Presenting for the company today is Dr. Shankar Musunuri, the CEO. Welcome, Dr. Musunuri. Thank you, Robert. Thank you for having me today. Okay. Well, the first question to open up with is, you recently presented some data on OCU410, a product in development for geographic atrophy. This is a lesion in advanced dry age-related macular degeneration. Could we begin by comparing the dry form of AMD with the wet form and mention things such as the incidence, the patient population, and the market values? Yeah. Absolutely. I mean, the wet AMD, there are multiple drugs that are anti-VEGF. I think, obviously, people when they see the TV, they see the ads too. The drugs have been there. That market size is $10 billion-$20 billion. That's established, there are a lot of new therapies coming up, that's only 10% of entire AMD. Age-related macular degeneration, 90% of the patients out of the more than 200 million globally struggle with, 90% of the population has dry age-related macular degeneration, where currently there are some therapies exist in U.S. They're not optimal, but there are nothing outside of U.S. for these patients. That's a large population. The late stage of the dry AMD is known as geographic atrophy, where you have the central blurriness in the vision if you are 55 or 65, and that's we call it a lesion. That blurriness grows, and so the life becomes debilitating for these patients. Okay. You mentioned that 10% of the age-related macular degeneration population is the wet form and the 90% is the dry form that you're developing OCU410 for. In terms of the mechanisms of action of your drug, how does it work and how does it differ from some of the existing drugs that are out there? Yeah. Good question. When you take something like GA, geographic atrophy, there are four complex pathways which cause the disease progression: oxidative stress, lipid metabolism, inflammation, and complement system. The two drugs which are targeting today approved in U.S. are targeting complement system. It's really if you don't focus on all four pathways, including the major one is oxidative stress and lipid metabolism, where you form the drusen, and so that's really important. It's good. The current targeted therapies, even the new ones, which may be in the clinical trials, most of them focus on complement system. You know how those drugs are today, and we have the data. What we do differently, our modifier gene, RORA, which is delivered through AAV, it regulates all these four complex pathways and also create cellular homeostasis and creates a healthy environment for retinal cells to survive, including photoreceptors and RPE cells. Why that's important? That's important because, Our retinal cells are non-dividing cells, right? If I can do something to reset them and create a healthy environment, potentially they should survive rest of your life. Our treatment compared to those therapies, those therapies currently which are on the market in U.S., and they're not approved in Europe, they have to be given every month or every other month. If you're elderly, 75 years old, somebody has to take you for those. They are seeing about 22% reduction in the lesion growth in two years. In our phase II, the data we released showed 31% in one year. Wow. Big difference. You have a greater effect in half the time. Yes. Our therapy is one and done, potentially. You give one injection in the back of the retina, it's subretinal delivery, and you're done for life. One treatment for life. A single injection compared with a schedule of regular visits. Yes, of six total injections per year. Number two, so far our therapy has been safe in the clinical trials. No severe adverse events related to the drug or our gene therapy. If you look at the data we released, certain% of the patients, about 20%, in that optimal dose we're going to take it to phase III, they didn't show any increase in the lesion growth. Wow. The lesion growth almost stopped. That's it. You're asking how it's differentiated. Complex pathways, creating a cellular homeostasis, and creating healthy environments survive, and those are the modalities, with our modified gene therapy, that's possible. It's not possible with some other modalities and targets going after one pathway. What does it mean? What does it mean is the patients, as I mentioned to you, some of these patients are kind of stabilized in the sense their lesion is not growing. It's very difficult to show with some other modalities that kind of an effect. That's important. Also, it's one and done. This could become a potentially new standard of care, gold standard for all the patients across the globe. Yeah. That sounds really interesting. Single injection, that makes it fit with practice and something that can be leveraged across multiple markets. That's another factor that weighs in its favor. Where is it in clinical development right now? Currently, based on the promising data, we're designed for the first time. Many companies did trials in U.S., trials in Europe separately, or they're doing it. I think what we did, we created a global trial, about 300 patients. We don't need that based on the effect size. For safety reasons now, we designed a very robust trial design for phase III, with good endpoints. Primary endpoint stays as a lesion. In the secondary, we are considering ellipsoid zone, which is a correlate of visual function, and we may monitor some other endpoints like LLVA and others. Once again, our clinical trial is only one year. Expecting changes in the visual activity based on disease progression is not too practical, but we'll monitor them. That's why we are using ellipsoid zone, which is a correlate of visual function, and we already showed in our phase II, we showed a 27% reduction or preservation of ellipsoid zone compared to control group. Our clinical trial design, we're working with FDA, EMA, single trial, and we are anticipating alignment with both the agencies in the next few weeks. After we get the alignment, we're going to file the IND amendment in U.S. and initiate the trial by third quarter this year. Following that, we'll initiate some work in Europe too. The idea is this is going to be a trial for a global single trial, not two trials, single trial, very robust. We are looking at almost a primary endpoint power of 95% or more. I mean, highly powered. We're also including an adaptive design where halfway through when 50% of the patients complete, any time you can take a look under DMC strict guidance, it's always a good thing, right. You have any reason to believe you need some adjustment or de-risk further, you can do that. This in a nutshell, I just want to summarize. A single trial, about 300 patients or less, with a high power for a primary endpoint lesion reduction compared to control arm. It's a 2 to 1 ratio. That means if it's 300 patients, 200 will go under treatment group, 100 on the untreated group. The optimal dose we picked is going into phase III from phase II. It's a one-year trial. Okay. Just one thing about the endpoints. You mentioned the ellipsoid zone, and that would be a cellular marker and something that shows anatomical survival of the cells themselves. Then what sounded like a functional marker to show that these cells are actually doing something and that the patients are actually benefiting. Is that correct? Absolutely right. If you do a two or three-year trial, you can directly measure some visual function measures. Here, what we are trying to do is do what the product got approved with, which is practical and reasonable, even though it's a structural anatomical marker, like lesion growth, because that's practical in one year. If you do two-year trials, you have more options. Also, ellipsoid zone, we can see those changes, which correlates to visual function. In addition, we'll still monitor some visual function in a low luminance visual acuity and see if we see any trends. We'll monitor those. At least by the time we submit the BLA, obviously we'll have at least two to three years of data from our phase II. That phase II data should reflect more of those direct measures from visual function, like LLVA or BCVA. We're going to look at those markers. That additional data will be provided. Yes. You provided some of that data with the phase II. Yeah. It was able to show that the cells are surviving. Yeah. Supports the idea that the function is improving. You have one that supports the other and gives a basis for the conclusion. Yeah. Yeah, that sounds like a very robust trial. In terms of the OCU410ST, that's in development for Stargardt disease. Yes. Which is an orphan indication that people might not be very familiar with. Can you give a little bit of background on what the disease is, who gets it, and a little bit about it? Yeah. Stargardt disease is a debilitating disease. Currently, no approved treatment for these patients across the globe. It's really debilitating. Why? Because it starts the central vision, just like GA, and the pathways are similar for degeneration. It's an inherited retinal disease. If your family has it, you may get it from birth. Unfortunately, this is a fast decaying disease. In some cases, it's a very large gene. It has potentially 1,200 mutations. Some of these patients at very young age can become legally blind with this disease. That's why we do have a Rare Pediatric Disease Designation from FDA for this, for Stargardt program, OCU410ST. Currently, there are about 100,000 patients in U.S. and EU alone together. There are many number of patients across the globe, and they're all desperately waiting for rescue, from becoming blind. That we are the first company with a novel modifier gene therapy program. We are in the phase III. That phase III, we completed recruitment in record time. We announced it early part of this year, and we're anticipating a outcome analysis based on the adaptive design sometime in the third quarter under strict guidance of Data Monitoring Committee. What it means is, again, as I mentioned before, just like GA, that allows you to take a look in the sense, in a strict guidance of DMC, and see if your predictive analytics show you're going to hit it in 12 months, you don't need any changes. It's a good sign. If they need to increase the size to further reduce any risk to the program, that's great opportunity, right? During the phase III, if we can adjust. Those are the outcomes we'll share with the market after vetting with FDA and getting that buy-in. That milestone is coming up in third quarter. If everything goes according to plan, we should have top-line results in the second quarter of next year. That's 2027. Few months later, we'll try to file the BLA, followed by market authorization in Europe because Europe has agreed the single trial we're doing in U.S. is robust. They agreed with the trial for approval in EU. Great. Okay. In terms of the markets and introduction, you would expect that in 2027 as well? I think, practically by the time we file it, like mid-2027, even though it has Orphan designation in the U.S., that should give us accelerated approval of six months. I would consider 2028 early potentially approved and launch. Okay. Whereas, yeah. All right. The most advanced trial that you're working on is with OCU400 in retinitis pigmentosa. Could you just talk a little bit about how OCU400 can work on a disease with over 100 possible mutations? Yes. The OCU400 targets retinitis pigmentosa. Retinitis pigmentosa is another inherited retinal disease that can be caused by defects in over 100 genes. The first gene therapy ever got approved, LUXTURNA, 2017, targets one mutation out of the 100+ genes. That's a very small population, maybe a 1%-2% of 300,000 patients in U.S. and E.U. The prevalence rates outside of U.S. and E.U. could be much larger. Recently, we got a publication from Turkey, that showed enormous numbers, almost like 8%-10% of Turkish population has it based on that. I think, again, these prevalence rates in U.S. and E.U. are probably more closer to accuracy based on the diagnosis. Other parts of the world, as the diagnosis improve, maybe they're large numbers. The complexity of the disease is, if you take the traditional gene therapy, which got approved, right, in 2017. Yeah. You need more than 100 products. It's almost impossible to develop for the entire population, right? It means you need more than 100 products to treat entire RP population. Whereas our gene therapy, the modifier or master regulator, one product is good enough. I'll explain why. Genes don't work in isolation. They work as a network. When you have inherited retinal disease, it's there from the birth, right? Depending on what genetic type and what mutation you have, they have a different course of the disease progression. When you have any dysfunctioning gene, it's there from birth. That dysfunctioning gene produces dysfunctioning protein that may have toxic effects on the network of key function factors. What we found out, the key transcription factor responsible for key functions such as inflammation, cell development, metabolism, to cell survival, they're depressed. The missing link we found is NR2E3 for RP. When you upregulate this whole network of genes responsible for key functions, they get upregulated, resets the homeostasis, and creates a healthy environment for these cells to survive. Since the retinal cells are non-dividing cells, what you have is what you have. If there is anything we can do to reset them, I think like re-energizing and recreating environment. Yeah For healthy survival, potentially they survive for rest of your life. Because of that, if you use a traditional gene therapy, why more than 15 companies tried to develop different therapies, parts of the RP, taking like a high prevalence ones, including XLRP, one of the companies had the negative results last year. Because people assume when you give it at any point, it should work. Yeah, theoretically, it should. You give a functioning gene, you got a defective gene, but you are not removing defective gene. It's still there. The ill effects are still there. Whatever network effect you did, whatever degeneration you caused on the cell death, whatever you caused it, inactivating those photoreceptors, they're still there. You cannot unwind it. However, by using a modifier gene therapy approach, we're able to show not only decrease in the progression in patients, some of the patients showed stabilization, many of them. Some of them, it's actually reversing the disease. You know, when you lose some peripheral vision, it's coming back, right? The central vision is improving. They can see much clearly. These are amazing things we are seeing it in patients. That's the difference. I think, number one, traditional gene therapy is transformative. However, depending on when you give it'll have the impact. You really have to understand genes as a network, not a single gene. If you do that, your results will vary, you'll be disappointed. Whereas we actually focus on the entire network using our modifier master regulators. That's a big difference. We can go after the entire disease. That's why our clinical trial has 140 patients. It's the largest genetic medicine clinical trial to date in the world. 140 patients. We included about 25 genetic mutations in the trial. Nobody has done that. That includes. Yeah All the major types like XLRP, PDE6B, rhodopsin, Usher, you name it. If we say that has 3% or 4% of RP prevalence, we have it in the clinical trial. We took a good representation. It's a very robust trial. Our goal is to get a broad RP indication. That's what our clinical trial are. Inclusion criteria is early to advanced, pediatric to adult. Yeah. We want to be a syndromic, non-syndromic, including, we do have a expanded access program ongoing, which is on the side, when some patients are not qualified for the clinical trial or they don't want to wait for two years, they're desperate, they're becoming legally blind and they really want to get a rescue, we have an option for them. We created. In that also, we have a very broad range of patients getting enrolled in that, with various mutations and syndromic, non-syndromic. Some of the RP types you may not be able to genetically diagnose. What we want is a broad label. If you're clinically diagnosed, you should be able to use it. There's nothing for these patients. In summing it up, we are targeting a broad RP, early to advanced stage, pediatric to adult, encompassing all genes, defective genes which can cause RP. That's our goal. Yes. I think you've used the term mutation agnostic. Yes To apply to all forms of RP. Yeah Regardless of the exact mutations. That's right. Gene agnostic. What stage of development are you at right now with the product? We are currently in the middle of the phase III. We have completed recruitment, as I stated, 140 patients, largest genetic medicine trial this year. We're anticipating top-line results in the first quarter of next year. We do have Regenerative Medicine Advanced Therapy designation from FDA. EMA agreed with our, aligned with our clinical trial design. We don't need any new trials. Same data can be used in EMA for approval, filing the market authorization. Also under RMAT designation in U.S., we are eligible to initiate rolling submission. Sometime in third quarter, we'll initiate that. That means this year we can submit non-clinical, as well as CMC sections, modules. As soon as the clinical data comes out, we'll drop that in a few weeks next year. That'll start the beautiful clock of six months accelerated approval. We're anticipating approval in the fourth quarter of next year if everything goes according to our plan. Yeah. Those sound like significant milestones with rolling approval so that you don't have that big gap in between phase, between the final results and the time needed to compile the application. You can just finish it right away and get the clock going. Yeah, that's right. That's terrific. How have the results thus far been, and what have the patients said about the therapy? Yeah, the results so far, I think phase III results were promising. That's why we got into this robust phase III clinical trial. Obviously, some of the patients from phase I, II, they continue to improve. There are some testimonials. Obviously you can see it. What is amazing is some of these patients, year 2 to year 3, they're seeing more improvements. Also, one of the key endpoints, because we had to monitor all our gene therapy patients for 5 years for safety on annual visits. Obviously, if you look at evaluable subjects at the end of 3 years from phase I, II, there were 10 subjects, they all showed either stabilization or improvement. Using Low Luminance Visual Acuity, which is very good measure for these patients because they lose their peripheral vision and night vision first, then they'll have central vision. LLVA is more accurate measure. If you see the data we actually publicly shared, at the end of three years, the LLVA measure looks good. There is a one to two line, close to about two-line improvement, which is like 10 letters compared to untreated eyes, which is really good. Yeah, that's a significant improvement. Yeah. It's consistently showed at one year, two year, three year. That really demonstrates the durability of the therapy. Of course, if you take some individual patients and they're improving year-over-year, which is a good sign. Yeah. You've shown photographs that show the change in visual field for a patient from advanced disease and after the therapy, or from the other way, the loss of vision. In all three programs, what you're doing preserves vision and not only helps the patient see better but reduces their dependence on custodial care, which is a subtle point, but I think it underscores the value of what you're doing in preserving vision. Yeah, absolutely, Robert. I think some of our patients, if you see them, they must have an RP case or Stargardt, various cases. They get used to what they lost, right? They're still functioning. What they're looking for is a hope. Can I hang on to what I have? At least maybe I'm semi-dependent. Maybe I'm not that dependent. I'm managing myself. I lost my peripheral vision or night vision. I have the good central vision. At least I'm managing myself. Can I hang on to it? Yeah. From the patient perspective, you put yourself in their shoes, not only if they're hanging on to it, they're getting something back, that's phenomenal. Yeah. When you see these patient, it really touches our heart. It's amazing. That's what we do for these patients. Our employees get very excited meeting them, and all the hard work, everything, that's what we do, protecting these patients from vision loss. Yeah. Rescuing them basically from these debilitating diseases. Some of the testimonials that I've seen on the website and at the investor days have been very inspiring. Just listening to these patients after they get some of their vision back is just really gratifying. It was something that I wasn't expecting. I thought most products slow progression of disease but don't actually reverse it. You're actually saving cells from dying and restoring cells that have lost some function, which is a big difference between them. Yes. Yeah. It's very rewarding for patients. It's really gratifying for us. Yeah. I can see why. Just in the little time we have left, could you just sum up some of the milestones going forward for each of the programs? You mentioned some things in the third quarter. Yeah Some data expected over the next year. Absolutely. This year, third quarter is big. We're talking to on taking the big program, geographic atrophy. We're working with FDA and EMA. We're hopeful we'll get a very good alignment for a global trial, first time any company doing this, with a very robust clinical trial design and robust endpoints. We're already in June, in the next few weeks, we're ready to initiate the phase III clinical trial in third quarter this year, as we've planned. Second program, OCU410ST. In third quarter, we have the outcome analysis, we'll share that with the market as soon as we're done, internal and also aligned with FDA on that. What the outcome will tell, everything based on predictive analytics going fine, there's no change. Still get the top-line data. If there is any adjustment needed, there may be some impact on the timeline. Still it's good. We are reducing the risk. The third one, which is actually the most late-stage program, RP, we're going to initiate rolling submission this year in third quarter. What does it mean in the next two years? The RP and Stargardt disease programs will complete BLA filings next year. That means late next year, you start potentially getting approvals for RP, OCU400, and late next year, early 2028, OCU410ST. The clinical trial for GA will complete in 2028. We'll file the BLA. Followed by that, we'll file MAA. The important thing to note, again, by 2027 and 2028, we'll have three BLAs as Ocugen. Three BLAs in three years. Three years. That's substantial. Also, we're not just focusing on BLAs. We're in parallel working with EMA. As soon as the BLAs are filed, within months, we'll have the market authorizations filed. In parallel, we're also developing a strategy for Japan behind the scenes. That's Ocugen. Okay, great. Well, that's a lot to look forward to. I'm looking forward to following those milestones and keeping in touch with the company. Thank you, Robert. Thank you very much. Pleasure speaking with you. Same here. Thank you.