Ocugen, Inc. (OCGN) Earnings Call Transcript & Summary

Good morning. Thank you for coming to Ocugen Clinical Showcase. As all of you know, we're a biotech company focused on gene and cell therapies, targeting unmet medical needs, vaccines for public health. Our goal is not only take these game-changing technologies to the market, work even harder to make sure we provide global access to patients who need them. In today's agenda for the meeting today, after my talk, our CSO, Dr. Arun Upadhyay, is going to go through our gene therapy platform and provide you clinical update, including upcoming Phase III. And then Mike Shine, our Head of Commercial, is going to give an update on market potential for these gene therapies global -- focusing on mostly U.S. and EU. And then we'll have a break. Before the break, we'll have a Q&A session. So after presentation, all presenters are going to sit on the stage, then you can ask any questions. We'll have 10 minutes for that, and then we'll have a break. And then we'll have the panel. I'm very excited to -- it's going to be moderated by Dr. Swayampakula Ramakanth, we call him RK, Managing Director of Equity Research at H.C. Wainwright. And we got an incredible panel. I'm very excited about it. Dr. Lejla, she's from Duke, she's going to chair our SAB. Then Dr. Lam, who is a Professor of Ophthalmology. Actually, he treated, at the start of this program today, the patient, Mr. [ Manny ]. He'll be on the stage with the Dr. Neena Haider, our inventor of our modifier gene therapies. So you're going to see how she developed it, how the patient got treated and the patient experience. You're going to see the whole thing today with a couple of key experts in the room. And so what is Ocugen? We're really making an impact through courageous innovation. We've been around for a little more than 10 years, started in 2013, headquartered in Malvern, Pennsylvania. We got around 60 employees. I think we're very efficiently managed. Companies of our size with multiple 3-gene therapies in the clinic, typically, they have a lot more employees, very efficiently managed. Kudos to our team, they work very hard. We also opened an R&D center in India to efficiently manage our operations and clinical programs. And we do have 4 values, we try to walk the walk: respect, integrity, teamwork and accountability. So now coming to where we are with the programs. We have 3 first-in-class platform technology, starting with gene therapies. Today's focus is going to be on our gene therapies, but I'll briefly talk about other programs before I get into gene therapies. We do have innovative inhalation platform technology for vaccines targeting COVID and flu. Last year, NIAID picked us as one of the few next-gen companies to participate in collaboration with them, and they're going to do the clinical studies, early stage for our COVID program this year. And the next one is regenerative cell therapies and other first-in-class platform technologies for cartilage repairs. We got RMAT designation for that. And we have recently completed construction of facilities because it is autologous cell therapy, it's personalized medicine. Very exited about it, it's first of its kind, first-in-class. And again, that's gearing towards Phase III. We got everything ready to go. And coming back to gene therapies, the focus of today's program. So we're so exited about it. Thanks to Neena. That's our life research, got into -- we licensed these gene therapies many years ago, worked extremely hard. And now we have 3 programs in the clinic, starting with OCU400, which is going to be in Phase III very shortly. Arun is going to take you through that. FDA also gave us regenerative medicine advanced therapy designation that will allow us to frequently interact with FDA and allow us to accelerate the development and approval process. And the most important thing is we're the first company, I'm very proud to say, to take this program in gene therapy space for a broad RP indication. And thanks to FDA for allowing us to do that. So as soon as FDA clears our IND, we're going to initiate dosing patients, hoping to dose them in March, April this year, in the next 2 months. And then OCU410 focuses on dry age-related macular degeneration, big disease burden. The late-stage GA has 1 million patients in the U.S. The current therapies, they require 6 to 12 injections. Again, they do have significant adverse events in some cases, getting neovascularization. So we believe this contain the paradigm how you treat patients, something which is not only going after a few thousand patients. So far, gene therapies, the best gene therapy target is around 6,000 patients. Now coming to RP, we are targeting like 100,000 to 200,000 between U.S. and EU together. And coming to GA, you're talking about 3 million, actually. From U.S. and EU, 1 million in U.S., 2 million in EU. It's about 3 million patients that we're going to target. That's a big paradigm shift, how you're going to treat this. Also, there is a program, Stargardt disease, it's a big unmet medical need. More than 40,000 patients in U.S. struggle with it today. And we're also doing the Phase I/II. And the goal is this year, we're going to initiate the Phase III clinical trial, continue to provide updates on that. And then Phase I/II, GA is ongoing, and same thing for Stargardt disease. And we're hoping, by the end of the year, we'll be able to see some signal in Phase I/II trial, and we'll probably update the market. And so for the last few years, all the hard work, we released many updates to the market last year, starting with the alignment with FDA at the end of last year moving into Phase III for broad RP indication. We initiated dosing in OCU410 geographic atrophy patients. We also initiated dosing Phase I/II in Stargardt patients last year. Those are great achievements on gene therapies. And this year, we have many, many milestones coming up. Our goal is not only initiate the program and work even harder to recruit appropriate number of patients into the clinical trial, so that our key goal is to make these therapies available to patients sooner than later. So our target BLA approval is 2026. So we're going to really work hard to complete the recruitment and complete the clinical trial very efficiently so that this product can be available for patients who are desperately seeking rescue. The next one is OCU410 and 410ST. And both those programs, we're going to recruit -- complete the dose escalation and initiate Phase II and try to recruit the patients in the Phase II, also provide updates to the market by the end of this year. We believe Phase I/II itself will be able to see the signal. And one of the -- another thing, as a growing pharma company and biotech, we do need support from big pharma. Even though some of us came from big pharma, we don't have infrastructure for commercial and payers network. And it's really important while we are doing Phase III for OCU400 for RP, we partner with potentially big pharma companies. We're actually working with them. And that partnership is very, very important for the company to maximize value for our patients as well as shareholders. So our gene therapies, I want to look into all the biotechnology evolution. Starting in 20th century, you have penicillin to polio vaccine, and you have many monoclonal antibodies came into the market. And then early 21st century, we got human genome, fully sequenced. And then we got into gene and cell therapies and CRISPR gene editing. And first commercial gene therapies were launched, including mRNA vaccines, which saved a lot of lives during pandemic. I'm going to put Ocugen's Modifier Gene Therapy Platform in the same space. As I mentioned before, traditional gene therapy, including gene editing, CRISPR, is costly, it's mutation-specific and it addresses ultrarare diseases. As we are addressing today, taking even RP within the U.S. has more than 100,000 patients, more than 100 genes can get mutated. It's almost impossible for companies to develop 100 products. So that's the paradigm shift with the modifier genes, the way they function, looking at the entire network and the gene expressions under that network, we're going to change the paradigm of how you treat diseases. And we're starting with ophthalmology space, and it has potential to treat broad population like RP with many, many genetic mutations; and also going after big diseases such as GA, which has 1 million patients in U.S. alone. And I think if you take dry AMD itself, it's more than 200 million. So we are only talking about late stage. So that's the paradigm shift. We're going to continue to develop and bring them to the market in the next few years. Now I'll let Arun take over and walk you through specifics of our gene therapy programs and dive into our Phase III clinical design we're very excited about. Arun?

Thank you, Shankar. Good morning, everyone. So I think Shankar already talked about the potential of the programs and pipeline we are working on. In this particular session, I'm really going to focus on understanding how this is working, okay, and how we are different than other people in the same space who are developing cell therapy, gene therapy or taking different approaches of gene therapy to treat genetic disorders and other disorders. So the way I look at our modifier gene therapy approach, in contrast to other approaches, is that the traditional gene therapy approach is either gene augmentation or gene editing. And your approaches and assumption is that if you have a mutation in a certain gene, that lead to the disease. And one way to treat that is like you give the normal copy of the mutated gene and you do the augmentation of that copy so that you basically make cells or tissue, enable them to restore the function, okay, related to that particular gene. Gene editing is more like you are correcting it. So rather than supplementing something from outside, you are correcting at the place where the defect is. But the limitation of those approaches is not just only that it is applicable to the one mutation or one gene with one product, but also it is limited by the very fact that when you have a mutation in a certain gene, disease is not just an outcome of that mutation. Disease is a manifestation of various other factors which get imbalanced, which are not normal as we develop disease or we acquire the disease during course of our life. And how we understand that? The basic way to understand that, we all -- those who have inherited the disorder, they have the mutation in those genes since birth. But do they have the disease fully manifested at the birth? No. Do they lose the vision completely at the time of birth? No. These are slow progressive diseases. What might be going there? There must be something else because if gene is mutated, their function is impacted at the time of birth, but the impact of the clinical manifestation or what we call phenotype associated with the mutation is not present at the time of birth. It means there are other factors which are responsible, which modulate how a mutation may lead to the disease. And that is where the modifier concepts come in the picture. And now we are understanding that in not only in this particular disease area, but in other disease also where I think scientists and this whole community is talking about, epigenetic regulation, other modulation, bringing the homeostasis, bringing the balance. Disease is all about imbalances in the various -- whether it's at the cellular level, molecular level, biochemical level, whatever level you can think of, it is some way imbalanced in the system. So what modifier does in contrast to other gene therapy approach that in the retinal disease condition, especially for our modifier gene therapy program, it brings the balance, it restores the balance. And by restoring that balance, we are able to either improve the function, lost function; or you stabilize it, at least you prevent the progression of the disease. That's the whole concept. So keeping the -- and how this work? The genes are master regulators because there should be a way, like how they are regulating multiple imbalances. So the way they regulate -- because these are master transcription factors, and they not just impact one pathway, but they impact multiple gene network, which Neena, our inventor, she has kind of explored during discovery work, and she's going to talk about it. So this is the whole concept. So goal is to restore the imbalances in the various gene network or molecular pathway which are impacted in the disease condition. And by doing so, you are able to basically provide the treatment benefit to the patients and potentially in terms of restoring lost vision or by stabilizing the vision. And we have 2 products in that particular pipeline in the development: one, OCU400, that we are developing for retinitis pigmentosa and Leber congenital amaurosis; and another product we have in the pipeline is OCU410, that is best known as a modifier RORA, and that molecule we are developing for age-related macular degeneration, currently like advanced form of age-related macular degeneration that is geographic atrophy. And in addition, we are also developing this for a genetic disorder called Stargardt disease. And the way this molecule, similarly like our OCU400, this molecule also targets multiple pathways, which are impacted in the -- in this disease condition, macular degenerative condition, like complement pathway and inflammatory pathway, oxidative stress pathway, altered lipid metabolism pathway. So all these pathways are regulated. They are altered in the disease condition, and they are bringing back to the balance when you get with the RORA. So this is just high-level overview, like more than 125,000 people are impacted by RP and LCA in the U.S. alone. And if you look at the global prevalence, it is in millions for RP and LCA. And another thing which we need to keep in mind that all these diseases, it's not one gene. You have like hundreds of genes impacted or mutated in this disease condition. And as we mentioned, like if you want to kind of develop a therapy gene-specific or mutation-specific, then it's such a daunting task that it is almost impossible to achieve in a reasonable time frame. And also, like if you look at where the current unmet medical needs are, so, so far, though this -- in this field, we have been working for last -- close to 10, 20 years, but we have only one product. And that product is just able to take care of only very small fraction of the patient population, I'm talking like a few hundreds. So there is such a significant unmet medical need in this space. So our goal and our belief is that, based on the mechanism of action of our modifier approach, that this molecule has potential to provide benefit to not only hundreds of subjects, but thousands and thousands of people who are impacted by retinitis pigmentosa and Leber congenital amaurosis condition, and much beyond in other disease area such as age-related macular degeneration and Stargardt. So as Shankar mentioned, like we have been in constant interaction with the regulators related to the further development of our OCU400 pipeline. So we have a good alignment with FDA on our overall study design and primary endpoint. And we are advancing to the Phase III clinical development for this particular molecule. And our design is based on favorable safety and efficacy profile in this patient population. That has been the basis for us to move forward with the broader RP trial. And this is the first trial, which is going to be gene-agnostic, purely gene-agnostic in nature, not just like covering 1 or 2 particular mutation, but pretty much all the known mutation in the RP space. And the follow-up for this study is also not longer, it's just 1 year after the treatment. So we expect that time is going to be shorter and, hopefully, we'll be able to get the molecule in for market authorization in 2026. So this is a high-level safety and efficacy summary from our Phase I/II study, primarily for RP patients. So, so far, we see that OCU400 is generally well-tolerated and safe across all dose levels. So we tested 3 different dose levels in Phase I/II study. Not only that, it is also well-tolerated across multiple mutations. It is not just a dose level, but dose levels are also tolerable across multiple mutations. And we also noticed that most of the patients, they showed improvement or stabilization on various parameters linked to the visual function or functional vision, such as Best-Corrected Visual Acuity and LLVA and also the real-life mobility course under different light conditions. 89%, 16 out of 18 RP subjects, we saw that there is a stabilization or improvement in the vision on either of these parameters. And when we further looked at the mobility course, which has been kind of a biomarker or the endpoint which has been used for the approval of the Luxturna, even on that parameter, we see that close to 78% subjects showed a stabilization or improvement. And when we further do the sub-analysis -- and why am I stressing sub-analysis? Because I did mention about modifier function. It's not gene augmentation. For RHO subject, this product is gene-agnostic because product is NR2E3 and we are treating the RHO subject. So even in that gene-agnostic arm in Phase I/II study, we have 80% RHO mutation associated subjects experiencing either stabilization or improvement on mobility course. And this is fantastic, actually. This also tells about how modifier can really modify the disease and provide the treatment benefit. So coming back to -- so based on those Phase I/II study outcome, we moved forward with the Phase III design. So this Phase III study is going to be multicenter, randomized study to assess efficacy, safety and tolerability of subretinal injection. And this is going to be the assessor-masked study. As you all know, in the subretinal surgery, we cannot mask the control. So safety is going to be assessor-blinded study. And as I mentioned briefly, what is the approach? What is the goal for us to these patients? Our goal is to stabilize or provide improvement in the vision. We are not just looking for a stabilization, we are really looking for improvement. Our Phase III is designed to provide benefit, not just a stabilization. That's our primary endpoint in design. We want to demonstrate that this molecule does provide the benefit in terms of functional vision to these patients in our Phase III trial. And this is the Phase III study design where I'm going to spend some time with you all. So our trial will consist of total 150 retinitis pigmentosa subjects. These subjects will be qualified based on not only their clinical phenotypes, but also we'll be confirming through the genetic diagnosis that they are RP patients. And in this trial, we are going to enroll the subjects 8 years and older. So it does include pediatric patient population, not just adult. Those 150 subjects will be equally distributed between 2 arms: the rhodopsin gene arm and the gene-agnostic arm. The reason for us keeping rhodopsin arm is that this is the arm where we, in the Phase I/II study, we had quite a bit of subjects. So to also derisk the trial, we wanted to have a separate arm for the rhodopsin. So that's why you see the rhodopsin arm alone; and then another gene-agnostic arm, which will consist of all the patients with different kind of mutations linked with RP disease. And further, in each arms, these subjects are going to be randomized 2:1 to receive either active treatment of OCU400 or as an untreated control. And after light treatment, these subjects are going to be followed for a year, and that is when we will be doing the primary endpoint assessment. So primary endpoint is linked to the change from baseline to the 1-year endpoint assessment. And our plan is that once the primary endpoint analysis is complete, we do the BLA filing. At the same time, it is not good that you leave the untreated control, okay, without any benefit. So as a part of the study design, this untreated control subject will be offered to cross over to the treatment. However, this crossover decision will be made only after we analyze the treatment benefit in the treatment arm for these subjects. Only then, those things will be offered to them. If you look at the eligibility criteria, we are covering the broad range of the retinopathy, the subject with, say, significant vision loss to those who are even early stage of disease. And also as a key eligibility criteria, we are performing the LDNA. LDNA is basically modified mobility course. It is Luminance Dependent Navigation Assessment. And this is different than the MLMT course we used in Phase I/II, which I'm going to talk about in detail in later slides. And our goal is basically to implement this test because we want to really eliminate the ceiling effect because a lot of subjects, what we learned in our Phase I/II study, that they are able to pass the course at the lowest light level. And that was the primary reason for us to basically modify this test and come up with the new range for this particular -- for Phase III study. And our primary endpoint is going to be proportion of responder, which is defined as 2 lux or more improvement from the baseline at 1-year time point in treatment versus control arm. As a part of secondary analysis, we are not just looking at the responder just in the study eye, but we are also going to look at all the treated eyes in the treatment arm and compare between treatment and control. And another parameter we are planning to look at as a secondary endpoint in this Phase III study is Low-Luminance Visual Acuity. And why it is so important? Because in retinitis pigmentosa, as you all know, nyctalopia is one system, like we start with not having difficulty with the night vision. And LLVA is one of the test which does capture that particular deterioration. So it is sensitive to that low-light condition. That's the difference between BCVA and LLVA. And when we look at the statistical consideration, how this Phase III study is powered and what is the possibility of success for this study, so as I mentioned, this study will have total 150 subjects and 75 in each arm, randomized 2:1. But this sample size is sufficient to achieve the statistical power in this study for both arms, RHO and gene-agnostic. And assumption are that there are -- we are assuming that 50% will be responder in the treatment arm. And when I say 50% is responder, what does it mean? That if you dose 100 subjects, 50 subjects will be able to demonstrate 2 or more lux level improvement at the 1-year endpoint. And for the untreated control, we took the responder criteria of 10%. And the reason, because always in any trial, you know that it's progressive disease, you don't expect untreated to gain any function because that's not the nature of disease, but somehow, like it's random, what you call false positive kind of response. So to account for that, we took 10% in our sample size estimation. And this study's power, more than 90%. And our hypothesis is basically to demonstrate that response rate is higher with the treatment group compared to the control, in RHO subgroup. And also, as a part of conditional efficacy hypothesis, we are going to demonstrate that response rate is higher with the treatment compared to control in gene-agnostic group as well. Now you learned about our Phase III study design. I would also like you to understand, what was the basis for that design? What data we used to make that decision and to consider those responder criteria and other assumption we made in the design consideration? So total, as I mentioned, total, we had 18 subjects in Phase I/II study, but out of those 18 subjects, 8 subjects meet our criteria, intent-to-treat population criteria for Phase III study. And this population represent, you have RHO as well NR2E3 mutations. But before I go into the data, I really want you to pay attention to these 2 scales, one like in orange and blue. So the orange scale, MLMT scale, which we used in the Phase I/II study. And when we started the study, that scale was only from 0 to 6 lux level. Even the seventh, what you see 0.1, we introduced much later in the study. So most of the subjects by that time has already enrolled, but we wanted to capture some additional data for that. And the below the scale is LDNA, which we are going to use in the Phase III study. And you can clearly see the difference, not only the number of lux level, which we have in the newer scale, is much more compared to the old; but in addition to that, if you look at the spacing of the lux intensity, it's much uniform. It's uniform in the newer scale compared to the older scale. So in older scale, like lux level improvement is not that homogeneous for a given light intensity. So those are the 2 changes we made. So we wanted to look at our data to intent-to-treat population, how they respond in the new scale. And it's just mathematical conversion, by the way, okay, for you all. There's nothing like that we ask patient to do the -- like walk the new course, but it is simple mathematical conversion of light intensity to the lux level, okay? And as you can clearly see that most of the RHO subject here, we see that they are responding more than 2 lux level. Not only that, some subject, if you look at like 2 RHO subjects, we see the lux level improvement 3 even on older scale. And when we convert that data to the newer scale, it becomes 4 lux level. When you look at autosomal recessive NR2E3 patient population, we do see that on older scale, we have 1 lux level improvement. But why that was restricted to 1 lux level? Because for these subjects, baseline itself [ wired the 5 ]. So when they improved 1 lux level, you reach to the ceiling effect of the older scale. So even though there was a treatment bandwidth, but you don't see 2 lux level again because of the ceiling effect of the assay at that time. And overall, when we also look at other parameters for these subjects, like BCVA and LLVA, we do see that on all these 3 parameters, these 8 subjects either demonstrate stabilization or improvement. And further this slide, again, to reiterate the gene-agnostic mechanism. So further, I narrowed down to this RHO population. And if you just focus on RHO population, you can see that more than 50% intent-to-treat RHO population meet responder criteria. And that is what has been the basis for our Phase III design. So clearly, our Phase III design is powered based on the Phase I/II data, which indicates that with this assumption and sample size, we should be able to meet the primary endpoint if the molecule does the way it performed in the Phase I/II study in intent-to-treat population. So this is what our overall plan is for this particular program. So we are planning to initiate the Phase III trial this year soon. And the indication is going to be treatment of retinitis pigmentosa. It's a broader indication. In addition to that, we are also expecting to pursue LCA indication in second half of 2024. As you all remember, as a part of our Phase I/II study, we have LCA patients also enrolled. But data for -- we are waiting for the data for those LCA subjects, 1-year data point. And once we have that data level, then our plan is to have interaction with the agency and potentially initiate the Phase III trial for LCA also this year, in the second half. So -- and with that, I will pause, and I will invite Mike Shine, our Commercial Head, to talk about our commercial projects and for the molecule.

Thank you, Arun. Good morning. So based on all the data that Arun and Shankar shared with you, we've taken some initial efforts to try and put a value or market assessment on our OCU400. And as a commercial guy, this really excites me because the upside potential is quite terrific with a gene modifier therapy. It doesn't suffer from the same things that gene editing and traditional gene therapy suffer from, which is very small patient populations where millions of dollars have to be charged because that population shrinks as those patients get treated. So in this analysis, we looked at sort of standard market penetration over a 5-year period, ranging from 3% to 15% in the U.S. and Europe. We looked at the pricing assumptions based on current modeling for gene therapies, and the number is big. It's $47 billion of cumulative revenue over the first 5 years, from 2026 to 2030. So we pressure tested it a bit, and we looked at the downside scenario and said, well, what if we just price at parity to Luxturna, the current only approved therapy in RP indicated for RPE65. And using that as a proxy, we can see 5-year revenue of $30 billion. While those numbers look very large, I think there's a broader and more important point here. What this really proves -- because you can toggle the penetration numbers, you can toggle the price points, you can drive them down and take them up, but what this shows is the value of modifier gene therapy. There's 175,000 patients in the U.S. and Europe with RP and LCA. With a broad indication, we have the potential to reach a very large patient pool, and you don't get that with traditional gene editing. So while the numbers are impressive, the real value calculation here for modifier gene therapy and how it's different, as Shankar alluded to earlier, than traditional gene therapy is the size of the patient pool. And it's even more extreme when we look at geographic atrophy. I think Shankar mentioned the number of 3 million patients in the U.S. and Europe with geographic atrophy. And if we take really a nominal penetration rates, and again, pricing that would be considered at the very low end of gene therapy pricing, you're still seeing calculations that show the value of this therapy in the range of $75 billion in revenue. And so sometimes, these numbers look almost overly impressive. Certainly from a commercial standpoint, it gives us a lot of range and a lot of flexibility. But then some people might say, well, how are those people going to access it? And I really want to make an important point here. Shankar pointed out that our mission is access. And one of the great things about having gene therapies that can be used for large patient populations is it gives us enormous flexibility on pricing and it allows us to guarantee that regardless of ability to pay, we're going to be able to make these therapies available to patients. So we are working already on payment plans and strategic access plans that will allow these gene therapies to be used by patients who couldn't afford these prices. But in order to establish the value of the gene therapies, we had to run these models using the traditional gene therapy approach. And again, what it just offers the company, incredible flexibility with pricing, penetration and access. And those are my only 2 slides. But I want to close on something, again, just to reiterate that point, these are valuable technologies. We're changing the paradigm of gene therapy. It's no longer one-for-one treating a mutation. And if you don't have that mutation, you don't get a gene therapy. In RP, we're developing something that can be used for patients regardless of their mutation, and they'll get a benefit from it. That's got enormous value. But it only works if the patients can access it. So again, just to reinforce the point, in our mission, you see access as a priority; in our vision, you see that Ocugen is intending to become a fully integrated, patient-centric biotechnology company focused on vaccines for public health, selling gene therapies for unmet medical needs to create this innovation. We take that very seriously. And with that, I will close and invite Shankar back up.

Yes. So now we're going to open up for some questions.

Any questions?

This is RK from H.C. Wainwright. Shankar and team, thank you very much for doing this. When Arun was talking about the data, he was also talking about the subset of RHO patients. So just for us to understand, what percentage of RP patients end up having RHO mutation?

It's about 10% to 12%, around 10,000 to 12,000 patients.

And then you are introducing LDNA as an endpoint and now in the Phase III study. Has LDNA been used by any other entity as a primary endpoint? Or is this something that we need to teach FDA how to deal with it?

I don't think we need to teach that to FDA because with this particular test, we came up with in the collaboration with FDA. And this test is no different than any visual mobility course. The differences is not as such in the principle of the course, but more like what this course can cover in terms of reducing the ceiling effect or, you can say, potentially eliminating the ceiling effect, which we see in some of the subjects; and also providing the range so that you can enroll a lot of RP subjects, which could be potentially eligible for this treatment. So not new. We don't have to do anything extra to establish that this could be a primary endpoint. This is something which FDA is fully aware of. And it has been put in place with the FDA alignment with their recommendation and discussion with us.

Any other question?

Yes, Robert? Could you pass the microphone? Thank you.

Just a question on the clinical trials. And you just mentioned that the RHO mutation is about 88% to 90%. And in the trial, it's going to be mutation-agnostic. You have RMAT designation for the RHO mutation. So I'm just wondering how the design of the clinical trial would fit with the RMAT designation and the benefits for approval and then how that fits with your post-marketing plans and addressing the entire population. Would you have approval for all RP patients and just how the designation fits with the commercial plan and the clinical trial?

I'll answer the first part of it, then I'll give it to Arun. The clinical trial, we got RMAT based on Phase I/II because we have relapse in patients in their NR2E3, and that's what they covered. So now we're going into gene-agnostic. So eventually, we can get RMAT for that in the future. And our goal is to get a broad RP indication. That's how the clinical trial is designed. RP and gene-agnostic, those are the 2 groups. And we already have orphan drug designation. So that will help you to get accelerate the approval in 6 months, irrespective of what the data comes out in either group. So with that, I'll ask or give it to Arun.

Yes, thanks, Shankar. I think you pretty much answered. So you just mentioned RHO, I think, in your question. So our RMAT is for RHO and NR2E3 both, okay, just -- so both populations which were part of Phase I/II. And as a part of approval, the way the study is designed, as I mentioned, if you look at the hypothesis, the primary hypothesis is to demonstrate the efficacy in the RHO. And once that is made and when we demonstrate further the efficacy in the gene-agnostic arm, then FDA gene alignment to give the broader approval, okay?

Okay. Okay, yes.

Yes. And whether RMAT, can we extend it to the gene-agnostic? Always, RMAT extension is based on the clinical evidence. So once we have that clinical evidence in that group of patient population, then definitely, we'll apply for that and we'll have...

I see that's an important point. The clinical trial is designed so that it could -- all of these designations could be extended to the entire population, not just what you have designation for it today.

That's correct. Exactly. But already, we have other designation which applies to the broader population. So we have orphan drug designation from FDA for RP disease, not for mutation-specific RP disease. So we have broader RP orphan drug designation. We have broader LCA orphan drug designation from FDA. And similar designation, we have also received from EMA for broader RP and broader LCA.

Michael Okunewitch from Maxim Group. So I guess for my first question, I'd just like to see if you could comment a little bit more on pricing. And specifically, would you expect there to be some pressure from payers to price a little bit below where some of the ultra-rare gene therapies are targeting, given just how large your indication is in comparison?

Mike?

Yes. The answer is yes, we always expect price pressure and negotiations with payers. So that is a given. I think what we tried to do for this initial run was look at all of the existing data and models and plug-in without really considering initially patient population. So we looked at quality adjusted life years, we looked at potential improvement in quality adjusted life years. We applied the ICER model. You saw some references at the bottom of my slide. So we've been fairly exhaustive in this first run. And I think what's encouraging to us is there's so much headspace for pricing because the population is so large that, ultimately, because we are committed to access, we're going to be able to find a price that everyone is going to be satisfied with and is going to give a very significant return.

Yes. And then as a follow-up, I just want to ask a bit of a stats question. When looking at the powering for both arms in the Phase III, are they powered against each individual control group? Or is there a pooled control group that you're comparing?

Very good question. Individual control group. So 75 subject in each arm will be randomized 2:1. So each arm has its own respective control. So 50 in treatment and 25 for the control. And the power is 50 versus 25, not 100 versus [ 75 ].

Just a quick follow-up to Robert's question. I wanted to confirm for the Phase III study, would you still hit your primary endpoint if you got improvement in the RHO population, but not in the broader RP population?

That's correct. And that's why it is a conditional efficacy hypothesis, that will be tested only if RHO patient meet the primary efficacy endpoint. Yes. And...

Perfect. Helpful. And -- go ahead, Arun.

Yes, you first.

Just 2 quick follow-ups. I think the first one here is just, are there other things that you've modified in terms of the baseline patient criteria from the Phase I/II to the Phase III?

Yes, we did, actually. So one of the important criteria is related to the primary endpoint test itself. So in our Phase I/II study, we enroll the subject anywhere between someone who is failing at the higher lux level to even passing at the lowest lux level. But for this trial, if you look at our LDNA course, the range, we have a starting from 500 lux to 0.004 lux. So the way we are setting the [ inflow ] gene criteria, that anyone who fails at 0.35 lux intensity will not be eligible. And why -- but again, at the same time, we are increasing the range, you can see. Someone failing at 1, 2 now, we came down to 0.35. So it will allow us not only to enroll a wider group of RP patients at the different stage of disease, okay, but also, it gives us a window to demonstrate the treatment benefit. So anyone, say, who fails that 0.35, it means they must have passed that 1, that's the next level. So from 1 to 0.04, we have total 3 lux level to demonstrate the benefit. So -- and our criteria is 2 or more, okay? So that is how it is different.

Perfect. And then last one, I'm going to put you on the spot a little. The data looks really interesting. So you have LCA data coming up. What do you think your efficacy is going to look like relative to Luxturna?

Good question. So in our -- the current LCA trial, we are not enrolling the subject what Luxturna enrolled. So Luxturna trial was focused on a particular mutation in a gene called RPE65. Our current LCA trial is with the patient CEP290 mutation. And CEP290 gene mutation is one of the most and common prevalent mutation in the LCA patient population. Now coming back to how it will fail, okay, if we have to look at the lux level improvement, of course, it is early to say. But so far, whatever we are seeing in terms of modifier, I think I'm quite hopeful that we'll see something.

Any other questions?

I'm with the American Macular Degeneration Foundation. Looking a little bit further down the road to OCU410, what's to prevent the same molecule from treating the disease at much earlier stages even as early as early AMD, if it's been identified?

I mean it doesn't prevent -- I mean, obviously, we need good diagnostics. I mean, currently, there are 2 products which got approved in the market. They look at the lesion, so you need to identify. If we come up with a biomarker, that's where we want to go. And somehow, if we can identify early stage, we can prevent it. I think that will be the future, agree, 100%.

Yes, I think it's going to be an amazing development because that population is huge.

Agree. Agree.

Okay. Any more questions? All right. We're going to take a short break. If everyone would like to get some refreshments.

Thank you.

And then -- yes, thank you, our speakers. We'll take a look...

Also -- Tiffany, just a moment. I would also like to really -- we are very thankful and we really would like to acknowledge inventor and our investigators and all the clinical sites and the patients and everyone who has been part of this incredible, I think, Phase I/II study. We take pride, and we take pride in completing this study in such a short span of time not just because of what we do, but also like all the support we get from you all. Everyone is so important, our investigators, our patient population and all the advisers, KOLs and everyone. So thank you. Thank you all for your support.

Okay. We'll start back in a few minutes with our panel. [Break]

Hi, everybody. I'm Tiffany Hamilton, Head of Communications at Ocugen. So I oversee IR and PR for the company. And I think I've spoken with most of you, so it's nice to meet you in person. So I'm going to do a very, very brief intro of our panel because we had their bios on the screen during the break, and I cannot do any of them justice. First off, I'm going to introduce RK, who is Managing Director of Equity Research at H.C. Wainwright. He'll be moderating the panel. We have Dr. Neena Haider, who is the inventor of modifier gene therapy. Then we have our patient, [ Manny Fernandez, ] who is a patient of the Phase I/II clinical trial, and he'll be sharing his experiences. Dr. Lejla Vajzovic, and she is a retinal surgeon at Duke and a lead expert in the space. And we also have Dr. Byron Lam, who's at the Bascom Palmer Institute at University of Miami and is our lead investigator from the Phase I/II study. I'll hand it over to RK.

Thank you, Tiffany. Good morning, folks.

So just to get started with this panel, I'm going to ask Dr. Haider to define for us, again, what modifier gene therapy is. I know Arun just did a great job. But just to get this started, what is modifier gene therapy? And when you got started, what were the benefits that you wanted to get out of this?

Wonderful question. And Arun, you did a great job earlier defining what this is. I'll expand on that definition, and I'll start by telling you, very lay terms, what is a gene? A gene is a coated part of your DNA, we have about 30,000 of them. I was part of the genome project. And when we were first doing it, by the way, we thought there were going to be 100,000. And then as we sequenced more and more, we're like, oh, there's less, there's 50,000. No, there's only 30,000. They work in concert. They work together. You don't have all 30,000 expressed that make a protein. Protein does the work in your body. And they don't all express in every part of your body. The retina, the camera of your eye, which is the focus of today's conversation, actually, expresses maybe 1/10 of them, 2,000 to 3,000 of these genes. So what a modifier gene is it's one of these 2,000 or 3,000, but it's a master regulator. Think of it like the master conductor or a circuit breaker, it regulates several hundred to 1,000 of these genes. And it can make things worse sometimes, it can make them better. It's a balance depending on how your particular genetics works, right, what particular changes you might have and the nuances of them. And so when we first started studying modifier gene therapy and the impact it could have on the human condition, that was actually a really next step of profound discovery science that happened that in the context of, say, a disease mutation, something that will cause a detrimental effect, in the presence of that, there were other genes that if you have a particular variant of that, you never saw a disease. Now we saw that in the early 2000s, and that was what led me to today that, wow, we can have, in the presence of mutation, completely disease-free retina and it can function normally. That's the power of the modifier gene therapy. And that's what -- when we talk about what we were thinking in the future, we saw this in many models that we can just, by having a particular part of the DNA gene, be a variant that can normalize and stabilize, and we can talk more about that if you want. The homeostasis, like just like everybody during the pandemic wanted to go smell the flowers, take a walk and do yoga, every cell in your body also wants to be zen and wants to maintain the state of normalcy. And that's what they help do.

Thank you. And so within the modifier gene therapies, you also focused specifically on NR2E3. And as a potential gene to regulate these conditions, whether it's an RP or the LCA, so we don't need all the details of the mouse experiments, but in general, so how did you land on NR2E3?

That's a fun question. There were several of these modifiers, right? There's not just one. How did I land on NR2E3? It's a class of genes that are master regulators. It's in that class, there's about 52 of them. And this one, in particular, was really expressed just in the retina, whereas most of them are expressed throughout your whole body normally. And I thought, okay, this is something, if it can master regulate, will have such a specific effect on that part of the eye that I thought it would actually be a more potent and powerful therapeutic option because that's where it's expressed, that's where it's master regulating. And in the context of diseases where something like RP or LCA, you have hundreds of roads to get to this. My driving force was always there's about 30% to 40% of patients that will never have a molecular diagnosis. They can tell them, this is your mutation and feasibility of making 200 therapies is not still very realistic. How are we going to help those people that have nothing? And that was kind of the driver for it. And NR2E3, being this master regulator that has a specific function in that area, was why we chose that.

Thanks. And then you spoke a little bit about this in terms of homeostasis, we know that NR2E3, being a master gene, regulates multiple functions, including retinal cell homeostasis, metabolism and visual cycle. And me being a toxicologist, I always worry about adverse events. So what -- since it regulates so many different, I mean, mechanisms, so what sort of adverse events would you be on the lookout for when you're treating with the modifier gene therapy?

So it comes back to another reason why we chose this class of genes and NR2E3 in particular, and we do these large studies in published papers, and there's always this little tiny data. Those are my favorite figures in the papers. NR2E3 self-regulates, so you don't have to worry about having too much of it. And that was a bonus reason why we also choose that addresses that problem of how is it going to have a toxic effect. Many of these -- this is why we chose this class. They actually auto regulate, so you don't worry about having too much. They regulate inflammatory response. They regulate not just cell survival, but cell death and protection. So because of the things they were regulating, we didn't really have a great concern in terms of was it going to be toxic. And in our preclinical studies, we saw in many, many models, and I'm talking about thousands of studies here, no toxic effect. And so I was very confident that, that would not be an issue.

Thank you for that. So moving on to the disease itself, Dr. Vajzovic, how do you -- how would one define inherited retinal diseases? And what's the incidence of RP and LCA, not only in the United States, but also worldwide?

I think we heard that very well earlier from Arun. Kind of summarizing, really inherited retinal diseases is a group of disorders with very variant types of genes involved. And because of the diversity, it's a challenging problem process hence to find treatment or options for those patients. It is a rare disorder, but one that's across all genes, quite prevalent. And as we kind of saw earlier numbers, 1.5 million across globally. And LCA specifically is a smaller number, but one that's clearly, if we're talking about all the genes that are affected and involved in inherent retinal diseases, it's quite a few patients, for certain.

And then in terms of the diagnosis itself, how easy is it to diagnose these patients? And once you diagnosed one patient, since it's an inherited disease, do you start questioning the patient and his family and, immediately, you get to see multiple patients within that family? How often does that happen?

I think ever since with the emphasis of gene and understanding genes that are involved, we talk about retinitis pigmentosa, LCA, but we really should be talking about gene-specific disease and redefining how we define these diseases to begin with. But we are moving to that direction. And there are about 280 genes that have been described in IRDs per se and their main cause. And more and more now, we're basing our clinical diagnosis earlier because we are defining it by doing genetic testing. We used to not be able to do that to the same degree. That's definitely has changed the paradigm that we practice. And nowadays, we can do a simple saliva testing, just send a kit to a patient via mail and even do virtual appointment to help them actually identify this disease. And knowing that it runs in the families, of course, encourage family members to get tested in broadly. So I think it's defined from -- it used to be these patients come to our office with late diagnosis because of the fact their vision is now affected, and we start to figure out things at that stage. Now we are seeing these patients much earlier because of the genetic testing.

I think I know the answer, but still, I think I have to ask the question. Obviously, for these IRDs, is there a therapy or you -- even though the patient comes to you, you've got to give them something. And what would that be? Is it more how to manage life physically? Or is there a real treatment of some sort?

Yes. No, I think it's a challenge for certain -- first, we used to have a challenge of diagnosis. But once you're diagnosed, it's really become more of a counseling session, unfortunately, because the options are limited. We really have -- Luxturna is the only option currently for one gene-specific. And it comes down to really doing more of a discussion of like what the prognosis may be in this case, involving our visual rehab center to help really these patients learn how to function with the vision and what the future may hold and to empower them with those resources outside of treating disease, such as low vision system devices to help them really function in the best ability they can with the vision they have.

Thank you. And then Mr. Fernandez, how did you find out that you have RP and what age? And how has the journey been with the disease itself?

Well, we have generations in the family that had the disease. I do not know for sure if my great, great grandfather had it because there was no information. I don't have any information. I know my grandfather did, my father did and his other 3 siblings. Now my generation, we have 3 brothers, and 2 of us have the disease. Mine always -- I came along to the United States and I knew about the disease. So every time I went to the eye doctor, I told them about it and they can't find anything. Until I was, I can't remember, it was 40, 43, they start looking at spots in the eye, and that's when I realized that I had it. At night, it was not so difficult. It's been increasing more and more, the vision decreasing. And I don't drive at night anymore. So that's -- but I want to do something. Everybody has a white page in there, I hope you do that.

No, no. No, go ahead.

I want you to draw an eye in the corner. This is homework, okay? I want you to punch a hole on the corner, 2 holes. I don't care how they are, just punch 2 holes. Now this is what I want you to do, put it on one eye and look at me. That hole is too small. What can you see? Not much, right? That's what I can see. Okay? No. Thanks to Neena. And I have -- this is my actual vision here. So you can see it later if you want, where I can see through. Thanks to Neena. I was -- I've been in this story for about 1 year and 3 months. And for the first time, about a month ago, I was driving, and I always try to drive safety on the right side of the road. And I saw something going through and scared the hell out of me because I've never seen that before. And I can -- right now, I cannot see what it is, but I see a shadow somehow. I can't explain, but I see a shadow. And that is amazing.

Was it a car?

Well, it's obviously, it was a car. And before, I couldn't see that. I always have to look at the mirrors to see where I am and how the traffic is. So that little thing, for some people or probably 100% of you don't realize how big is for us to be able to do that. But not only that, this eye, which -- that's the one they performed the surgery, which I call a bacteria, I didn't know it was a gene, they started -- I forgot what I was going to say, I'm sorry.

That treated eye?

The treated eye was the worst. And now I can say that this one is not even -- it's better than this one, okay? It's better than this one. And it's -- I'm ready for the other one already. So that's what I wanted.

Thank you, Mr. Fernandez.

Would you like water?

No. Thank you.

So I was going to ask you how the journey was. I guess you already answered the question. So thank you very much for that. Thank you. So this is a question for the full panel. So as we understand RP, I know it does progress with age. But then -- but we see different -- differences among the different patients. And in general, how do you attribute that difference? Is that more on the number of mutations? Or is it how -- how does it get manifested? Or does it depend upon what modifier gene is actually running the show? Any comments, please?

I can start. Yes, it matters what type of mutation, it matters the context, right? The biological load, that's how -- actually, it's in another terms. One of my marketing people say I should start trademarking things. But it's rather than thinking of this, and I think Lejla brought up a great point, these diseases, as they were being discovered, were assigned names and put in boxes, but that's not how it works in the body, in the system. They work in concert with thousands of genes together. And so it's -- that whole mutational load on a biological system, that means that primary mutation, any modifier effects. Epigenetic, you're a product of your DNA environment, how all of that interacts in a very personalized, precise manner then determines your clinical outcome and, therefore, will also determine the robustness and the outcome of any therapeutic. And if you both can expand on that?

Well, so -- sure. So I can also add. I think the spectrum of the disease severity is also depending on which point the specific gene, which DNA point is affected, and that has a different effect on the protein. And there are so many factors that are mentioned. There are some modifiers and so forth. But let's say somebody have NR2E3 gene-related retina pigmentosa, but you can have a mutation in a different point. And that in itself causes changes in the protein, which we can try to predict either through a computer model or actually find patients with a specific mutation and gather them and find their specific effect in how they actually progress in terms of their condition. But when you think about that, you say, well, that's really daunting, then how do we do clinical trials? Well, you do clinical trials because, first, you can pick the genotype. Second of all, you can have inclusion criteria, like I just want to pick patients who have this amount of central vision, this amount of peripheral vision, this amount of ability to do the mobility test in a certain range. So that in itself is very important in the clinical trial, right? So you can then have patients who are appropriate, who can then fit into the therapy you have in what we call the therapeutic window, that range of patients that we believe the treatment can actually work.

Anything from you, Dr. Vajzovic?

No, I couldn't agree, I think it's such a diverse presentation. And just like it was alluded, and Dr. Lam beautifully described it and said, you may have that specific genomes involved, but what point is it really mutated? And what kind of protein production is that? But not only does it affect the protein, but everything surrounding that, modifiers and also your exposures in the environment, for certain, dictate that. So while we lump all of that in one category, even within that category, it's a very diverse presentation. So somebody may present earlier in the disease process in the -- earlier in the age group, with more severe for full vision loss and difficulties with night vision to somebody who is going to present the leader in their life with that specific -- those specific issues. So it's very diverse. But bottom line, you come down by grouping the patients into categories. They have a specific inclusion/exclusion criteria that's going to hopefully lead you to seeing that therapeutic window with this modifier therapy.

Thank you. So for patients, so just Mr. Fernandez, who are...

003, please.

003. Lucky 3.

So for patients such as 003, who may be concerned about passing on the disease to their progeny? So would therapies such as modifier gene therapy be of help? Or is it just personalized just for the patient alone?

Oh, no. No. I always worry about my kids, my grandkids. I was in the assumption that with the fifth generation, it will stop, and that is wrong. Dr. Lam told me that. He taught me that. So I'm very worried about my family. Actually, at one point, I didn't want to have any kids because I didn't want this to happen to them. That's how bad it is. So yes, it's very important. They've been tested. All my 2 kids and my 4 grandkids, make sure that they don't have that development yet, and I hope they won't. And now I know it's not going to happen to them. Now I can see the light at the end of the tunnel. So I'm committed to make awareness about it because a lot of people may have the disease and may not progress a lot because you cannot -- I cannot, right here, I cannot see this here. So there's a lot of -- but I will not notice, you cannot notice. So it's very difficult for us to identify the illness. It's really sad that the only way we can do it is going through the doctor. You guys were talking about, outside the United States, not many people had a chance to go to an eye doctor. And that's where probably the biggest problem, we may have more than the account that you have, the information that you have. So...

Thank you. So Dr. Lam and Dr. Vajzovic, as investigators, what attracted you towards OCU400? And how do you see this as a differentiated therapy that you wanted to start evaluating it?

So I think it's a very novel therapy because we have the traditional gene replacement therapy. Of course, we also have other things here on the pipeline like NAC and other type of treatments. But I think it's the first modifying therapy, and you can treat multiple genes and it has a good scientific rationale. So it certainly makes sense that clinical trial should be conducted as well as we can to assess its clinical efficacy. I mean I think we still are learning from it. And I think the design of the Phase III clinical trial is really pretty robust because you have the arm for the rhodopsin mutation and then you also have an arm that has the multiple genes. So I get attracted to clinical trials in any way that can help inherited retinal disease patients because it's really an unmet need. I mean it's a very progressive condition, slowly just sort of catches up with you, and it affects the person's whole well-being. So that's why I'm attracted to it. But specifically, for clinical trials, we look at clinical trials with good basic science. We look at clinical trials which are feasible and which are novel. And that's why we're doing the clinical trial.

And to add to Dr. Lam, I think all of us are sitting here because I'm thinking, in general, eyesight is really important. And I went into medicine, especially ophthalmology, because I really wanted to enable people improving, saving that eyesight and enabling them to be really part of the society. And we underestimate how much that sense really is important in day-to-day function. So when I see a patient who then gets a diagnosis of inherited retinal diseases, I will be honest, it's my least favorite diagnosis to make. Because to date, I have -- I went into medicine with hopes to improve things. When I have a diagnosis where I can't make the change, I can help them function better, but not make it better or stop it. I'm not too thrilled with that, for certain. So to have options and to participate in clinical trials that we can change this for the patient, especially in more of a gene-agnostic approach, meaning delivering it for not just a specific gene, but for multiple genes, multiple diagnoses and potentially even for common retinal diseases, I think it's very exciting. And I think the novelty of that and also the -- a broader approach to helping many more patients, I think, is very exciting for me.

And then, Dr. Vajzovic, as a surgeon, in terms of doing this surgery itself, how difficult is it? And in general, what's the learning curve? And once this gets approved by the FDA, is that option by these surgeons a difficult one? Or is it, it can be done and it's easy?

Yes. I mean any time we talk about surgeries, in particular, we always think about, gosh, there's an extra step, we're exposing patient to risks for certain; and we are. I mean eye surgery is definitely a specialized field. One, it takes lots of years of training. But I would tell you, as a retina surgeon, the #1 step that I do or in any surgery is the step that's being done in this surgery. So while it sounds like it's something unique, it really truly is not. Every retina surgery starts with removing the vitreous and kind of taking care of the back part of the eye. So the only additional step that's added to this is really delivering the drug underneath the retina. And that, I think, is also not quite challenging at all. So to summarize it, I would say, yes, it's surgery, it definitely is, but we are delivering therapy in exact spot where it's needed, in the localized areas. We're minimizing exposure systemically to things, minimizing the risk for the rest of the body and delivering the therapy exactly where it's needed. So I would say just really one that every retina surgeon would be able to perform something that they're already doing, the extra step is just adding that medicine underneath the retina.

Thank you. So Dr. Lam, without going into specifics, we already heard the story of 003 here, what has been the experience of some of your other patients who are within that current trial right now?

Well, I think in a Phase I trial, we definitely have patients who responded and some patients, of course, did not. And I think that was presented in the first part. So I think it's important to really to -- for the Phase III to home in those patients, which was in the presentation this morning, about how to choose patients that are really the best candidates for the treatment, right? Not for every disease that all the patients are going to be -- is going to be in the right criteria. So I think the fact that we have a group of patients that have responded and that they also teach us about which endpoint that you're going to choose for Phase III, I think it's terrific. And I think that experience is very valuable, especially in a Phase I/IIa study, because that's where you learn about safety as well as trying to find signals of efficacy. So I think you'll find the signal of efficacy. And I'm certainly glad that some of our patients did improve and that you know it's helpful. So I think that sort of propels you into the next phase and you design it and then you got a greater group where you have more criteria and you have other primary endpoint and secondary endpoint, you choose them, and then they will help to determine the efficacy of the treatment.

So there's a question for both of you physicians. As you evaluate OCU400 and as the data starts being -- as the data gets read out, so what sort of clinical endpoints or clinical data you're looking for so that it can help not only yourselves, but also your other colleagues to prescribe this drug? Is there something outside of the endpoints that you're really looking for in terms of quality of life or anything else?

Overall improvement in their functionality. And I think just hearing improvement in peripheral vision ability, that will translate to ability to drive in darker settings and more unfamiliar settings as well. To really -- your peripheral vision is very important to day-to-day function of you being able to get from this point to that point as well and making sure that we're using that to identify the step is where. So what I'm looking is, yes, I'm looking for visual acuity and kind of like the function in low-light settings, their visual field in sense, but it would be nice that very much translate to their ability to function in their day-to-day lives for certain. So...

So I mean, that's well said. I think, one, of course, is improvement in your vision. And that's why we want to capture it in endpoint tests, like the mobility test and so forth. We also want to learn from patients like what exactly they improved on. It's well described here because that allows us to know, for example, which aspect of vision should improve, and I think that's very important. I think the other point that we want to know is that we may have patients, let's say, didn't respond and how do they, over time, maintain their vision and so forth. Of course, that's helpful. And I think the safety profile is also important. That's why you need a larger group. I mean you will expose them to new a gene therapy with surgery. And we want to know how many of the patients has inflammation and how many people have complications. And pretty much like Luxturna, right? Luxturna went through Phase I, Phase III, and then they learned about all these aspects. And clearly, they had a good efficacy signal. So I think there's the whole package in any treatment so that you can understand all aspects.

So in cell therapies in general and even including stem cell therapy, the treatment needs to be done at a certain -- the initial stages of the disease progression to be beneficial. And as RP is a disease which progresses with age, is there a time point where you think OCU400 is most beneficial within the progressive stage of the disease? Or could this be beneficial at any time point?

I think that's exactly what we hope to find out from the clinical trials. I think that question particularly needs to be answered for the future. I mean, ideally, we want therapy that we can use early on to not only stop disease progression, but have influence in improving things as well. So we hope that this will be the answer or one of the answers. But I think that question is going to be kind of teased out, I think, in trials.

So I think I agree. I would just add that, clearly, like any disease, you have people in different stages, right? So of course, people with milder disease is harder to prove efficacy, they have the ceiling effect. They're so good. I mean how can you improve? So that is something that you don't enter those patients to a clinical III trial and, subsequently, depending on the labeling of the product that the FDA allows you to do, right? Because there are patients who are really advanced in, let's say, [ pure light ] perception vision. Of course, at that point, you wonder if any treatment can help them, including optogenetics. So in those patients, you can't really test in Phase III, and that also will be dependent what the FDA label on is. If you look at Luxturna, I mean, Luxturna, actually, you have to have viable retina and -- but you also can treat patients as young as 1 year or older. So labeling of different treatment are very specific and very helpful. So that's, of course, something we will discuss, discover with Phase III. And then subsequently, I think the determination is what will be the labeling the product and then when would the regulation agency based on the data with -- in terms of the type of patients that will be treated. But I think we certainly look forward to learning about all that. So...

Thank you. And in closing in, Dr. Haider, so based on the clinical data that Ocugen has published to date, hearing from the physicians and from 003, so what do you think now, from where you started, and what has been achieved to date? And are there any gaps at this point that you think needs to get filled? And lastly, is modifier gene therapy something that can be used outside of eye, especially diseases like cancer where there are multiple genes, which interact before the disease gets manifested?

Three great questions. Let me address them one at a time. It is truly a full-circle moment to answer your question one. I sequenced chromosome 15q22 and sequenced NR2E3 and then found the patients with that, had the disease mutations and then developed a model and then the therapy and then now I get to meet 003. I can't express in words how profound that is to me to see this come to fruition. A lot of many dedicated -- many times, putting chairs together and sleeping in the lab to -- because we knew what exciting and impactful signs we were participating in. That's answer for question number one. Question two, regarding the clinician and what they have said and how they can better inform and the gaps in the space here. So what I see -- and actually, you gave a perfect segue to my next segue is the health care company. I'm starting Shifa Precision, because what's the next stage is helping the clinicians identify who would be the best, you're a product of your DNA and environment. When Dr. Lam was talking about those DNA points, that's points on your DNA for a modifier or a disease mutation. For us, when I was part of the genome project 20 years ago, and I think why have we not harnessed this technology for health and wellness and diagnosis rather than recreational signs, we're changing that. We're going to do that. And so we're developing the biomarkers. We're developing actually an integrated AI system that will give us personalized precision medicine that will give us then precision therapies so that they have better informed decisions. So they're not just left with -- when a patient comes in and what kind of physical diagnostic tools, let's have molecular diagnostic tools also, so we can get to early diagnosis. So then hopefully, my hope is we get past just this stage of reacting, which is amazing, and phenomenal will be when we get to prevention. When we can predict and then prevent, that will be beautiful for your grandchildren, for future generations to say, you're not going to have to worry about this even if you have that because you've got other options. And I think that then is to empower the clinicians. The third answer, the impact -- and you brought up other diseases, and many of you, if you look me up online, you'll know the story. I'm a cancer survivor actually. So near and dear to my heart, what you brought up. Again, maybe a little part of impetus for Shifa, but yes, the impact of modifier therapy, the whole goal of that was thinking how -- when we have multiple roads to the same problem, how can we get to that root of the problem? How can we solve it? And how can we function and have a better quality of life in the context of everything in the inside molecular that we're thrown in with? And I think what we're going to see actually is more therapies like this that are a modifier based, that are broad spectrum, that have this kind of broader impact and effect. And you partner that with precision medicine, precision therapies, then you'll get to personalized medicine, then you'll get to a personal wellness and optimal wellness for each of us. So I think this is a platform and amazing partnership with Ocugen that has brought this to the forefront of that we see the potential and value of it, but it doesn't stay just within a retina or an ocular surface. This actually can be impactful. And I think the future of therapies may actually even be combination therapies. Maybe a follow-up to the Spark Luxturna will be put in OCU400 and then you might have an even more robust effect, for example. However, that's where I see the future is going to go for therapeutics.

Thank you very much.

Great. That's a great panel. Thank you so much, Dr. Lam, Dr. Lejla, Mr. 003 and Neena. It is incredible. I mean this is what we do every day. And thanks to all the investigators, patients and consultants, our Scientific Advisory Board members. And foremost, my -- all our staff at Ocugen, they work day and night. I mean you saw Arun, Huma and others, they work so hard for that purpose and what we believe in. We can help these patients. They should not be left thinking there's no rescue for them. And we are the hope. We are going to continue to work hard, and we're going to get this hope, actually get it to more patients. So your grandkids, Mr. 003, can have a hope, right, and so we can prevent it. Thank you so much. It's an incredible journey, and we all learned a lot from you. And that's what we do, what we do. And you're actually exciting us and motivating us more. Thank you so much. Thank you all for attending today.