All right. Great. Excellent. Good morning, everyone, and welcome to the Ocugen presentation. Happy to have Shankar Musunuri with us today, CEO of Ocugen. As you know, Ocugen is developing gene therapies for various diseases causing blindness that are gene agnostic. Maybe to give you a little bit of a better description than I did, Shankar, you can come up and give your presentation.
Thank you. Thank you for having me here today. Good morning, everyone.
Morning.
Forward-looking statement. We are leaders in ophthalmology gene therapy. If you take vision loss or blindness diseases today, the major ones, inherited diseases, as well as diseases such as dry age-related macular degeneration, we have products targeting all those diseases. I mean, covering the majority of the vision loss diseases today. They are all in late-stage phase III clinical trials. How are we able to target large populations compared to gene therapy for everybody is like, you know, precision medicine. You got a genetic mutation, you target, sometimes it is 50 patients, 200 or 2,000. We have modifier gene therapy platform, which are like master regulators. When you have any genetic defect starts from birth. The toxic protein you are producing that has impact on the entire gene network of functioning genes. That is always there.
By giving a traditional gene therapy, it is good depending on when you give it early on. What we found out, the key functioning genes responsible in the genetic network, genes don't work in isolation, they work as a network, such as cell development, inflammation, metabolism to cell survival. These key functioning genes are depressed, and there is a link that links up to a nuclear hormone receptor gene master regulator, and that is depressed. When you upregulate, the whole system comes back to life and resets the cellular homeostasis, restores the function. That is very important. Why? Retinal cells are non-dividing cells. If I can do something to reset them, potentially they should survive rest of your life. We have four groundbreaking publications in Nature. Today, we see the results in humans.
I cannot sit here and promise every patient is going to stop their disease progression and reverse it. You do not need to do that to get drugs approved. If you slow down the disease progression, you will get the drug approved. In some of these cases, we are getting long-term data. I can see these patients, some of them, they stopped disease progression. Some of the patient, it is reversing it. Also, complex diseases such as macular degeneration, they got many pathways. There are a couple of products for GA today, dry age-related macular degeneration. They target one of those pathways. If you target just one pathway, the results may not be optimum. Our another master regulator gene modulates all those pathways, also resets the cellular homeostasis. That means creating a healthy environment for retinal cells as well as RPE cells to survive.
The programs in phase III clinical trials today, the top one is OCU400, targeting retinitis pigmentosa. We have a gene-agnostic indication. It targets RP can be caused by mutations in over 100 genes. This one targets all the population, very broad indication. Also, pediatric to adult, early to advanced stage. Topline results are expected in first quarter next year. Today, I will go a little more into that, what it means, what these results mean to us. The second program, OCU410ST, targeting Stargardt disease, is going through phase II/III parallel clinical trial. Topline results are expected in second quarter of next year, and followed by the BLA and market authorization applications. The last one, OCU410, is a large program. Our team, I am very proud of them, they have done a phenomenal job.
Within four months, after phase II data came out, they had a meeting with FDA, end of phase II. Followed by that, we got a Regenerative Medicine Advanced Therapy designation, which is rare, given to a large disease burden. Typically, it is given to cell and gene therapies, which are orphan in nature. Because of significant unmet medical need, promising data we generated in phase II, even though there are a couple of products in the market for GA, we still got our RMAT. FDA still believes there is a significant unmet medical need. This is going to be a game changer for this patient population. We are recruiting patients right now. This clinical trial is going on in U.S., Canada, and EU. It is a global trial of 240 patients. We are hopeful to complete recruitment next year. It is a one-year duration.
All our clinical trials are one year, because we are able to show effect in patients in one year. Since all these diseases are significant unmet medical needs, regulatory agencies are working with us. Anybody in this space, they all do two years clinical trials. With that, what I would like to do, walk you through OCU400. The topline results are expected by first quarter of next year, in 2027. I wanted to just to recap, what is the primary endpoint? How did we drive into that? And what the results mean. In phase I/II, we had a gene-agnostic approach. We had multiple mutations, including rhodopsin, which is a significantly autosomal dominant, which is very difficult with the traditional gene therapies. It is 10%-12% of the entire 100,000 RP population. We had promising results. The safety looks good.
We don't have any SAEs related to our gene therapy. The majority of the patients, about 89% showed stabilization or improvement with one of the critical functional measures. We also released this year three data, long-term durability, and it looks good. Patients are continuing to do well. That's important. What is the primary endpoint in phase III clinical trial? It's based on mobility test. This test is similar to one of the products, LUXTURNA, first product got approval. What it means is, most of the RP patients lose their peripheral vision first, then they have night vision, then they have central vision left. Some part of their life, they'll become legally blind.
What it test measures is, if very analogous to, if you go to a restaurant, today, I need somebody's help to take me in a dull light to go sit in my chair. Here, after the treatment with the gene therapy, if I can go walk through in a dull light, and navigate and sit in my chair, that means I have improved. That's improving quality of life. The test is similar to that. It goes through from bright light to dull light, bright light, sunlight to dull moonlight, you can think of. If I'm improving couple of levels after the treatment, after one year, that means I'm making significant progress in functional vision. In phase I/II, we used mobility test. That's orange bars show that. There, we compared ITT population which meets phase III clinical trial.
Only certain percentage of the phase I meets phase III population because there are some restrictions, because there is also ceiling effect. In phase I/II, for example, the score ended at 0.1 lux levels. That means if I'm at 0.1, even you're improving, I cannot measure you. FDA worked with us, thanks to them. They said, "Why are you stopping at that? Go to 0.24." That way, you can still take patients at 0.1, you can show the improvement. Also, we expanded on the other end to 500. Because of that, the levels increased. You can see the score. FDA actually asked us to change that. You don't need to have logarithmic differences in some levels. You can actually even them out, which makes it easier actually to pass in phase III.
If you take that phase III score, we had a 71% passing two levels. That's a metric we had to meet in phase III. We used the data, we moved into phase III. It's 140-patient trial, largest genetic medicine trial in the world to date. All the gene therapies approved by FDA, many of them had about 50 patients or less. We have recruited about 30 genetic mutations in this clinical trial. Anything which has a 1% or 2% of RP and above, major ones, they're in the trial. Having that 140 patients, a pooled analysis gives a very good power, 99%. So we pulled a buffer at 70%, 71% in phase I/II.
We said, "Okay, we'll build a buffer, 50% responder rate." Even though you saw zero untreated eyes reaching two levels, we said, "Okay, 10%, a risk mitigation." That gives us 99% power. In reality, my team thinks, we validated the score for phase III. It's sensitive and specific compared to what others have used in the past. My team says it's very robust. KOLs believe it's a very robust score. Even improving one level is clinically meaningful. My team believes reaching two levels for untreated arm, two levels is almost very difficult. That means if they don't reach, just like in phase I/II, if they have 0 or 1%, all we need is 20% responder rate to hit the endpoint. This is a very nicely designed trial, and we are very excited about looking forward to the phase III data.
This is geared, the team is working hard. The data should come on time by the end of first quarter, and we're going to immediately meet with FDA for a pre-BLA meeting and keep moving with our BLA. The goal is to file the BLA by second quarter, and then that will give us accelerated priority review because we have orphan drug designation, RMAT designation. That should put us in fourth quarter of 2027 of PDUFA date potentially, and get approval and launch the product. Right after FDA BLA filing, we'll also file MAA in Europe. We're also working with PMDA in Japan. All those filings will go, and the international filings will follow. Now, I'll spend a couple of minutes before we go into Q&A. I want to focus on the commercial potential. The three products we're working on, we're not even surfacing beyond U.S. and E.U.
We just take these two markets, and RP has 300,000 patients. The pricing based on pharmacoeconomics, $1 million-$2 million is very reasonable. If you take a midpoint of $1.5 million, 300,000 fraction of the patients, that's a huge opportunity commercially, multi-billion dollars per year. Same thing with Stargardt. When you go to GA, that's a huge opportunity. I mean, 2 million patients in U.S. and E.U. If we can treat 100,000 patients a year, if you pick a midpoint or even the lowest point of $300,000 a patient, it's a huge opportunity for Ocugen and our shareholders. All these products, again, we are not targeting 50 patients or even 2,000 patients. We're going after hundreds of thousands to millions with a potential one-time treatment. That means we have a very significant commercial opportunity. Now, I'm going to show you what it means. Take these three diseases.
Irrespective of people are working with other modalities, it doesn't matter. At the end of the day, if you have, it doesn't have to be Ocugen. If somebody comes up with a one-time treatment with gene therapies, even for GA, Stargardt, they can compete with Ocugen. That's the market size. I mean, RP is close to half a trillion. GA is bigger than trillion dollars opportunity. That's just in U.S. and E.U. The pricing, we picked like a midpoint in our GA, like $450,000 a patient, which is very reasonable because currently enzyme treatments, some of them you have to use on annual basis. They're getting that kind of reimbursement. Stargardt and RP, $1.5 million is a very reasonable target. In fact, there are publications out there, some of the big pharma were trying in this indications. They were positioning to price $2.5 million and up.
This is a very reasonable pricing. If you look at it, the market opportunity for these therapies is huge. We are leading all these programs in phase III. We are leading for one-time treatments. That is an opportunity for us as a first mover. We will have that first mover advantage with one-time treatments. With that, now I would like to turn over to Q&A.
Sure. Okay. Thanks for that presentation and for taking some time to discuss this. I guess I have a few. I guess just going back to the gene modifier concept and the master regulator, I guess, starting with RP. How many mutations for RP did you look at in the first phase I/IIa trial? How many patients were there, and to what extent can that translate into possibly a much more varied mutation population in the phase III since you are including all of the different mutations?
Sure. Yeah. Good question. In phase I/II, we had three mutations.
One of the major ones is rhodopsin. That is because rhodopsin is 10%-12% of entire RP. Why traditional gene therapies didn't touch rhodopsin? Rhodopsin, most of the rhodopsin mutations are autosomal dominant. That means if you try with traditional gene therapy, the defective gene is so powerful, it can turn the functioning gene signal into more negative. It is called gain of function, or you can call it gain of dysfunction. That is why it is actually almost like a 2x of XLRP. That is why traditional gene therapy companies didn't touch it.
Because of safety issues. We took those patients and we showed very good effect. Other two are related to NR2E3, so that gave us a lot of confidence. In phase III, obviously, as I mentioned, we had about 30 mutations. We also, in parallel to phase III, because there is lot of unmet medical need in RP, and we are getting a lot of calls. Because of the Regenerative Medicine Advanced Therapy designation, FDA suggests when you're in phase III, because some patients may not fit into phase III clinical trial, and the phase III clinical trial closed out, and then some of the patients are desperate. The way RP hits, depending on the mutation, you may be okay until 40, 50 years. Suddenly it hits you, and they get desperate. So, they suggested, you can always open up expanded access program.
Unlike France, we cannot charge for expanded access program commercial price. In France, you can charge commercial price. We opened one in Bahamas. There you can charge commercial price. Here, of score, you can get some reimbursement, but mostly surgeons' cost. So we opened it up. I mean, to date, in one year, they treated like more than 50 patients. They had 15 different mutations in EAP program. Obviously, I didn't see the data yet, but I can see, I talked to some of the investigators, some of the patients are coming out on YouTube after nine months, and they're doing better, and they have multiple mutations again. Since we took the hard one in phase I/II, that gave a lot of confidence to us. Even agency, when we talked to FDA, they liked it.
We took one of the toughest mutations and based on some EAP, what's going on in the field right now, real-world evidence, it looks like it is working the way it's supposed to work, gene agnostic. That gives us more confidence.
Okay. When you're talking about improvement, are you talking about improvement from baseline or are you talking about improvement from placebo?
Yeah. What you are looking at here in this case is, in both the cases, you compare from the baseline.
You start, you are a control subject or a treated subject, it does not matter. If you are, let us say, at one lux level, now you got two levels before 0.24. So if you hit the second level, that means you are a responder. So you do the same thing for control subject. You start at one lux level, do you pass two levels? So you compare the percentage of the patients, the responders in treated and untreated. That is a statistical comparison.
Okay. Well, I am only asking because
Yeah
some of these treatments are meant for vision restoration and some of these
Sure. Yeah.
treatments are meant for-
Sure
slowing of progression.
Yes.
I'm just trying to figure out exactly what you're capturing there.
Yeah. From mobility test, you are looking at improvement of functional vision.
Right? What you're doing is, if the percentage of responders is statistically superior to control, that means your treatment is benefiting these patients. That's number one. That's primary endpoint. The secondary endpoint, we're still looking at low-luminance visual acuity, because the mobility test is very complex. People have to walk through the maze. It takes a lot of effort. Patients get tired. In the long term, even for payers, right, you want to look at outcomes the second year, third year. How do you measure that? LLVA, because most of the retinal diseases, what we are finding out, the LLVA is a very good measure, when you're looking at two or three years timeframe. BCVA takes longer because in bright light you can see it better, so that may take longer. LLVA is a good sensitive test.
That is a secondary endpoint we're measuring as a function of time, right? One year, if you're looking at LLVA, that you're talking about baseline. You're looking at the baseline where you started. Are you stabilizing?
If you are within like one line, which is like five letters, that means you're stabilizing, plus/minus, right? Then you can compare with, where are the untreated controls? Are they dropping compared to treatment? That's another secondary measure we have, and we'll continue to measure that. That's a easy measure when you're looking at long-term data. That's what we published in like three-year data. Fourth-year data is going to come out sometime before our top line too.
Okay. As far as the patient population that you're enrolling in this, are these patients who still have some level of vision function, and you're completely eliminating the moderate to severe patients who have already lost vision? Is there any kind of restoration of that population, or are you primarily trying to catch them before they lose vision?
Yeah. I mean, definitely we take from early to advanced stage.
There is another terminology people use in this field is called severe disease. We're not treating severe disease. Severe disease is beyond 20 by 200 in BCVA terms. That's legally blind. That means you don't have any photoreceptors left. For our therapy to work, you need to have some retinal photoreceptors left, and we go to the target and inject. There may be other therapies out there, optogenetics. They may be useful for that small segment of the population, very small percentage, where people are legally blind. Then, they put a gene which can absorb and emit light, and they may have some functional effect on the way to optic nerve. So they're not really going into retina. Obviously, we cover most of the disease population, early to advanced stage. In the clinical trial, of score, you need to meet certain BCVA criteria.
You look at the OCT scans. That means you have certain retina left.
In that population, you are going to get a range of responses, obviously, from early to advanced. Did you have any data that, I guess, characterize each of the various responses of the different stages of disease, and how might that impact that final outcome that you get for this specific trial?
Good question, because we have a lot of heterogeneity.
30 different mutations, then you are looking at early to advanced stage and pediatric to adult. However, one of the things we looked into, our phase I/II, some of these patients in, as you know, early-stage clinical trials, you have a lot of late-stage patients because of safety reasons, you recruit. Some of these patients have lost their peripheral vision. They started stabilizing after year two and year three. They are actually improving.
Their peripheral vision is coming back. We do not need to go that far, right? If you stabilize it and if you slow down the disease progression compared to control, that should be good to get the drug approved. Here, what it tells you is these patients are almost in the advanced stage. They lost like most of their peripheral vision is gone. If they are showing improvement, they can see the hand moving, they can see the cars moving, and third year, they can see the lines on the walkways when they are sitting in the car. That is a remarkable difference. Some of the patients, in fact, there is a video on our website, and she has a dark adaptation and a central vision. She works in a departmental store. They use special lenses to look at the price because customers should not know she has a genetic defect, right?
After treatment, after one year, she does not need those glasses. She can actually see. The other eye, her dark adaptation has improved. When she goes to movie theaters now, she can just like regular. These are different mutations. People are getting different effects. I think it is good. I mean, once again, because of unmet medical need, our clinical trials are one year, because number one, it benefits patients. It will be very capital efficient as a company. If you wait for longer term, we are seeing a better effect.
Okay. I guess, just stating the obvious, you have three programs-
Yeah
ongoing right now. Can you tell us a little bit of the difference between, what, OCU400 targets versus, what, OCU410 targets?
Sure.
This is going to get into the whole commercial aspect of it, but Stargardt disease is obviously a rare disease, and GA is not. Are you using the same compound for OCU410 and for OCU410ST versus OCU410?
Yeah. No. OCU400 uses nuclear hormone receptor master regulator NR2E3.
Very specific to that. That's OCU400. OCU410, GA, geographic atrophy, or Stargardt, it uses RORA gene. Why? Because RORA can regulate those four pathways, oxidative stress, lipid metabolism, inflammation, and complement system. These pathways degenerate in both the cases. Even though Stargardt is an inherited disease, the same pathways cause the degeneration in these patients, same thing as GA. There is a commonality there. RORA has the ability to regulate all these pathways. There is a Nature publication which goes into a lot of details, and also resets photoreceptors and RPE cells, creates a healthy environment for them to survive. Why that's important? Because the oxidative stress and also the lipid drusen and aggregate formation are very important, and they mess up the RPE layer. If you can make them function, that's very important for these patients. So the difference, that's a distinction, right?
Those two different genes targeting these two diseases. The second one is, yeah, it's the same product. It's not the same product, it's the same gene. Stargardt concentration is different, the product itself, compared to GA.
They're not technically the same product.
They're not technically the same product. Because for FDA, everything has to match. Even though we are using the same gene, it's the same AAV vector, the product is actually differentiated.
How are you delivering this product? Is it through intravitreal or is it subretinal administration?
All our products are subretinal. We believe these are one-time treatments for life. It's a 40 minutes vitrectomy. Many years ago, like 15, 20 years ago, when EYLEA and other drugs got introduced for wet macular degeneration and DME, people are questioning the same thing. If you talk to our KOLs, they'll say, "Any of our retinal specialists can do this." Subretinal is not a big deal. It's a small surgery. It targets why it's important. We did our own non-human primates, things like going into GA, too. We looked into intravitreal, we looked into suprachoroidal. In large animals, we looked into subretinal. From safety perspective, effect perspective, this is the way to go. It's a one and done. I don't think it's a big issue for patients. That leads into what we do for commercialization.
The commercialization, let's say we have 30, 35 centers in our network today for our clinical trials. We are going to improve those and then take it to 50 to 100 centers. They will become centers of excellence. We are going to direct all the patients to those centers. Same thing we will do in other countries. Why that is important? Even though all the retinal specialists we have in this country, they are smart, they can do this, that is not the issue. The issue is we have a surgical procedure, we mastered it in all our clinical trials. We treated more than 300 patients. We do not have any SAEs, severe adverse events related to our product. We want to make sure all the surgeons are like a manufacturing process, following the same surgical procedure that gets one and done. We want to make sure patient safety comes first.
We just want to pick those centers. Also, with the gene therapies, you got a multi-year outcome analysis, right? When you have these centers for excellence, it is easy for the same specialist to monitor the patient and say, "Ah, year two is still doing good. Year three is doing good." There are a lot of long-term things we had to think through. This is a disruptive way of thinking. The molecules we have are disruptive. The targets we have are disruptive. Large populations we are targeting. Nobody thinks gene therapies can go after millions of patients. The commercialization, the way we are thinking, is disruptive.
Just going back to subretinal administration. I guess we all understand the immune-privileged area.
Sure.
It is an immune-privileged area of the eye. From a safety perspective, it is probably better to administer it subretinally. Have you done any bilateral studies, or have patients had an option to enroll into any bilateral treatment, and is the FDA going to request that of you?
Yeah, I think it is a good question. Our RP study today, in fact, several patients have bilateral. We pick a worst eye as a study eye. If other eye is qualified within a few weeks, they can get that.
That is number one. Ethically, that is important, patients get both the eyes done. Number two, when you go commercial, Spark did the same thing when they launched LUXTURNA. There is no animosity or ambiguity with the surgeons. "Hey, they got the first eye. When do I do the second eye?" We covered it within like three, four weeks.
That way, it becomes very easier when you commercialize it. I mean, our goal is to get both the eyes.
Do you have a rate of opting into that bilateral treatment?
I mean, obviously, the study eye is the main eye we look for.
In our primary endpoint. All that analysis will be done at the end of phase III. We're also looking into the other eye if it's treated, and we're going to look at all those
Okay
Analytics too.
All right. I guess maybe more of a logistical question. You're ready to file three BLAs in relatively quick succession. Where are you as far as the operations or the manufacturing, and how rapidly can you scale up? Obviously, you've got a relatively large population for RP, but then moving into GA, which is coming rapidly behind it, that's like 1 million to 2 million patients.
My team has done a fantastic job. A lot of biotechs struggle with the gene therapy. Some of us came from big pharma. We have a vision. We got it done way ahead of time. All our phase III programs, we're introducing commercial scale lots, two commercial scale lots. That's needed, and we're not asking any favors from agencies. We're already done with our PPQs, process validations. We have also successfully That material can be also used for commercialization. We have launch supplies ready to go. Second thing is, same thing with the GA, our ex-U.S. partners have plenty of capacity for global supply. We also have facilities in Malvern, Pennsylvania. Our goal is to get them up and running in the next two, three years.
The goal is, because when you're doing in phase III, the quality of the products we are making is very good. During phase III, agencies don't want us to touch anything and change. Once you get the product approved, if we get the U.S. facilities up and running, we can just register them and we can shift.
Okay, great. We're just about out of time, but maybe you can talk about your cash position and what your runway is and how you're going to accomplish all of this.
Yeah. We have runway into 2028 right now. It'll allow us to finish up all our development programs. Obviously, after the top line results are coming up, that'll open up several ways of raising capital for us to support our commercialization. We're very careful on commercial spend and capital on it. We're doing all we can in our working with the payers, including CMS, all the background things we can do, including centers of excellence. We focus on these partnerships, ex-U.S. Also, when the top line results come, it'll open up multitude of capital options for us. Equity financing to royalty financing and other options. Our goal is always look into non-dilutive mode first to minimize any dilution to our shareholders. We are comfortable and confident, and when the time comes, we'll be able to raise adequate funds and continue to keep moving.
Okay, great. Well, thank you very much for your time.