivery like what we're doing. And so there are some pretty common methodologies in the ophthalmology trial landscape that we can use to hopefully control for fluctuations in visual acuity caused by development of cataract from the surgical procedure.

Our next question is coming from Albert Lowe with Craig-Hallum.

Thanks for sharing the data today. I want to ask a little more about the remaining discussion points for alignment for the pivotal trial. Is it still expected to be the small single-arm study? And I guess it sounds like there's a lot of remaining discussion about endpoints. And I know the FDA recently provided some guidance on approval for ultra-rare genetic diseases. So I was also wondering if this gives you any advantages or changes your approach for LCA5 or any of your other programs?

Yes. Great questions, Albert. You're hitting on exactly what we're spending most of our time thinking about right now, which is with -- the FDA is being wonderful. And with them funding the study and also with the RMAT designation, we enjoy really frequent communication with them. And they set out in the new draft guidance that they want to see safety and they want to see biologic plausibility. And so that's what we're out to achieve.

And I'll turn it over to Sally to talk a little bit about how she's thinking about the potential pivotal trial.

Thank you, George. Yes. So we're planning to speak with the FDA about the potential pivotal trial for this. As George says, we're having discussions with the agency of how we can accelerate the clinical development for this product given the ultra rarity of the IRD. And we're looking at a pivotal trial that will focus on the endpoints that we've showcased today. So visual acuity, spatial resolution, FST and MLoMT. Again, looking at the correlation as well between what the patient's vision is at screening and knowing that we'll expect to see more enhanced responses in particular measurements dependent upon what their screening visual acuity is. And we'll be having discussions with the FDA on the number of patients that will have to be part of this pivotal trial as well when we meet with them later this year.

Great. Maybe a follow-up. Actually, I was wondering in some patients, it seems like there's on the multi-luminance mobility test. It seems like there were fewer objects identified in some of the brightest conditions. So this seems a little unexpected. And I was curious if you had any ideas on what may be causing this?

So my theory is that these patients naturally have some photophobia. So these patients really, really have trouble in brightly-lit environments. And so I think that what you see here is in this data set is that these patients with already very low vision have difficulty at the lowest extreme and the highest extreme of brightness. And I also think that, that's not -- and what we care about and sort of what Deb was hitting on with the lower -- with sort of the middle luminances is those are more like daily life type luminances. So it's really -- those are the ones that I think we care about the most.

Our next question is coming from Dev Prasad with Lucid Capital Markets.

Congrats on the data. I have a couple of questions. So the first one is the cataract patient that was linked to the surgery. Just wondering, can you do any refinement to reduce such procedure-related complications? And second is we see adult patients having improvement sustained up to 18 months now. What are your -- how do you envision long-term durability in pediatrics? And any thoughts from CMO that these could -- these early treatments can have more persistent benefits?

Yes, Dev, thank you for the question. So to tackle your first question, the -- so cataract is well known from vitrectomy and there are certain technical procedural things you can do during the procedure that minimize cataract that are pretty standardly done. However, you still will get cataract. So the trick, I think, is really to make sure that we control for that in the trial, right? And so using mechanisms within the clinical trial setting to ensure that there's no confounding of our endpoints based on the development of a procedural and not therapeutically related event. So that's how we're sort of thinking about the cataract.

The second part of your question about durability, yes, absolutely. So in the adults, these were adults that had never had formed cortical pathways for vision. And the medical term for that's amblyopia, and that puts a ceiling on the potential benefit that the patients can get because the brain just doesn't form normal visual pathways. As you go earlier and earlier, you have more opportunity for the brain to actually form those pathways. And so as we get younger and younger, we would expect not only the durability, but potentially to have a more -- even more impactful benefit for these patients. And that's, I think, what we've seen by going from the adults into the adolescents. And then as it naturally goes younger and younger, I think we'll continue to see that pattern emerge. It's my hope at least.

Our next question is coming from Matthew Caufield with H.C. Wainwright.

Congrats, George and the team on the encouraging update. It was really great to see. So based on the observed LCA5 success, do you believe there's translatability or level of derisking when you consider the comparable delivery and approach for the forthcoming BEST1 program?

It's a great question, Matt. Yes, absolutely. So it's delivered the same way. A lot of the endpoints are similar, although it is a very different sort of pathology. And we think that it's a -- it just falls right into our sort of platform of going after gene augmentation in these inherited retinal diseases. So the BEST1 program is flying right now. It's going really well, and we're really, really excited about more data coming from that program or initial data come from that program in Q1 of next year.

Excellent. Really great to see the updates today.

Thank you, Matt.

Our next question is coming from Boris Peaker with Titan Partners.

I'd like to add my congratulations on the excellent data and the progress. I guess my first question, I just want to understand, you talked about younger patients deriving more benefit, which I guess could be attributed to cortical pathways and maybe preserved retinal structure. Can you comment maybe out of the 200 or so prevalence that you estimate of LCA5, what fraction of them you think could be eligible for treatment? Or the other way, which fraction you think may be not eligible anymore for whatever reason?

Great question, Boris. So -- yes, so when we think about the 200 patients, that is like a total prevalence. And so the natural incidence each year is only several patients or handfuls of patients. So when you think about it, if you think about it from other IRDs that have had penetration into the market, you would expect that most of these patients would actually get treated because there is nothing else available for them. So even if they are more towards the end stage, they're older in life and they have more -- they have less functioning photoreceptors present, I think they still will go for the treatment.

So I think the penetration will still be fairly high. I do think that a lot of these are children. That's when they're diagnosed, and that's when the genetic testing is done. So of the 200 people that are out there in the United States that have been genotyped, a vast majority of those were genotyped within the last 20 years at age 2 or 3 of life. And so as genotyping has become more and more available by the good work at places like the Foundation Fighting Blindness and others, we're finding more and more of these patients younger and younger. So I do think the population skews younger. I think should this treatment prove out to be safe and efficacious and should it garner approval by the FDA, the penetration should be may be very high.

Got it. And maybe my last question on the regulatory front. Do you think there's any parallels we could draw in terms of Luxturna or learn things, extrapolate from Luxturna that may impact kind of your regulatory pivotal path forward?

Well, I think there's a recognition of all stakeholders that more of these things need to get developed. So Luxturna was developed in -- it was approved in 2017, I believe. And since then, nothing else has been able to make it across the finish line. And I think that, that is a function of the requirements of programs.

And I think that as all the stakeholders involved become more and more willing to work with the community on what are the right endpoints, what are reasonable trial designs, what are the ways that we can actually get these things to patients? Because as you can see, it obviously is affecting these patients' lives. I mean we've treated 6 patients and 6 patients have had their lives changed by this treatment.

And so I mean, the real question that I have is pretty simple. It's like, well, if you've restored meaningful vision in 6 out of 6 patients, I mean, how many more times do you have to repeat that? So I think we're in a unique scenario right now, unique time right now where people are really becoming more and more just first principle logical on this topic of what do we really need to feel secure that these drugs are safe and provide benefit to patients.

Got it. Great. And again, congratulations on the progress.

Thank you, Boris. Good to talk to you.

Our next question is coming from James Molloy with Alliance Global Partners.

I'd like to -- looking at the potential Phase III endpoint, would it be reasonable to think that this would be something that you should direct only at pediatrics going forward given sort of the good anecdotal -- the better anecdotal evidence you saw in the pediatrics than you seem to see in the adult, although there was ample evidence of visual improvement in the adults. And I guess what -- all of this anecdotal is not evidence, but in the small population, you have to do what you can. What does constitute you think, the final defining approvable endpoint?

Yes, it's a good question, Jim. So I think -- the way I think about the final primary endpoint for a pivotal trial is that we have a number of -- so this is taking the second part of your question first. We have a number of endpoints that are all pointing in the right direction, whether it's visual acuity, FST, MLoMT, even microperimetry. We feel pretty strongly that this just needs to be a discussion with the agency. And so that's exactly what we're going to do. I think any of those is a clinically meaningful type endpoint that could be used for an approval. And we'll just have to see, right? It will have to be a discussion amongst the company and the agency to see what is the most realistic endpoint to use in an ultra-rare program like this.

The answer to your first part of your question, Jim, is, yes, for pediatrics to a degree, right? So I think Boris in part of his comments mentioned that not only cortical plasticity, but structure of the retina is important. So cortical plasticity or the ability of the -- to get to these patients before they become amblyopic is certainly a function of age. And so for that, you need to treat younger. But the presence of photoreceptors, what we've shown on the FST data is when you restore lebercilin into the photoreceptors, you get -- you really do get improved sensitivity of those photoreceptors to light. And so what we're after are people who have present photoreceptors.

And so in addition to age that you mentioned, that's what we care about are patients that have photoreceptors that we can potentially modify. And sometimes that persists into the second, third decade of life. And I think that's the improvement that was such a surprise in the adults was that they were able to regain such vision with limited photoreceptors remaining.

Good question, Jim.

First time for everything, right? But we're looking at Phase III then what would be the ideal for a trial then? Would it be the same as this trial, same size? Or do you think you need some more? Again, no need to going up again the restriction in fact, it's only 200 of these people in the U.S.

Yes. Yes, Jim. Yes, I think the ideal trial would be use visual acuity as an endpoint and treat enough patients where we feel comfortable we're showing a meaningful difference.

Would it be enough?

I don't have that for you yet. Let me come back to you on that with the -- after we've discussed it with the agency.

Our next question is coming from Madison El-Saadi with B. Riley Securities.

I was just wondering if any of the variability could perhaps be related to the surgery procedure and if there's any, I guess, procedural optimization work that needs to happen on that front? And then are there any medical conferences upcoming you plan to present some of this data?

Totally. Yes. So medical conference is upcoming for the data. We'll announce those as they get accepted. But yes, it's going to be presented likely at multiple conferences over the next 6 months or so. The adult data is actually -- was published in Molecular Therapies in the October issue and will be the cover of that journal for October. So you'll be able to see our patient on the front page of molecular therapy. Pediatric data will come out in conferences, and then we'll publish that in due time.

So that's the conference question. And then Madison, remind me the rest of your question, the other part of it?

I asked about the surgery procedure and [indiscernible] variability.

Totally, totally, yes. So it's becoming -- so one of the great things with this is that Luxturna has really paved the way. There probably are 50 or so surgeons in the United States, who are pretty well versed at doing this procedure. It's a -- technically, it's pretty well refined at this point. I will say that this is like the most precise of precision medicine, right? You're delivering these vectors directly to the photoreceptors. I mean I don't -- I'm not aware of anywhere else in medicine where you really can get this targeted to -- on a cellular level with minimal off-target effect, right? There's very minimal systemic exposure to these gene therapies, very minimal exposure and really even in the rest of the eye to these gene therapies.

And so this is really, really precise stuff that there's some really amazingly talented surgeons that are doing. And we're obviously going to continue to be very involved as we as we -- as each patient is treated to make sure it's as optimized as possible. I think that goes back to one of the sort of final points that we have, which is that we got a team that's really executing. We've read out 2 Phase IIIs. Now we've read out this ultra-rare study. We've got the BEST1 study that's rolling. I mean the team -- for a small company, the team is really executing well. There's a lot of activity and a lot going on. The sNDA for presbyopia is going to happen this year, just tons of milestones, and a huge congratulations not only to the investigators and everyone else, but the team, too, for pulling it off.

Got it. Understood. And maybe if I could squeeze one more in. You spoke of pediatrics having perhaps more intact circuitry. And obviously, there's a higher level of neuroplasticity one presumes with younger patients. Do you expect that can drive separation within, say, a 12-month time frame? Or is that something that would kind of drive separation years down the road? And do you have a sense of what that delta would need to be that the FDA is kind of looking for in the pediatric cohort?

No, it's a good question. Well, I think the delta that we're seeing is -- I can't speak for the FDA. I don't know yet. We'll have to go talk to them. But certainly, the effect that we're seeing even at 3 months and in the adults at 3 months and then out to 18 months is indicative of a dramatic improvement in their quality of life, and it has been safe and therefore, it should meet the criteria for what we would consider a viable product.

To further answer your question, though, about the pediatrics, I do think you're going to -- I think it's going to be -- if you compare it back to Luxturna, like when I've seen these patients, they -- it takes a while to really adapt to your new vision, to develop the new vision. And so I do think it's going to take probably years of kind of gradual improvement. But I don't think that's going to be required to be shown prior to approval. I think what we've shown is fairly compelling.

Does that answer your question, Madison?

It does. I mean it looks like you have 6 patients who really delivered a material benefit, too. So congratulations to the team on that.

Thanks, Madison.

As we have reached the end of our question-and-answer session, I would like to turn the call back over to Mr. George Magrath for closing remarks.

Sure. Thank you. And I very much appreciate everybody's questions. Q&A is always the most fun part. We are very excited about this data, and we're very excited not only about the data, but the current environment that we're in, where these treatments that appear to be safe and appear to be efficacious are getting prioritized. And so we do think that there is a lot of room to accelerate this program. And I think that's needed to get this kind of life-changing effect to patients in a reasonable time frame.

And so our team, as I mentioned earlier, is really performing at a high level and will be going as efficiently as possible to bring this further to patients. And you'll see that we have the FDA meeting coming up in the fourth quarter on this program, and we'll report back to you guys after we have some clarity on that. We've got the BEST1 data coming in Q1. We've got the sNDA for presbyopia coming later this year. We've got the dim light disturbance trial that's ongoing right now and is enrolling really well.

And so there's a lot of activity. It's a fun time at Opus. I was joking around with someone the other day that this is really a blast right now because we're in the middle of executing against a lot of really important science. And it, for the most part, seems to all be working. So I very much appreciate everybody's time and attention this morning, and we look forward to continuing to update you guys as we get material updates. And please contact us if you have any questions.

Thank you. Ladies and gentlemen, this does conclude today's conference. As a reminder, you may view a full replay, including the video of today's call in the Investors section of the company's website at opusgtx.com.

You may now disconnect your lines, and we thank you for your participation.

Hi, everyone. I'm Debanjana, Senior Analyst at Jones. Welcome to our Presbyopia Export Panel. Today, we will explore the presbyopia landscape and how emerging therapies are set to transforming. It's my pleasure to introduce you to our presbyopia KOL, Dr. Weldon Haw. Dr. Haw is the Chief of Ophthalmology at San Diego Veterans Affairs Healthcare system and a clinical professor at UC San Diego School of Medicine. I also have here with me Henric Bjarke, CEO of Tenpoint Therapeutics; and Jay Pepose, Chief Medical Adviser at Opus Genetics. So Henric and Jay, would you like to briefly introduce your company. Henric, do you want to go first?

Sure. Happy to, and thank you for having us here at this webinar. So we're a small ophthalmology company, about 55 employees. That has three drugs in development, two in early stage. The first one is an intravitreal injection for reversing or preventing cataract. It's a once yearly intravitreal injection, commercially incredibly interesting.

Then we have an early-stage cell therapy to prevent geographic atrophy or blindness from geographic atrophy. And our late-stage product, Brimochol, which is a drug for presbyopia that has a PDUFA date of January 28 next year. So exciting times at the company, a great team of people. So happy -- looking forward to tell you all a little bit more about the company as we move along here.

Great. And Jay, do you want to go ahead?

Sure. Thank you so much for this opportunity. So Opus Genetics is a publicly traded clinically stage ophthalmic biopharmaceutical company. It is focused on developing important new therapies for IRDs, inherited retinal diseases and refractive disorders. Our lead candidate is phentolamine ophthalmic solution or POS, and it's in development for the treatment of presbyopia as well as for reduced low-contrast nighttime vision and associated visual disturbances following keratorefractive surgery.

I'm a Board-certified ophthalmologist with over 25 years' experience in ophthalmic drug and device development. I work closely with both leading strategics and early-stage companies. I currently serve as Chief Medical Officer for Opus Genetics.

Okay. So Dr. Haw, we would love to know more about your practice, but maybe you can start by telling us what is presbyopia and how is it currently managed?

Absolutely. So good morning, everyone. It's good to be here. So presbyopia, I don't even actually consider a disease. It's something that we actually all will develop at some point in time in our lives. In fact, I imagine there are a lot of people already on this call that are 40 years of age or older who are probably even now putting on their glasses just to be able to see the computer.

So what presbyopia is understanding kind of the natural way that the eye works, is when you're young and you're 20, 21 years of age, and you could see everything from the Eagle, 1 million miles away to the tip of your nose. And the way that you're about -- you're able to focus is that your lens changes positions. And by changing kind of shape, it's able to kind of adjust focus rays.

So at any one point in time, 100% of the focus rays are kind of at that focus point. And that's kind of the ideal circumstance. With presbyopia, what happens as we get older is a couple of things. I think one is that the lens begins to harden. So even though we're trying to change the shape of our lens, the lens just won't move.

And over time, that results in less ability to focus. The other thing that happens as well is there is a muscle that drives that change in shape, called ciliary body. And that muscle over the course of time, just like any muscle, can get a little weaker over the course of time. So both things kind of add up to kind of diminished focusing range. That is progressive. So when you start at maybe age of 40, which is kind of the typical age, that tends to get a little bit worse.

People often will end up first when they develop presbyopia, just holding things a little further away. So your arms no longer are able to kind of be able to hold far -- things far enough away. And then all of a sudden, you're in glasses. So most people, they're getting the reading glasses that you can get at the drug store, in patients who have underlying prescription, they're getting bifocals or progressives with a reading ad on their spectacles.

There are other fancy things that we can do. We can do contact lenses that are multifocal. We can do monovision with one eye for far, one eye for near. But unfortunately, there's not any specific directed treatment or therapy that we can change the inherent kind of progression of the disease.

So most of the kind of treatments and the therapies that we do are designed to kind of mask kind of this as much as we can. And so glasses, contact lens, we can do things when it comes -- when patient gets older in terms of cataract surgery with special lenses. We can also do refractive surgery where we can aim one eye for distance, one eye for near. But again, no ideal option for patients, particularly those who are used and accustomed to not wearing glasses for anything.

Sure. So Jay, maybe you can tell us like how the presbyopia eye drops can actually benefit patients and serve as an alternative to reading glasses?

Sure. So miotic drops work by constricting the pupil, increasing the depth of focus by blocking the unfocused peripheral light. So it's much like increasing the f-stop on a camera, expands the depth of field. So compared to reading glasses, which magnify the image, but shift the blur point from near to far, miotic drops offer a different balance of benefits and limitations.

So when a patient puts on readers, near vision is enhanced, but distance vision becomes blurred. In contrast, miotic drops can simultaneously improve both near and intermediate vision without compromising distance acuity, though they do not provide magnification. So this makes miotic drops particularly useful for everyday functional tasks such as checking your phone, reading a menu, adjusting their car radio, activities that rely more on intermediate and near clarity than magnification.

However, for prolonged fine print reading like working through war and peace, magnification from readers may still offer greater visual comfort. And in this way, miotic drops can reduce dependence on reading glasses, but may not entirely replace them. And as a refractive surgeon, I've learned that under-promising and over-delivering is the key to patient satisfaction. I think that setting realistic expectations around the capabilities and limitations of miotic drops will be just as important to their clinical success.

Sure. And Henric, what is the standard clinical endpoint required by the FDA for the approval of miotic eye drop? And does the EMA follow similar regulatory framework?

Well, so the FDA has a requirement that you should gain three lines of vision near without losing one line of vision on distance. That's sort of the overarching requirement. What's interesting, though, is that on the device side, when you look at intraocular lenses, et cetera, there are standards on how you measure lighting conditions, et cetera.

On the medical side, however, there's not these standards. So comparing between trials is a little bit hard when it comes to the drop side. But the overarching endpoints is the same. Europe has slightly different endpoints looking at area under the curve response versus this cutoff rate of three lines of vision gains.

And Jay, what do you think is the clinical significance of this endpoint that like [ FDA ] or the EMA is asking for?

Well, the FDA -- there was -- sorry, Jay, go ahead.

Sure. Well, I think the proposed endpoint is appropriate because it ensures an improvement in near vision, doesn't come at the expense of distance vision. And that's an important consideration, especially if the miotic drop stimulates the ciliary muscle and induces accommodation in addition to enhancing depth of focus via miosis.

So while the FDA and the EMA have established clinical efficacy endpoints, I think several studies have shown a strong correlation between patient-reported outcomes and the number of lines gained in near vision. And notably, even a two-line improvement in distance-corrected near visual acuity has been shown to align closely with patient satisfaction.

I think it's also important to recognize that while the regulatory agents, as Henric has mentioned, it focused primarily on distance-corrected near vision, I think improvements in intermediate vision, these are critical for computer use and handheld device interaction. They are also highly relevant to daily functioning and quality of life. And although intermediate vision may not be a primary endpoint, I think its impact should not be overlooked.

So I mean, Dr. Haw, we would like to know from a clinician's perspective, how well does this endpoint reflect what you consider a meaningful treatment response in practice? And are there other secondary efficacy endpoints that you also look for?

Yes, I think absolutely. So I think when we look at FDA clinical trials for many things in ophthalmology, I think us as clinicians are obviously looking for both a structural and a functional benefit, and it should both corroborate one another. So something like wet macular degeneration, they have their mean best corrected visual acuity and then we look at the OCT for confirmatory results.

For patients -- for trials on dry eye disease, we look for signs and symptoms where the symptoms can tell us how the patient feels like they're doing. And the signs are something that we can actually point to and look and kind of, again, confirm that the patient is actually doing better.

With presbyopia, we rely a lot on kind of -- more kind of the functional, how the patient is doing. We don't really have that OCT result or the corneal staining that we can actually measure from the clinician's perspective that, yes, you're doing better or no, you're not.

And so I think when we look at distance-corrected near vision, I think that, again, I also agree that it's a completely appropriate primary endpoint because it reveals a lot of different things in terms of how the patient is able to see some of those near visions without losing again their distance -- their vision. And that is, again, important, as Jay said, because when we are particularly with the miotics constricting the pupil, we are somehow taking away some of the physiological responses of the normal pupil.

So when you go -- when you're driving at night, your pupil dilates and it does so on purpose to allow more light in when it's dim. And so we don't want to detract from the ability of that eye to function under those dim lit circumstances.

In addition, I think, as Jay alluded to as well that many of the pupil constrictors depending on their mechanism of action, can also constrict again the focusing muscle, ciliary body, which induces a little bit of a near shift.

And if so, can also sometimes, again, detract a little bit away from the distance. So having improvement in near vision, again, three lines is quite significant. And I would agree with Jay, two lines is even something that would be functionally beneficial without impacting their distance functioning is something that I think is really clinically meaningful for us.

I think when we look again at the secondary endpoints, as we talked about, we don't have that kind of structural kind of endpoint that we can point to that as a clinician and say that is working. So again, the surrogate, I think, for that are some of the things like patients perceive value. And some of that we can kind of tease out a little bit in some of the studies in things like some of the quality of life studies, how the patient feels as though they're doing, Discontinuation rates are patients discontinuing in the trial because they don't feel that the efficacy is there or they're having safety issues related to it. So I think those kind of secondary endpoints that kind of speak to patients' perception of how they're doing becomes really important in the absence of a structural endpoint that we can look at.

And I think it's particularly important with these kinds of medications because as we'll talk about perhaps when they, let's say, come to market, it's not us telling the patient, you have glaucoma and you're going blind and you need to take these medications, it really is the patient is paying out of pocket. They're going to pay out of pocket and they want value.

And the value is going to be dependent upon patients' perceptions, right, how they feel like they're doing when they're paying completely out of pocket for a medication. And so I think those secondary endpoints can tease out a little bit of that. And at the end of the day, that will become an important aspect in a post-market setting when you have other competing drops.

Yes. So there's already one miotic drop like approved, which is AbbVie which is commercially available, I should rather say. What proportion of your patients are using it? And what are some of the limitations with this drug in your experience?

Yes. So we have Vuity, we have Qlosi. With Vuity, I think there was obviously a lot of initial excitement that surrounded kind of the first approved kind of medication for presbyopia. And the number of patients I had on it then upon launch is very different from the number of patients that I have on it now.

So I think as most of us got experience with Vuity, I think that the value that it provided patients probably wasn't there. So it could work, and it had a very fast onset of action. But one of the problems with the product was the durability. So a patient would put the drop in the first thing in the morning, and they would feel that as the day went on very quickly within hours that they needed something additional, something more.

And eventually, the once a day became a twice a day with the FDA, and so we could use it a second time. But with the product, I think, it just kind of underperformed, I think, expectations. The other thing I think with Vuity is, again, with these drops, we rely on a drop that is going to be also tolerable.

With pilocarpine in itself, it typically requires an acidic environment and the ocular surface is pH neutral. So if you're adding a drop with -- that's acidic, the eye doesn't tolerate that. You get a lot of site instillation discomfort, you get a little burning. The eyes can become a little red. And then at the kind of the end of the day, there were still -- there were some reports as we knew could happen with pilocarpine that you could have this kind of life-changing vision-threatening event of a retinal detachment or retinal break.

And I think that was kind of a nail in the coffin for them in terms of perceived lack of efficacy, kind of the durability, the drop wasn't as comfortable, did have some headaches. And I think from a provider perspective, when we don't see that patients were that satisfied with the product and that it could cause potentially in addition to that, a kind of a vision-threatening kind of event, that really just kind of changed the product profile.

And I think from there on, we just saw that there was a lack of motivation by many providers to prescribe it. And there was a lot of lack of consumer sentiment wanting to follow through with the product as well. And in fact, again, when patients prescribe -- were prescribed the first bottle and got the first drop in and use it for a little bit of time, we actually saw very low refill rates, again, speaking to kind of the patient's perception of value just wasn't there.

Sure. And like you mentioned that it could be applied a second time, but I was curious, like if someone has like contact lenses on, can they still apply like the drop a second -- they would have to take the lens off. Is that like an issue?

So even the second drop can be a little bit of an issue, right? So if you're in the middle of a busy day and the last thing you want to do is have to remember to put your drop in. And so once-a-day dosing, I think, will be important for just kind of -- it's a marketing advantage, I think, in today's market. Certainly, the contact lens issue just makes it a little bit more challenging on top of the fact that you got to remember to take the drop a second time.

We had some ways to navigate that. I mean -- so we have the patient make sure that they didn't have a drop at home that they take it in the office so that they don't put it in the first thing in the morning when they get up and it's worn off by the time they get to the office. Things like that, we could help navigate. But again, the contact lens issue is just one additional complicating thing. You just want durability.

Sure. And so LENZ Therapeutics LNC100 is up for approval in August. It appears more durable and safer based on the data thus far. So Dr. Haw, like what's your take on the profile?

Yes. So LENZ uses aceclidine, which kind of decouples a little bit of the pupillary miosis from the ciliary body contraction. It was something that actually was used -- in the United States, we used pilocarpine as our glaucoma agent 30, 40 years ago. In Europe, they had aceclidine, and I think with the data that we've seen from LENZ Therapeutics, I agree with your assessment, it seems to work fast. .

It seems at least to be more durable than what we had with Vuity and can last, depending on, again, when you're looking at 10 hours, and they have, I don't know, maybe 70%, I think it was with two lines and 40% with three lines.

I mean there is some potential. It looks better than what we had with Vuity. There is some site instillation discomfort. There are some headaches. There is some red eye, and we're going to have to see how that plays out. And again, at the end of the day, patients will decide, we'll give them the product, and they'll decide whether the value proposition is for them. But I would agree that the data looks at least better than what we've seen from Vuity.

Sure. So it sounds like the new therapies like this, they have the potential to like see more adoption in -- among presbyopia patients. So today, we will learn more about Tenpoint Therapeutics Brimochol, which is commercial ready with a PDUFA date of January 28, 2026, and also Opus and Viatris partner phentolamine ophthalmic solution, which is headed for a regulatory filing. So we'll start with Opus Genetics. So Jay, could you walk us through your clinical experience with phentolamine so far?

Absolutely. So as part of its development program, phentolamine ophthalmic solution, or I'm going to call it POS from this point on. It has completed 1 Phase II and 2 Phase III clinical trials. And VEGA-3 was most recently demonstrated positive top line results, meeting the primary endpoint of a three or greater line gain in distance-corrected near visual acuity without the 5-letter loss in distance at day 8, and it had a p-value of 0.0001.

And in addition, significant patient-reported functional benefits at days 3 and 8 in week 6 were observed with patient's reporting satisfaction with near vision upon awakening and improvement in their near vision. Again, with p-values of less than 0.0001. And also, there is no evidence of tachyphylaxis at 6 weeks.

So how do you see phentolamine differentiated from like some of the other pilocarpine-based eye drops that we discussed previously in the call?

Well, phentolamine ophthalmic solution or POS, it's distinguished from other miotic agents by its unique mechanism of action. It is a nonselective alpha-1 adrenergic antagonist. POS works by blocking the alpha-1 receptors, which are on the iris dilator muscle, leading to moderate pupillary constriction. So this enhances near vision without the excessive miosis that can compromise nighttime or low contrast vision.

So unlike some agents that constrict the pupil below 2 millimeters and are associated with visual complaints such as dimming or darkening, POS moderately reduces the mean pupil diameter but to greater than 2 millimeters. So it enhances near and intermediate vision while preserving retinal illumination and low light function. And that's particularly relevant as newer agents show increased duration into the evening hours.

So this distinction is clinically significant because studies have demonstrated that when retinal illumination drops below what we call 100 trolands, there's a sharp decline in contrast sensitivity and which directly affects the ability to detect low-contrast objects in dim conditions.

So to put that -- to make that clear, just to illustrate, so under dusk lighting, let's say, your physiological pupil might dilate to 4.5 millimeters. If a drop pharmacologically reduces the pupil to 1.5 millimeters, that means that retinal illumination falls ninefold. So that's equivalent to driving at night wearing sunglasses.

So while some miotic drops might be -- are being studied and they report high-contrast vision under low light for safety, it's really mesopic low-contrast vision that correlates with real-world low light challenges like night driving. And so in practical terms, when I'm driving at night, I live in St. Louis, my concern is low contrast, not high-contrast objects. I don't -- I worry about hitting a deer, not a Zebra, okay?

So many miotics carry label warnings for night driving, while we are developing POS both for presbyopia and specifically to enhance night vision in keratorefractive patients with reduced mesopic function. And it has been discussed already from a safety standpoint, which is paramount, POS offers really meaningful advantages because as a sympatholytic, it does not engage the ciliary muscle and it thereby avoids potential added risks such as vitreofoveal traction, retinal tears, retinal detachment.

And these are adverse events that have been observed in association with parasympathomimetic agents like pilocarpine. And these concerns are reflected in the current pilocarpine containing drug warnings on Vuity and Qlosi labels.

But in contrast, POS 0.75% is already approved and marketed as Ryzumvi for reversal of pharmacological mydriasis with no class warning for increased retinal complications. And this is particularly important for myopic patients who inherently carry increased risk for retinal detachment. There's an up to fourfold increased risk for retinal detachment for moderate myopes, 1 to 3 diopters of myopia and 7 to tenfold for high myopes.

So notably, myopes account for about 37% of the presbyopic population, and they represent the majority of patients who have undergone refractive surgery, many of whom have longer at-risk eyes. We changed the front of the eye, not how long it is with refractive surgery. So in addition, an additional benefit of POS is the low incidence of headaches, likely due to its lack of ciliary body engagement.

In the VEGA study, headaches were reported in only 2.6% of subjects and remain consistently below 5% in all -- across all VEGA trials. So the most common adverse events were mild transient conjunctival hyperemia, instillation site discomfort and dysgeusia. And finally, the greater than 20-hour durability of POS enables night, evening dosing. So that allows patients to wake up with improved vision.

And that contrasts with other agents that must be dosed in the morning and require time to take effect. And those might be less ideal for patients who want to read their phone or shave, apply makeup soon after waking without glasses. So just to summarize, so POS stands out amongst miotic agents because of its unique alpha-1 antagonist mechanism.

It provides moderate miosis without compromising low light vision. Its safety profile is particularly favorable in myopic and keratorefractive patients with no engagement to the ciliary muscle, avoids increased retinal risk associated with sympathomimetic agents and has a low rate of headache.

And with this greater than 20-hour duration, it supports nighttime dosing and immediate visual benefit upon awakening. And these are all features that enhance real-world convenience and patient satisfaction. And I think these combined attributes really position POS as a differentiated and highly relevant option for a broad spectrum of presbyopic individuals functioning under a wide range of lighting conditions.

I mean you already touched upon the opportunity of nighttime vision improvement in patients with dim light disturbance. Could you tell us a little bit more about how big is that market? And what has been your experience with phentolamine ophthalmic solution in this indication?

Yes. So there are currently no FDA-approved trials for -- no FDA-approved therapies for night driving disturbances. And when we had our discussions with the FDA, the FDA asked us basically to find one patient population to study for approval for registration. And we have a SPA agreement with the FDA.

And so when we did our initial trial, we had -- we included multiple etiologies, but the largest subset was keratorefractive patients. And so that's what we're focusing on for this -- for these trials and for registration. If you look at the FDA applications for Excimer laser systems up to 2004, about 35% of those patients complain to reduced night vision, glare halos and starbursts.

I mean it's gotten better, but there's still issues and there's a whole unmet need. There's a whole group of patients out there with reduced mesopic vision. There's about 40 million keratorefractive patients worldwide. In the United States, the numbers vary between 800,000 and 1.2 million per year. LASIK and -- PRK has been around since 1995, and LASIK was approved in 1999. So I think that there's clearly an unmet need as was demonstrated by the FDA granting us Fast Track designation.

And so to conclude this part, maybe tell us what are the next steps in terms of your regulatory review? So what does the FDA want to see to grant an approval for the indication of presbyopia?

So as I said, we've -- this is our second Phase III trial for presbyopia. And we plan to submit an sNDA by the end of this year for presbyopia. We are about to embark shortly on our next Lynx trial would be night -- would be for keratorefractive patients. That will be our -- actually our third Phase III trial. But again, the FDA asked us to focus on one group of patients. So this will be our second Phase III trial with keratorefractive patients, and we're about to embark on that.

Okay. Great. That's very helpful. So Henric, I mean, maybe you could start us by giving an overview of Brimochol and its mechanism of action.

Okay. Happy to. So Brimochol is a fixed combination of brimonidine and carbachol. Remember, all other companies in this category tried to develop a fixed combination and did not make it. We actually managed to do that. So we have carbachol, which is the ingredient that actually creates the miosis and has an effect on the ciliary muscle.

And then we have brimonidine that has several advantages. And those advantages are, number one, it actually increases the duration of carbachol in the target tissue. That's what gives us a longer duration, right? It also provides redness relief. So for patients who have red eyes or patients who get red eyes from taking eye drops, we don't see that in our studies -- at very, very low rates. We also see, which was interesting to us in the study that the rate of vitreous detachment in our Brimochol group was 4x lower than carbachol alone and that's because of brimonidine. There's literature about that, that shows that brimonidine actually slows down the contraction of the ciliary muscle and therefore, seems to be not as -- the ciliary muscle doesn't do this as quick, which makes it a safer alternative.

The fourth thing it does is that it actually gives us the opportunity to get composition of matter patents. We're the only product in the category that has this actually, and we have done exclusively out to 2042. So there are four key benefits of this combination product.

So what makes this product different? Why are we excited about it? Well, it does have a very strong and lasting pupil miosis. That's number one. We do see, which is -- we talked about a little bit this, what does letters mean to a patient, right? Patients don't know if they see 5 letters more or 10 letters more. But we actually see an increase in reading speed up to 40%. We see that at 6 months and we see that at 9 months, and it's a validated measure.

So patients actually can see or feel the improvement of the drug. Also, in our trials, we asked the patient about the duration of this product. And the patient came back to us, this is after 12-month study saying that this duration for us is just right. As Jay said, it's important that the pupil relaxes a little bit at the end of the day, so you get enough light in, and we can see that on our pupil response.

And then the biggest thing, I think, for us is this redness relief. It's a really big differentiator that we can actually -- brimonidine is used in Lumify, and we have a fourfold concentration. So we will see that patients don't develop red eyes that they can get from taking this drug -- taking drug from other companies. So we're excited about the prospect of the drug and looking really forward to bringing it to market.

So you have run like two successful Phase III trials. How did Brimochol perform compared to its individual constituents and also compared to the vehicle control?

Yes. So we -- in the first trial, we had to show that it was superior to the individual component on the same endpoints. And we did that. And remember, carbachol itself is a very strong pupil dilator, so -- or constrictor, sorry. So we -- but we managed to see superiority out to 6 hours in the comparative trial there. In our second trial, we compared to placebo. And there, we could see a benefit out to 8 hours, statistical benefit. We saw benefits longer than that, but statistically different up to 8 hours. So we met our endpoints in both our trials, and that's what we're using to file our drug application with.

Sure. And you already mentioned a little about the clinical experience with carbachol and brimonidine. Maybe tell us a little bit more on the safety because that has been kind of a problem point with the pilocarpine-based assets. So how does the historic safety of carbachol and brimonidine compared to what you're seeing with the combination like for Brimochol clinical trials?

Yes. So carbachol and brimonidine has been used for glaucoma for decades at higher concentrations that -- what we have in our drug and usually dosed 2 to 3 times a day. So we are lower concentration and less frequently. That's number one. Number two is that we did the longest and largest study in this category ever.

It was a 1-year study with over 70,000 dosing days. And we saw no serious adverse events. We had a very favorable tolerability profile. And what's also important, we saw no waning of the drug effect. So people take it in the morning, the pupil reacts the same way day 1 as it does at the end of the year. So from that perspective, it -- we haven't seen any unwanted effects from the drug thus far.

So looking ahead, you already have your PDUFA date. So what are some of the regulatory milestones for Brimochol. And also tell us how you are prepping for the potential commercial launch?

From a regulatory standpoint, we are working with the agency, and they've been very proactive so far, right? So they've been asking us several questions. In fact, we've probably gotten questions we usually get later in the review already now. So things are moving forward from a regulatory perspective.

I mean we -- I think what we're really excited about, we have brought together probably the strongest team, commercial team in the ophthalmology space. So we're really prepping now to build everything around the product. And we're going to launch pretty quickly after we get approval.

We already have all the API manufactured. We have the trade name conditionally approved by the FDA. We have sample packs packaging. We've done market research. We're out in the field with that Congress as a convention. So we are really right now in the position of getting ready for a potential launch if we would get the approval in January. So a really exciting time within the company.

Sure. I am just curious, like with all the shifts that we are seeing in FDA internally and also like all the news around tariffs, does it impact at all your plans? Or how do you incorporate that?

Well, there's two questions there. The first one about the FDA. We have obviously been concerned about what this could mean for not only us, but any of the drugs that are in development and being moved forward. But we haven't seen anything so far.

And as I mentioned, they have been very proactive in asking questions and things like that. So from that perspective, it seems like business as usual from the FDA. From a tariff perspective, we manufacture the product in the U.S. So we are not concerned at this stage. However, who knows what's going to happen? I don't want to predict anything. But currently, at this stage, that's not a big concern for us.

Sure. So in the remaining time, I would like to shift gears and explore the actual market opportunity for presbyopia eye drops. So there are approximately 125 million presbyopes in the U.S. So Henric, based on -- you've done like a lot of extensive market research, which age groups do you think are most likely to adopt these eye drops? Also like the usage frequency in terms of number of days per week that they're using this drug, does it vary by age?

So generally, you could say that age over 40 is a potential candidate for these drugs. But I think both as Jay and Dr. Haw said, I think it's really important that you set the right expectations. Who are going to benefit from these drugs. So if you're a severe presbyope, you might not get enough bang for the buck on this.

So it's really important that you target mild-to-moderate presbyopes that can really benefit from the drug and get the duration you want. But that in itself is an enormous opportunity in the country, we're estimating somewhere up to 40 million patients that would fit this category that also would be willing to pay cash out of pocket, right? So there's room for more than one product here. And as many people say, the tide raises all boats. I think this is going to be a category with several successful products in it. And so there's, as I mentioned, a very big market here.

And Jay, would you like to add something to it?

Well, from what I've seen just in my own clinical practice, I think people who are not used to needing glasses, either because they're born with great vision or they wore contact lenses or they had vision correction surgery, that's the group that feels just especially frustrated when presbyopia sits in because one day, they're seeing fine and the next, they're holding their phone or their menu at arm's length and they find out that their arms aren't long enough anymore. And -- because they're just not used to relying on glasses, the adjustment is just very unsettling. And I think it makes them very motivated, highly motivated to find nonsurgical alternatives.

Sure. And Dr. Haw, does this also align with what you're seeing in your clinical practice?

Yes, absolutely. I think there is an enormous opportunity here for kind of a noninvasive, easy kind of pharmacologic lifestyle drop that can reduce the patient's dependence on spectacles. I would probably say that in my practice when we see these patients with presbyopia, I would probably say that 1/3 of them at least are really hungry for that kind of option, something that person, that individual -- who's that individual that's never worn glasses for their entire life and all of a sudden hits 40 and just really just hates putting on his glass. They can't find them.

They're not keeping them. And it's just a really significant kind of lifestyle impediment, then I would probably say there was probably another 1/3 that are kind of on the opposite ends. My 80-year-old presbyopes worn glasses for their entire life and doesn't mind putting them on and just had them on every single day of the week with the bifocal or progressive.

And then -- and again, those are probably the older patients that tend to just have -- that's the way they've adapted over 50 years. And then I think I have a third in the middle who's kind of like if there was an opportunity that was simple, easy, they would take it, and -- but they're okay with where they are. But certainly, it was a simple, easy, safe option that was effective, and absolutely, that could be a patient population that could be converted towards using a drop like this. And at the end of the day, like I said, it's going to be about value.

It's going to be patients putting a drop in, seeing how it works and seeing if they feel like it's something that they want to continue. And as providers we can educate, we can get them that first medication. And samples, I think as -- as was being said, I think if the product works, this is a great opportunity to penetrate this population very quickly because if, again, if it works, they will go out and get their secondary refill.

But yes, so I think there's an enormous opportunity. I don't think it's been tainted too badly by the release of, let's say Vuity. I think there's still a lot of people even who have tried Vuity who are, again, willing to take the next step and the next generation product and give it a go.

Sure. And we discussed that these eye drops might be better for like the more mild-to-moderate segment. How does that like overlap with these younger versus older patients that you have in your practice?

Yes. So I think there's a few things. I think the mild-to-moderate presbyope are often kind of the ones that we think of -- because, again, you will get -- as time goes on, that presbyope gets more presbyopic, requires a stronger reading prescription. And that early kind of moderate presbyope is one that is new into presbyopia who, again, all of a sudden, they're in glasses, and it's quite a shock for them.

And versus kind of, again, that 80 severe presbyopes had many years to adapt. So I do agree that I think that, that early moderate presbyope who hasn't had time to adapt, who can remember just 6 months ago that they were without glasses and now they're in glasses and now their glasses are getting stronger every month. That's going to be a motivated patient who's going to be very willing to try something different to kind of reduce that.

So one more thing I would like to understand is like the status of the LENZ, right be, phakic, pseudophakic, emmetropic or non-emmetropic, like a lot of medical terms. So how do these categories impact the patient's ability or response to miotic eye drops?

So I think many of the clinical trials that have been run have actually been fairly diverse in the inclusion criteria, taking post-refractive people who -- and people who have never had LASIK, people who have phakic, never had cataract surgery and people who have had cataract surgery with a very diverse age group, 45 to 75 and sometimes even beyond.

And I would suspect that, again, because it's a miotic pupil response and that's the effect of the depth perception independent of the phakic status, I would imagine we would get and see some response. In terms of whether we get more or less, I mean, I think if you're phakic and you do have some crossover reaction on to the ciliary body, I mean there is probably a little bit of a myopic shift in those patients. But again, the predominant role of the people with miosis is should work independent of whether the patient has a lens in place or not.

Sure. And Jay and Henric, like any additional thoughts here? Henric, do you want to go?

Yes. No, I'll say just on the age side, we have patients up to 7, and our oldest patient was 79 years old. We had different severity of presbyopia. So age is not necessarily the criteria for whether you should use these drops or not.

I think the criteria is where -- what is your starting near vision, right? Will you get the benefit for you that's good enough that you're willing to pay for something like this. I think that's going to be a very important piece. And the sample -- we will have a 5-pack sample pack and patient -- the drug works after 30 minutes. They will know pretty quickly whether this is for them or not. So I think that's my comment.

Okay. And Jay, anything else you'd like to add?

Well, I believe that both for phakic and pseudophakic patients with -- who have monofocal lenses, I think the baseline refractive error does play a significant role in how well miotic drops work in patients with uncorrected distance vision, right? So they're not wearing glasses for distance or contacts for distance.

Because the drops are going to -- they tend to be more effective in emmetropes and in low myopes. They already have good functional distance vision, and they can gain meaningful improvement in near and intermediate vision from the increased depth of focus. But in contrast, hyperopes, they rely on that depth of focus, that added depth of focus just to see clearly or more clearly a distance -- so there's less remaining optical power to enhance the near or the intermediate vision.

So as a result, the benefit of miotic drops may be more limited in that group unless they were in contact lenses for distance. And these observations just based on my own clinical experience because in the clinical trials, a level playing field was created by requiring all visual testing to be performed through the full distance correction.

Sure. I mean we have discussed this physiological aspects, right? But there is another side, which is like, let's say, the price sensitivity. So eye drops are like -- will be generally more expensive than reading glasses, right? Vuity probably like priced around $80 per bottle. So Jay, what would you say is like the bar, right? How much is the cost sensitivity a barrier to adoption in this population?

Well, as we discussed, there are large segments of the presbyopic population who are very highly motivated to reduce their dependence on reading glasses. I mean there have been quality of life studies amongst presbyopes. They've shown that the average impact of presbyopia is comparable to that of arterial hypertension.

But in one striking study, presbyopic individuals were asked to first estimate their remaining lifespan and then how many years would they be willing to give up for a cure to presbyopia. And amazingly, some cohorts indicated they would trade 5% to 10% of their remaining life and just underscores how burdensome presbyopia can be for certain patients.

So -- and we see real-world evidence of this motivation, I mean, in the clinical setting. So for example, many patients are willing to pay between $40 and $69 out of pocket for an Optos ultra-widefield imaging to avoid onetime dilation or to use Ryzumvi. So that demonstrates there's a precedent to pay out of pocket even to avoid temporary blurred vision, right?

And as [ new miotic ] drops demonstrate long-lasting efficacy, enabling either convenient one time daily use or nighttime dosing with immediately onset upon wakening and potentially fewer side effects compared to earlier formulations, I think these advantages could significantly impact patient willingness to pay and help shape the demand elasticity over time. And so many presbyopes have told me their reading glasses are invariably in the other room. And so they're willing to pay for a drop that's durable.

Sure. So -- and Henric, I know that patients are meant to like pay out of pocket for these drugs, I mean, for the drop. So are there any insurance rebates or access programs available to offset the cost?

So there's no direct reimbursement like you see for regular glaucoma drugs or something like that because it's not deemed medically necessary, right? So -- but there is some ways you can -- we have the -- people have vision plans. That's a little bit clunky because that's a onetime coverage. So if you say it's $80, you have used your $500 on that. But it is covered. You could put it on your HSA and your FO -- FSA, sorry.

But I think Jay touched upon it. I mean we have done a lot of market research in very different types of sort of income levels, and there's a high sort of willingness to pay for something like this, right? And the $80 mark that we are talking about is not something that is that far-fetched for many people to get the benefit that these drugs could give them.

And do you have any plans for like sampling or free sampling for patients, doctors, all this?

Yes, we're going to sample heavily. We think that -- we think it's really important to sample because it gives the nurse a chance to educate the patient what to expect from the drug. And it obviously gives the patient a chance to try the product and feel the benefit before they pay for the product. So yes, we will be sampling heavily.

Sure. So maybe coming to you, Dr. Haw, like what we learned about the newer generation of presbyopia drops in terms of safety, efficacy and also like the price point that we discussed. What proportion of your patients do you think would opt for drops? I know you already mentioned that 1/3 of your subset, but taking also into account like the fact that it is more expensive than eye drops, do you still see the 1/3 of your patient base getting on these drops?

Yes. So I think when we look at kind of the ophthalmic industry, I think if we were to prescribe a medication that's covered well by the insurance on a generic. I mean the patient might be paying $30, $35 a month or so. And maybe the Tier 2 levels are around that $80 to $100 a month. With Qlosi, it's $79 for month 1, $99 for 2 months. And we've seen a lot of the -- even with Vuity, we saw a lot of the pricing structure that was heavily reliant on if you got refills, the subsequent costs would go down or there were kind of loyalty kind of discounts if you use so many, you got the nth one free, something to that effect that encourage kind of that refill, whether it's a discount or some other kind of variation of that.

When we look at kind of -- so I do think that kind of structure of the $70 a month around there is a very reasonable price point, particularly again for patients who are extremely motivated, that's not something that I think would dissuade a motivated patient from at least trying it. I think the sampling program is a good way really if the product works very well to really get it into the hands very quickly because often when we have those discussions with patient, it is that first drop that needs to be filled that they may or may not get and the sampling kind of takes that out of the equation.

With the patient population that I have, I would say, again, 1/3 is an easy population, the hungry people. But I still think there's another addressable patient population that is kind of that in between. And again, I would probably put that again as another 1/3 that, again, could be penetratable again, with the samples because, again, those patients may not want to go out and purchase that $70 first drop. But with the sample, absolutely, they're willing to try it and make their own decisions based on whether they want to get the refill.

And when these newer generation eye drops are available, do you think like patient would see ads online or liking on TV and come to you? Or like do you think that physicians proactively suggesting these drops? And I was also thinking how the cadence might look like in terms of like would you try it in first couple of patients and offer it to them and see how it goes? How would you prescribe?

Yes. So even with Vuity, when it was first launched, again, we were seeing patients who came to us with a specific request of, "Hey, I want to use this drop." I think the cadence generally dried up over the course of time, largely because there wasn't the momentum behind it as people begin to have experiences that again didn't kind of meet their expectations. So there -- I think the direct-to-consumer advertising can get you so far.

But I think, again, if your drug works, and if drug works really well, they talk to people. They talk to their friends and coworkers. And we do see people who come in requesting very specific kind of services solely based on conversations that they've had with friends, family members, co-workers who had a positive success with something. So I expect that with Qlosi, we haven't seen that. So again, I haven't seen people, specifically requesting that product, even though again approval available kind of -- and -- but I do expect that, again, there will be a certain momentum that I think starts to build and the awareness of these products will continue to obviously be more significant over the course of time.

Again, I still think, again, the value in terms of the patient's perception and how they feel it's working, we'll drive that forward because I think it's -- people talk. So I think that's -- we'll see it, I think, continue to improve. The more products that are in the space, particularly ones that work well, we will even see that go through faster in terms of the penetration?

That's very helpful. So in the last couple of minutes, Henric and Jay, please tell us what should investors be watching in the next couple of years in the presbyopia space? And how should we also think in terms of the launch trajectory for these products? So Henric, do you want to go first?

Yes. So first of all, we're raising capital. So that's one thing investors should look for. If they want to contact with us after this, please do. If you're listening to this, we are in actively about to close that out. That's number one. Number two, obviously, we are excited about the launch. Clearly, with the great commercial team we have, we can't wait to get out on the road.

And long term for us is to show sort of how we grow this market, right, showing that patients come in, they try the product, like it and then come back for refills. So -- and then eventually, investors should look for a Tenpoint IPO. That's something depending on how market looks, you never know what that looks like, but that's another exciting thing for the team.

So a lot of exciting things at Tenpoint, very excited team and really looking forward to launching this product. It's one of the most fun things you can do as a company to get a product over the finish line. There are so few that make it. We're not there yet, but getting the product over finish line and then launching it is one of the most exciting things you can do. So really looking forward to that.

Sure. And Jay?

Well, at Opus Genetics, we remain on track to submit an sNDA for presbyopia by the end of this year. And additionally, we're preparing to initiate the final Phase III trial for a second indication targeting keratorefractive patients who experienced reduced mesopic vision along with symptoms such as glare and halos and starbursts, and we also anticipate several key readouts across our inherited retinal disease programs in the coming months. So exciting times ahead.

Great. So a big thank you to all our panelists for this insightful discussion. And also thanks to our audience for your time. Hope you enjoyed the session. Thank you so much, and have a nice day.

Thank you very much.

Thank you.

Greetings, and welcome to the Opus Genetics Corporate Update Call.[Operator Instructions] Please note, this conference is being recorded.

I will now turn the conference over to your host, Jenny Kobin, Investor Relations. Ma'am, the floor is yours.

Good morning, and thank you for joining us today for a corporate update to highlight recent clinical milestones and upcoming catalysts for Opus Genetics.

Before we begin, I would like to remind you that during today's conference call, we will be making certain forward-looking statements. Various remarks that we may make during this call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our annual report on Form 10-K for the year ended December 31, 2024, our quarterly report on Form 10-Q for the quarter ended March 31, 2025, and our other SEC filings available on our website.

In addition, any forward-looking statements represent our views as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so even if our views change.

On the call today, we have Dr. George Magrath, Opus' Chief Executive Officer; Dr. Jay Pepose, Chief Medical Adviser; and Dr. Ben Yerxa, President. A replay of this call will be available on the Investors section of the Opus website at opusgtx.com.

I would now like to turn the call over to Dr. Magrath.

Thank you, Jenny, and thank you all for joining us this morning. For our call agenda, I will make the opening remarks about today's positive data announcement and how it fits into our overall corporate strategy. Then I will turn the call over to Dr. Jay Pepose, our Chief Medical Advisor, who will summarize the top line results from our VEGA-3 and LYNX-2 Phase III clinical trials. I will conclude our prepared remarks with a summary of our gene therapy programs and our many upcoming catalysts.

At Opus Genetics, our singular focus is on restoring vision for patients. We are developing gene therapies for inherited retinal diseases and small molecule treatments for other vision-threatening eye diseases. These include inherited genetic diseases, age-related conditions and complications from corneal refractive procedures such as LASIK. We believe we have a diversified and well-positioned pipeline with meaningful near-term catalysts.

Today, we are thrilled to share the positive top line results from our VEGA-3 Phase III program. Our latest program was Phentolamine Ophthalmic Solution 0.75%. Phentolamine was approved in September 2023 as the only commercially available FDA-approved product that reverses pharmacologically induced mydriasis, more commonly described as reversing dilation of the pupil in the eye. Phentolamine is being marketed by our global development and commercialization partner, Viatris, under the brand name Ryzumvi. Phentolamine is also being evaluated for the treatment of presbyopia and mesopic or dim light disturbances, which are related to trial results we will discuss today.

The positive Phase III trial results announced this month from VEGA-3 and LYNX-2 continue to demonstrate the potential for phentolamine to improve vision in multiple indications. I am pleased to report that both trials met their respective objectives. The studies achieved the primary endpoints with statistically significant outcomes, demonstrating rapid and sustained improvement for participants. Importantly, Phentolamine demonstrated a safety profile consistent with previous clinical trials and no treatment-related serious adverse events were reported. In both VEGA and LYNX trials, we also saw strong patient-reported outcomes. The VEGA-3 trial results reinforce our belief that phentolamine can offer once-a-day dosing to improve near vision for millions of adults affected by presbyopia, which is the progressive loss of the ability to focus on near objects that typically becomes noticeable in the early to mid-40s.

As the eye ages, the ability to focus decreases for reading and other near distance tasks cause the blurred vision and eye strain for many people. Presbyopia is one of the most prevalent ocular conditions and is estimated to impact 128 million Americans with over 2 billion people worldwide and this number is only expected to grow as patient population ages. Current solutions like reading glasses or surgical intervention are often inconvenient or invasive and we believe phentolamine may offer a differentiated option for individuals living with this condition. The positive results from both our Phase III VEGA-2 and VEGA-3 trials support the submission of an application to the FDA, which we plan to file in the second half of 2025.

We have a compelling innovative pipeline with significant potential commercial opportunities, and our small molecule phentolamine program is an important driver to our overall corporate mission. Through this program, we have demonstrated our ability to successfully advance assets through clinical development to regulatory approval.

Based on our co-development agreement with Viatris, we are eligible to receive up to $130 million upon achieving certain specified regulatory or net sales milestones. We received $10 million upon approval for Ryzumvi. We are also eligible to receive tiered royalties starting in the low double digits up to the low 20s in the United States and low double digits outside the U.S. based on certain sales metrics. We are pleased to partner with Viatris and continue to leverage their commercial expertise as these programs may deliver additional future upside for Opus' royalties and milestone payments providing non-dilutive funding to advance our pipeline.

Now I'd like to provide a brief introduction of our Chief Medical Advisor, Dr. Jay Pepose, and turn the call over to him to summarize our VEGA-3 and LYNX-2 results. Following Dr. Pepose's remarks, I will provide an update on our gene therapy programs and upcoming catalysts. Dr. Pepose is the founder and former Medical Director of Pepose Vision Institute. He's a Board-certified cornea and vision correction surgery specialist and served as Bernard Becker Professor of Ophthalmology at Washington University School of Medicine and Barnes-Jewish Hospital. As a pioneer in laser eye surgery to correct nearsightedness, farsightedness, and astigmatism, Dr. Pepose was among the first surgeons in the United States to conduct clinical trials for LASIK. Dr. Pepose earned both his MD and PhD from UCLA and completed his ophthalmology residency at the Wilmer Eye Institute at Johns Hopkins University, followed by specialty training at Georgetown University Medical Center.

Jay, thank you for being with us today. Please go ahead.

Thank you, George, and good morning, everyone. I'm excited to report our latest results for Phentolamine Ophthalmic Solution 0.75%. Phentolamine is a nonselective alpha-1 and alpha-2 adrenergic antagonists, designed to reduce pupil size. It is designed to work by uniquely blocking the alpha-1 receptors found on the muscle in the eye responsible for widening the pupil. This sympatholytic mechanism of action, avoids engaging decelerating muscle potentially reducing risks such as retinal tears or detachment associated with other agents.

Today, we announced positive top line results from our VEGA-3 trial which is the second pivotal Phase III trial, evaluating the safety and efficacy of phentolamine for the treatment of presbyopia. As George described, presbyopia is the progressive loss of ability to focus on close objects that results in blurred near and intermediate vision and eye strain. VEGA-3 was a multicenter, randomized, double-masked, placebo-controlled Phase III study that enrolled 545 patients across 40 sites in the United States. Subjects were randomized in the 3 to 2 ratio to receive either phentolamine or placebo administered once daily in the evening.

The VEGA-3 trial met its primary endpoint with a statistically significant 27.2% of participants treated with phentolamine, achieving a 15 or greater letter improvement and binocular distance-corrected near visual acuity with less than a 5-letter loss in binocular best-corrected distance visual acuity at 12 hours post dose on day 8. This compared to 11.5% of participants on placebo thereby demonstrating a strongly significant p-value of less than 0.0001.

In addition, there were several other positive outcomes. First, 20.6% of participants in the Phentolamine arm achieved a 15 or greater letter gain in distance-corrected near visual acuity at 1 hour post dose on day 1, compared to 6.1% of those receiving placebo, with a p-value equal to 0.0002. Second, significant patient reported functional benefit at days 3 and 8 and week 6 was observed with patients reporting satisfaction with near vision upon awakening and improvement in their near vision. Both with p-values of less than 0.0001. Third, there was no evidence of tachyphylaxis observed after 6 weeks compared to the primary endpoint at day 8, 12 hours post dose.

This means that phentolamine has shown that it can maintain the response after successive doses of the drug after -- over 6 weeks. And finally, regarding safety. Phentolamine demonstrated a safety profile consistent with previous trials with no new safety signal identified and no treatment-related serious adverse events recorded in this study. The most common treatment-emergent events -- adverse events, at 5% or greater included conjunctival hyperemia or redness, instillation site irritation and dysgeusia or a metallic taste, all of which were predominantly mild. There was a very low rate of headache reported by 2.6% of participants over the study period.

For the study protocol, VEGA-3 participants will continue to be monitored for long-term safety over 48 weeks, which will be part of the overall long-term safety data package required by the FDA.

I'd also like to highlight the recently announced positive top line results from our LYNX-2 trial for the treatment of decreased vision under mesopic or low light conditions following keratorefractive surgery. The LYNX-2 trial achieved its primary endpoint and built on earlier results from LYNX-1, providing evidence for efficacy in keratorefractive patients experiencing glare, halos and reduced functional vision in dim light environments. As we announced in February, the FDA granted fast track designation for phentolamine as a treatment for significant chronic night driving impairment in keratorefractive patients with reduced mesopic vision. This is a condition which currently has no FDA-approved therapies and is addressing an unmet need. We look forward to initiating our next Phase III trial known as LYNX-3 later this year.

LYNX-2 was a randomized, double-masked, placebo-controlled Phase III trial evaluating the safety and efficacy of phentolamine in 199 participants who have previously undergone keratorefractive surgery and reported decreased visual acuity under mesopic low contrast conditions. Participants were randomized to receive either phentolamine or placebo, self-administered in both eyes nightly, treated and observed over 6 weeks. LYNX-2 was conducted under a special protocol assessment with the FDA. The LYNX-2 trial met its primary endpoint with a 15 or greater letter gain for phentolamine and keratorefractive participants in mesopic, low contrast distance visual acuity or MLCVA.

In this study, 17.3% of participants in the phentolamine arm achieved greater or equal to 15 letter gain in mesopic, low contrast visual acuity at day 15 compared to 9.2% of those receiving placebo. This was statistically significant with a p-value of less than 0.05. During the course of the study, participants were assessed by the validated vision and night driving questionnaire, a self-reported questionnaire. The patient-reported outcomes at day 15 were also statistically significant for phentolamine with a p-value of less than 0.05, reporting less difficulty seeing the road because of oncoming headlights and less difficulty seeing due to glare when driving at dawn or dusk.

In addition, there was no evidence of tachyphylaxis after 6 weeks of nightly dosing. And phentolamine demonstrated a safety profile consistent with previous trials with no new safety signal identified. For the study protocol, LYNX-2 participants will continue to be monitored for long-term safety over 48 weeks.

In closing, I would like to say that over decades of my career as a physician who's treated patients with presbyopia, dim light disturbances and post-LASIK surgery outcomes, I am truly excited about the potential for phentolamine to make a meaningful difference in the lives of patients living with these conditions.

I will now turn the call back over to George to walk through the company's progress on its gene therapy programs and review upcoming catalysts.

Thank you, Jay. The recent successes in the VEGA-3 and LYNX-2 trials underscore the potential versatility of phentolamine, which is already FDA approved for reversal of pharmacologically induced mydriasis and now has positive Phase III data in presbyopia and dim light disturbances, large markets with high unmet needs. These achievements strengthen our pipeline and position Opus as a leader in developing ophthalmic therapies. In addition to our small molecule program, we are leveraging our expertise in developing innovative gene therapies to address rare inherited retinal diseases or IRDs. With more than 350 genes associated with retinal degenerative diseases, our strategy is to use our patented modern AAV vector approach to advance a series of programs targeting various genetic defects.

We believe this could lead to consecutive approved products rolling out over the next 5-plus years. Specifically, our gene therapy programs are focused on developing and advancing treatments to address mutations and genes that cause a loss of vision. We are utilizing a validated patented approach of delivering a onetime treatment to address these rare conditions. Our approach is based on many years of clinical research by our Scientific Advisor and Board of Directors, Dr. Jean Bennett, who was the pioneering force that led to the first U.S. FDA-approved gene therapy, Luxturna for an inherited RPE65 mutation-associated retinal dystrophy.

In the near term, we are targeting diseases including Leber congenital amaurosis, bestrophinopathy and retinitis pigmentosa. These conditions affect thousands of patients worldwide. We will continue to leverage this approach in effect in NGEN-2 efficiently solve for many inherited blinding conditions and expand our pipeline to address additional genetic targets across the IRD spectrum. I'm pleased to report that earlier this week, we announced that the retinal degeneration fund of visual philanthropy arm of the Foundation Fighting Blindness is providing non-dilutive funding to support the advancement of our OPGx MERTK program. Mutations in the MERTK gene cause the Rod-Cone Dystrophy with early macular atrophy with retinitis pigmentosa being the most common genotype. This funding supports our advancement of OPGx MERTK through preclinical development towards investigational new drug-enabling studies.

Looking forward, we have a number of key near-term catalysts coming up. First, in our OPGxLCA5 program, we expect to report initial data in the third quarter of 2025 from our pediatric cohort of patients in our ongoing Phase I/II trial for the treatment of LCA. OPGxLCA5 is targeting mutations in the LCA5 gene, which causes an early onset severe hereditary retinal degeneration. Early results have been encouraging, and we are optimistic about the potential to address this ultra-rare vision-driven condition.

Importantly, the FDA recently granted the Regenerative Medicine Advanced Therapy designation to OPGxLCA5 based on the early data from the first 3 participants treated. The RMAT designation program offers the potential for expedited development and review of regenerative medicine therapies that demonstrate the potential to address serious or life-threatening diseases based on preliminary clinical evidence. The designation provides sponsors with early interactions with the FDA guidance on efficient development and manufacturing, and the opportunity to discuss surrogate endpoints to support accelerated approval.

In our OPGx-BEST1 program, we plan to file an investigational new drug application with the FDA and begin a Phase I/II trial this year. This promising gene therapy asset is being developed for treatment of IRDs associated with mutations in bestrophin, the BEST1 gene, which affects approximately 9,000 individuals in the U.S. Beyond these programs, we are progressing preclinical work on additional AAV-based gene therapy targeting IRDs caused by mutations in RHO, RDH12, MAT1 and CNGB1.

For our phentolamine projects, we are coordinating with Viatris on plans for upcoming regulatory submissions for presbyopia in the second half of 2025 and the initiation of LYNX-3 trial later this year. With our recent funding investment from the RD Fund and several leading health care investors, we believe our cash position will be sufficient to fund operations into the second half of 2026 based on current projections.

In summary, these near-term catalysts, combined with the recent clinical successes position Opus for significant growth. The first half of 2025 has been incredibly productive and I want to recognize and thank our team, our stockholders, the clinical investigators and the many patients who have contributed to these achievements. We remain committed to developing innovative therapies for vision-threatening diseases.

We will now open the call for questions.

[Operator Instructions] Our first question is coming from Matthew Caufield with H.C. Wainwright.

Thank you, Dr. Pepose for the positive update. It was mentioned that the therapy can avoid effects on the ciliary muscle, and I was wondering for the 2.6% rate of headache, does that imply that there is any effect on the ciliary muscle or what could be driving the observed low incidence of headache? Thanks for any clarification there. And then I just had one follow-up, if that's possible.

Well, thank you for that question. I mean, the mechanism of action really is distinct for phentolamine in that we're not engaging the ciliary muscle. And we think that, that may be playing a role in the low prevalence of headache in the trial. So we do think that, that finding is consistent with the mechanism of action.

Okay. That's great. I appreciate the clarification there. And then in addition to that component, are there any other important highlights about the phentolamine mechanism in the context of pilocarpine or the other novel mechanisms that are currently in development?

Well, as mentioned, phentolamine has a distinct mechanism of action and that it's working uniquely by blocking the alpha-1 receptors found on the radial iris dilator muscle, which are activated by the alpha-1 adrenergic receptors. It's really reducing the pupil diameter with a sympatholytic mechanism of action and that may potentially reduce risks such as retinal tears or detachment associated with some of the other genetic therapies.

Our next question is coming from Debanjana Chatterjee with Jones Trading.

Congrats on the positive data. I was -- would you be able to give us a little more color on the competitive positioning that you are expecting for the therapy? And I had 1 other follow-up.

Yes. Thanks, Deb. So we think that this is a -- may offer a great option for patients. And we're working with our -- with Viatris and the commercialization team there for how it truly defined the position.

Okay. And so I was also curious to trials behind. So as we have seen with some of the competitor data set, there is a more of a time course that you shared like with onset at 30 minutes and then different time points at 3 hours and then, of course, the durability endpoint. Could you maybe explain a little bit more about the rationale for design of directly looking at 12 hours and at 1 hours? Or will you be sharing any additional data for other time points at the future medical conference?

Yes, good question, Deb. That is really important, and we're going to -- we will be sharing that in upcoming medical conference and we'll make sure that, that gets widely disseminated at the time.

Okay. And maybe 1 final thing. Now that you might receive a potential label expansion into a larger indication. Does that expectations for pricing?

I'm sorry, I missed your question, Deb. Do you mind repeating it?

I meant now that you might have potential label expansion for Ryzumvi in larger indications. Does that change anything in terms of pricing expectations compared to reversal of mydriasis?

Yes, yes. So that will be the responsibility of the Viatris. But certainly, the chronic indications that we're talking about today would be differentiated from the onetime use Ryzumvi product that's out there now.

[Operator Instructions] Our next question is coming from Dev Prasad with Lucid Capital Markets.

Congrats on the progress. I have one regulatory question. With both VEGA-2, VEGA-3 yielding positive results. What are the next step ahead regarding the filing the sNDA in the second half? Basically, additionally, do you expect any potential delay at the sNDA, given so much uncertainty going on?

Yes. Dev, that's a great question, and we're sort of always tracking that. To date, we have not seen any delays at the agency. And we certainly hope that continues. For the VEGA program for presbyopia, we are on track, and we expect to file the sNDA in the second half of 2025. And then we also are expecting to initiate LYNX-3 for the dim light disturbance, which should hopefully be the last study for the LYNX program.

As we have no further questions on the line at this time, I would like to hand the call back over to Dr. Magrath for any closing comments.

Thank you all for your time and attention this morning. We look forward to updating you on our progress as we continue to advance our pipeline focused on innovative therapies for vision-threatening diseases. Operator, you may now disconnect.

Ladies and gentlemen, this concludes today's conference. You may disconnect your lines at this time, and we thank you for your participation.