The company's proprietary gene therapy platform has generated numerous clinical candidates and has its lead clinical candidate, OCU400, in phase III clinical trials. There are two phase I/II studies in progress with OCU410 for geographic atrophy, secondary to dry AMD, and OCU410ST for Stargardt disease. So to discuss the company's ocular gene therapy portfolio, let's get started with Shankar. Shankar, glad to see you, and I appreciate you accepting our invitation to talk to our audience today. So to start off, could you briefly discuss your long-term strategy, especially, you know, with regards to the gene therapy product portfolio?
Yeah. Absolutely. Thank you. Thank you for having me, RK. And, obviously, we've been focusing, even though we have cell therapy and vaccine platforms first in class, our focus has been gene therapies.
Mm-hmm.
- modifier gene therapy platform for the last two years, and it's going to continue to do that way, because there's enormous amount of potential, for our gene therapies to treat many blindness diseases. And our long-term strategy is going to truly focus on gene therapies.
And then even within this platform, right, so there are other companies that are developing gene platforms, but whereas yours is quite a bit different. So if you can expand on, especially on the modifier gene technologies, especially the platform itself, that would be helpful.
The modifier genes, I think, if you take gene therapies, traditional gene therapies and gene editing, you're targeting typically one gene at a time, so you have a non-functioning gene. With the traditional gene therapy, you get a functioning gene, and you're supposed to potentially, you know, control the disease progression, and with the gene editing, you change the part which is defective, so we're assuming the network is okay. Many times when you have a genetic defect, the network is corrupt.
Correct.
I mean, we got more than thirty thousand genes in our human system. About 10% of them work in our vision system. And when you have a defect, what we found, the nuclear hormone receptor genes, the master regulators we work on, that's what we focus on. So these master regulators control the functional network in retina, from cell development, metabolism, inflammation, phototransduction to, you know, cell survival. And the expression of, you know, for example, OCU400, we use NR2E3, master regulator. So in these models, when we did, and the NR2E3 is depressed.
Mm-hmm.
So that means when you have a defect, why that's important? Because these genes, these master regulators, control the network and all underlying gene expressions. So many genes are suppressed because of this. So once you upregulate it, and it brings the homeostasis, all functioning genes which are supposed to function, start functioning, and it restore the function, and also create a healthy environment for cells to survive. I mean, recently, you know, just a few days ago, there were five companies, somebody wrote an article about anti-aging companies.
Mm-hmm.
So I think like the phenomena, and that's really important. So when you have a defect, it's important, photoreceptors especially, you know, they're there for life, the non-dividing cells. So if there's a way we can reset and create a healthy environment for cell survival, I think you have a much better potential for them to survive and create and prevent blindness diseases or stop, you know, progression of any disease. So that's why we're very excited about this platform. So that's why we believe the three gene therapy programs we have in our portfolio have potential to treat many blindness diseases.
Correct, so for OCU400, which you're developing, currently in phase III for RP, what sort of data can you highlight for us that gave you the confidence to go to the phase III, and also, if you can, discuss about your current design of the study itself.
So the OCU400, which is based on NR2E3 , currently we're targeting retinitis pigmentosa. Retinitis pigmentosa is a very complex disease. There's only one product approved, from Luxturna in 2017. After that, there are no therapies, right? And so there are currently. If you take the traditional platform of gene editing or gene therapy, you need about a hundred products-
Mm-hmm.
to treat these patients, because about a hundred genes can cause RP.
Yeah
... which is almost impossible. And so we're the first company based on phase I/II. We got a design approved by FDA to go into phase III, the broad RP indication. So that's the difference. And so we have two arms in the study, we have a rhodopsin arm, and there's an arm which is gene agnostic. And the reason we separated them is in our phase I/II, first of all, there's one product which is approved, and the two in phase III right now. Ocugen is targeting RP. We're in phase III. And J&J has a similar program, I mean, not gene agnostic. They're targeting very specific gene, RPGR. They're in phase III. And what is common in all these? One approved product, two in phase III.
The functional endpoint in all these three programs is mobility test, walking through a maze with the different light conditions. So if you're able to function, because most of RP patients, they lose their peripheral vision first, and night vision, then they have central vision left. Eventually, they lose that. So if you're able to stall or improve ability to walk in this maze in the lower light condition than when you started the therapy, that means a functional improvement. It means a lot for them. So all of them, what is common is mobility test. If I take that mobility test, when we looked at our phase one, two data, if you take patients who are improving two levels or more in the mobility test, and we have 62.5% response rate, we can call them responders.
Across multiple mutations, what we used in phase I/II. And if you take the product, which is in the market, approved phase III, they got around 52% responder analysis. So that's, that's really good, right? We are about just to comparing that mobility test. Then we set up the phase III at a 50% responder success. That means our threshold in phase I/II, we already proved with multiple mutations were at 62.5%. We lowered it to minimize risk for the phase III at 50%. So. And also, we powered the study over 95% power. So typically, phase III trials, you can start at 80% power, so this is further minimizing it.
So that means we also allowed, based on, you know, market product, if there is an anomaly, if there's, you know, response in untreated, typically, if it's a slow progressing mutation, genetic mutation, you may not see much change. Then in the test, you know, you may be stable. However, you should not show, like, you know, one or two levels improvement in this mobility test. However, we took that based on the data available, let's say 50 to 10.
Yeah.
That means 10% untreated, our responder is 50% untreated. In real life, our test is more sensitive and specific. If you have zero in untreated, you may not even have to hit fifty. That's why we're looking at the data, and we had data from 18 patients in phase I/II, including Rhodopsin, which is autosomal dominant. Rhodopsin consists of 10-12% of RP. That itself is 10,000-12,000 patients, bigger than any gene therapy which is launched in the market today. So that will also minimize the risk. So since we have good data on it, that's a separate arm, 75 patients on that, 75 patients in gene agnostic.
That means we can take early stage, mid stage, late stage, any RP patients, as long as they meet you know, our BCVA criteria to enter into a clinical trial, as well as ability to pass two levels.
Mm-hmm.
If they're at the edge of the core, we cannot take them. And so that's the criteria. So any RP mutations can be part of the trial.
So you, since you just spoke about the gene agnostic cohort, what's the significance of having that as part of your clinical trial itself?
I mean, that's big because, it's not easy, even a targeted therapy, like, you know, single gene mutations, why there are no products available in the market after, you know, 2017, we're in 2024, seven years. Like, it's not that easy. I mean, it's a lot of complexity. So why this is important? Because there are 1.6 million people global, 200,000 patients in U.S. and EU alone, and they're looking for therapies. They're desperate. Many are going blind. So the traditional, even there is another clinical trial in the, ongoing in phase III, but that's also targeting just a few thousand patients, one gene. So there is nothing out there, gene agnostic way, covering all those potential 100 genes which cause RP. That's why it's important.
We're the first company to get there with our therapy, potentially targeting all these patients. So if you get the results we're anticipating after phase III, that means this is it.
Yeah.
This is a solution for all these patients who are desperately needing globally to rescue from blindness.
Good. Recently, you announced the initiation of an expanded access program for OCU400. So, what's the relevance of an EAP, when, especially when you have an ongoing phase three, and also, would any of the data, could you use that, you know, in your application itself?
Yeah, good question. I mean, expanded access program, typically, I mean, with this program, OCU400, we have Regenerative Medicine Advanced Therapy Designation, which is highest you can get from FDA because of unmet medical need, because the based on the data we generated in phase I/II . What expanded access program, again, very few gene therapy companies have that from FDA. They need to be comfortable. What it does is two things: we have a, you know, a strict criteria to get into phase III, and, since there is a significant unmet medical need, obviously, you have to wait for, you know, until the end of 2026 , the drug to get approved. So in the interim, you don't want to wait, you can opt for expanded access program.
Number two, if you're getting into clinical trial, I mean, it's two to one ratio. I mean, you don't know whether you're going to be control group or you're going to be in the treated arm. And so if you don't want to wait, and you're desperate, and some patients, you know, they feel, you know, their eyesight is going down.
Mm-hmm.
And they're deteriorating, and they want rescue now, they can sign up for that. So, also, once your recruitment is closed out for phase III, it'll still take some time for drug to get approved. So that's why this is really important, and sometimes, you know, if a clinical trial, you don't fit into that, or you don't want to wait, you know, this program is always there for taking care of patients... and this is something we want to do. And the data from this, obviously, efficacy is based on the phase III design, what we did, but we do need to collect safety and follow-up, so all the data can be used from safety perspective.
So two weeks ago, you also got approval from Health Canada to include some of the Canadian sites for this trial. Since RP is a global indication, are you looking to add centers outside of Canada as well?
Canada actually follows pretty close to U.S., and we're getting a lot of calls from Canadian patients. So we thought expanding to Canada will speed up our recruitment, and we're going to open a few centers. Also, since European Medicines Agency already agreed, we don't need to run clinical trials in Europe, we can actually use U.S. data-
Mm-hmm
... to parallel track and apply for approvals in Europe. Adding Canada will help with our clinical trial, with the speeding up the recruitment, helping patients there. It's a neighboring country, and that will also add up with, you know, our Wave I, you know, approval, parallel approvals with the U.S., EU, and Canada. So those are the, you know, positives, and that's why... and they're very supportive of us, Health Canada. As soon as we applied, very quickly, in weeks, they approved it for us to start the clinical trial, but thanks to them.
In terms of the data itself, when should we expect, you know, an initial set of data or a preliminary data?
So this is a double-blind trial, as in any of the phase III clinical trials, and therefore, there won't be any efficacy data coming out until we close it. That means a data lock, after that. So currently, we're planning to complete our recruitment by early next year. However, we'll provide recruitment updates, and so early 2026, the data lock will be done. Final patient, it's a one-year duration. After last patient in recruitment, one year you have to wait, and then we'll analyze the clinical data. So the plan right now is, because of the designations we have, our RMAT orphan in U.S., orphan drug designations in EU, we have potential to start rolling submission late next year with other sections.
As soon as the clinical data comes out in 2026, we drop that, and that'll, six months accelerated clock starts for approval. So the goal is to get the approvals by, you know, end of 2026, and we'll continue to provide updates to the market on our recruitment rates and everything else so that, you know, we're on target.
Okay, perfect. So 410, OCU 410, is a second modifier gene therapy candidate, you know, the that you have in clinical trials in the phase I, II study. So, especially looking at dry AMD and also Stargardt. So how big are these opportunities?
I mean, dry AMD is a huge disease. I mean, you have 260 million people globally, 10 million in U.S. Late stage of dry AMD, called geographic atrophy, your central vision has a blurriness. They call it atrophy, and if you're 50 or 60, you're desperate, you know. In U.S. itself, it's one million patients with the GA, the late stage dry AMD. It's a huge burden, and there are two therapies in the marketplace, which were FDA approved last year, and they have limitations. One, you have to take 6-12 injections a year, and a moderate decrease in lesion growth compared to untreated. In two years, about 30%, about 10%-12% get wet AMD when you get a treatment for dry AMD in two years.
So a lot of these issues, and I think, another master regulator, RORA, is a very powerful gene.
Mm-hmm.
The therapies in the marketplace target complement system. Dry AMD is a very complex disease, and it has got four different pathways which cause the disease. It's oxidative stress, lipid metabolism, inflammation, and complement system. And so the oxidative pathway and lipid metabolism are very critical for the origin of the disease. When you have inability to get enough antioxidants, you have lipids like lipofuscin, which are needed for the function. And when they cannot function, they create aggregates, you know, so your system cannot clear. You get a cytokine reaction that results in AMD. But the last path is outcome, is complement system. So RORA can regulate all these pathways, and we have data we presented. That's why we are very excited about this program. With a single potential therapy, single injection for life, it has potential to treat these patients.
And then Stargardt disease is also, if you look at the disease pathology, ABCA4 defective gene. And when you have ABCA4 defect, CD59 expression is depressed.
Mm.
CD59 is needed to block complement, right?
Yeah.
So in our case, like another gene therapy company is working, large company, on CD59 gene, but it only goes after complement system. So we don't have to give CD59. The RORA, once you give it to these models we did, and as I mentioned before, it's another modifier gene.
Mm.
It modifies the expression of other genes. CD59 is depressed, CD59 comes up. It's a modifier effect. Therefore, Stargardt is a big disease. It's, like, 44,000 patients in U.S. alone, no approved therapies, and, they're desperately seeking rescue. And that's why, we're very thankful. We are already in, phase II for geographic atrophy program, and Stargardt disease, we just completed phase I. So we are anticipating some preliminary results from our programs in efficacy from our phase I, by the end of this year.
... So that's for the wet, I mean, dry AMD.
Dry AMD, yeah, yeah, and Stargardt.
Okay. So in terms of the GARDian study for the OCU410 in Stargardt, you know, you just completed or you're nearing completion of the phase one portion. What's the initial set of data that we would get from this?
Both these trials from preliminary phase one, we did the dose escalation for both GA and Stargardt, too. So, what we are looking for is at least some of the patients who finished six months. It's not a biological or small molecule, right? To see the immediate pharmacodynamic effect. Gene therapies takes time, especially master regulators work on this. So, whoever's passed, like, six months, few patients by the end of the year, we're going to look into. In both the cases, obviously, we're looking into the lesion size, looking at, you know, compared to approved product in the market for GA. Similarly, for Stargardt, also we'll follow the progress. How these patients are doing compared to baseline where they started. Is it, you know, controlling the progression, or is it stopping in some patients, the progression?
Those are things we'll monitor.
What's the regulatory pathway for OCU410?
Four ten, we're in phase II. Obviously, we had to complete it. We have a very essential blinded study ongoing, 15 patients in each group, 15 in mid dose, 15 in high, 15 in untreated. Once we get the data, our goal is to complete the recruitment, get the phase two done by the end of next year, and then obviously design phase III and move on. Hopefully, we'll put. It's a big disease. We'll find a potential partner to partner with us.
Yeah.
Before we go into phase III. That's the plan.
So the last question for you is on the cash. So how are you folks doing on it, and what sort of a runway do you have?
With the recent rise, our runway goes into third quarter next year. We want to be sensitive to our current shareholders, not to raise too much at once, and the markets are choppy, and we have a great potential. So we have some inflection points coming up. The data release on Dry AMD, you know, efficacy data from phase I trial, preliminary efficacy by the end of the year, and recruitment on OCU400 and the Stargardt disease, some preliminary data by the end of the year. We're also looking at, you know, potential partnerships, you know, for our gene therapies, and there is definitely interest across the globe.
And so we're looking into. We'll look at all these holistically in the first quarter next year, where we are, and at that time, we'll decide if we get some non-dilutive funding from partnerships, then we don't have to dilute the stock, so we just want to be sensitive to our current shareholders, and then we'll navigate accordingly. At that time, we'll decide if we need to raise a little bit more, we will, but I think we want to make sure we go into non-dilutive funding options first before, you know, we go back to the market again.
Perfect. Thank you very much, Shankar, and thanks for your time, and good luck.
Thank you. Thank you for having me, sir.