There are significant unmet medical needs. There are diseases which are associated inherited retinal diseases and AMD, bigger part of the AMD, which is a dry age-related macular degeneration. Currently, Ocugen is working on all three of the programs, starting with retinitis pigmentosa, which has over 100,000 patients in U.S. Stargardt disease, which is another inherited retinal disease, significant unmet medical need, about 50,000 patients in U.S. The late form of dry age-related macular degeneration, geographic atrophy, that's GA, has 2 million-3 million patients in U.S. and EU alone in that late stage. Currently, what we are working on, we have two programs, RP and Stargardt in phase III. We're about to embark on to global phase III with U.S. and FDA, as well as EMA alignment in EU and U.S. together for GA, in third quarter this year.
That means we'll have three late-stage programs, and we are targeting two BLAs next year for retinitis pigmentosa and Stargardt, and the third one with the GA in 2028. That means in the next two years, our goal is to file BLAs for all our three programs, followed by MAA and get global approvals and launch these products targeting many of the current unmet medical needs. We are trying to bring this hope for all these patients across the globe.
Got it. Maybe we can start with OCU410. This is a gene therapy for geographic atrophy, correct?
Yes.
Maybe you could just talk about the gene therapy construct, and just rationale on developing it, for patients with GA.
Yeah, absolutely. We have the modified gene, what we use is RORA, for this program. The same RORA gene is also used for Stargardt disease. RORA, if you look at the disease progression, is caused by multiple complex pathways, oxidative stress, lipid metabolism, inflammation, and complement system. RORA regulates all these pathways, and these genes have ability to provide cellular homeostasis, resetting them, and create a healthy environment for photoreceptors and RPE cells to survive. That's very powerful concept, because that will allow the system to reboot, in a way, and allow if there is a, not only focus on disease progression, slowing it down, and it has ability to control it or stop the progression. In some cases, what we have seen in other patients who have gone through two or three years, we're seeing a reversal of the disease, too.
Again, it all depends, but these genes have ability to reset the cellular homeostasis and regulate all these four complex pathways, which is very important. The current therapies only target like a complement system, right? That they're only approved in U.S. They may have limitations with that. That's why we are very upbeat with this program, excited. That program had a very good, solid phase II data, and we are planning to currently use this concept and go into a global phase III. Again, what we're able to show in phase II also, we're able to show a good effect in one year. Okay? The treatment benefit to patients in one year. Most of the trials in this disease area, people do minimum like two-year trials.
We're able to show treatment benefit in one year compared to anything out there with a potential one-time treatment for life. That's the difference.
The phase II data, I think, you reported on this several months ago, from the program. I think there was about a 31% reduction in lesion size with the median dose. Can you talk about the phase III? Are you moving forward with the mid dose or would you potentially also look at the high dose? Maybe if you could talk about the data across both the mid as well as the high dose.
Yeah, absolutely. In phase II, obviously, we consistently saw, when you do a cutoff from 2 mm sq- 20.5 mm sq, that's a broad range we looked at on patient pool. There are two products in the market, they looked at 2.5 mm sq- 17.5 mm sq because if you look at the patient pool, most of the patients are between five and probably 12.5 mm sq, most of the GA. I think for phase III, we're going to go to what the approved products used, 2.5 mm sq- 17.5 mm sq range, even though we used a broader range in phase II clinical trial. We also observed, in our preclinical studies, again, this is not a biological, this is not a small molecule. Okay. You don't expect a linear relationship dose response. What we saw is a bell-shaped curve in our preclinical studies, and that seemed to follow here.
That's why high dose obviously didn't perform as well as mid dose. That's the reason we do the phase II, right. You define what dose you want to take it to phase III, confirm, and move on. That's exactly what happened here. We got a very good output. Medium dose consistently did well across, take the entire spectrum of 2.5 mm sq- 20.5 mm sq. If you take a short segment of 2.5 mm sq- 17.5 mm sq, high dose seem to do better. On the lower end and higher end, there are some outliers. If you take them, high dose did well, too. In general, we saw about 33% reduction in lesion reduction, if you take the square root of the medium dose.
Based on that, we came up with the phase III design. That's the dose which did across the board well consistently. That's what we're going to use in phase III. Obviously that will be the primary endpoint is just like the two approved product, measuring the lesion, right. I mean, taking the square root of it. You want to look at the rate of change. Obviously we're going to use four-month intervals, four, eight, and 12 months.
Yeah. You mentioned baseline lesion size as one learning from the phase II. Were there any other learnings in terms of patient baselines that you're applying to phase III?
I think, yeah. If you have lesions, I think we really need to have certain size of the lesion, and obviously, at least one of them minimum 1.25 mm sq. We'll have some criteria if you have multiple lesions in there. Obviously, if you look at even the studies which have been done in the past, most of the people end up above 5 mm sq, right? Even though the criteria is 2.5 mm sq- 17.5 mm sq. I think it'll naturally, when you recruit patients, it'll fall in that range. Obviously, there'll be foveal and non-foveal differences, where the lesions are, and we're not eliminating anything. Our goal is to take a good pool of patients based on the lesion size and focus on our primary endpoint and two secondary endpoints, where in this case, we are looking at EZ, ellipsoid zone. Because it's a short trial, right?
It's one year. If you do two years, you may be able to pick up other visual function, such as LLVA. However, we are monitoring LLVA as a secondary endpoint in this. That's what we're going to focus on in phase III. I mean, continue to focus on lesion because it's a one-year trial. We need to be practical when you're designing a clinical trial. If it's a two-year trial, you have more leeway. I mean, what else can we use? Obviously, the two products in the marketplace, they used lesion, so it's a good comparator. We showed the data. In one year, we saw the effect size bigger than any of them achieved in two years. That's good, right? We're going to continue that, and within one year trial.
Of course, there'll be secondary endpoints, which will also look into the functional aspect of it.
How many patients are you planning to enroll in the phase III?
Based on this effect size, we are not anticipating more than 300, less than 300 patients. Since being a gene therapy, we introduced the adaptive design in our Stargardt program, which is really good. Halfway through, when 50% of the patients complete one year, you can take a look. Obviously, the size is so big here, our power is around 95%, when you take this design, what we have. Even when 50% complete of that population one year, you can take a peek in the sense under DMC. Is there any adjustment resizing needed? I don't think it'll have any impact because you already have double the size in the clinical trial. That should help us. It'll also really give an indication for the company, which is always good.
Under DMC strict guidance, somebody looking at the outcome analysis and say, Oh, this is looking good. Even you need to adjust already your power, double the patients, you should be fine. That's a good way for any clinical trial, right? Looking in the middle of the clinical trial, phase III, pivotal trials, a DMC able to guide and give a guidance on it. It's good for any company from risk perspective.
What type of effect size are you hoping to see in the phase III?
The data we had is about 33% difference, when you take that. What we did is we built a buffer. I think we didn't take 33%. We got it down to 25% or something like that. That's what we used for design. We did allow some buffer.
Got it. Then you mentioned you're using EZ ellipsoid zone?
Yes. Yeah.
From a functional standpoint?
Yeah. The secondary will have ellipsoid zone as well as LLVA. There are two secondary endpoints we are going to monitor.
What type of an effect would we want to see on EZ ellipsoid?
In the ellipsoid, in the medium dose, we saw about 27% preservation of ellipsoid loss with the treatment in phase II. We're hoping that anything in that range, 20%+, It's not a direct measurement of visual function, but at least a correlate, right? We believe when you do a one-year trial, that's a good marker to monitor, which correlates visual function. Obviously, we will look into low luminance visual acuity, too, which is a good marker. I mean, actually, it's a direct measurement of visual function. We're going to have that, too, in one year. We want to see directionally how it's looking.
You mentioned the trial, and the primary analysis at one year. Is there an option to follow patients out to year two?
Yeah, absolutely. All our gene therapy trials, the agency mandate is for safety and everything. We have to follow them for five years on annual basis. Even our phase II patients, by the time we file the BLA by 2028, we're anticipating three-year data, right? That data should definitely go on the visual function, like LLVA. Because currently in a one-year trial, yeah, you're looking at directionally, but when you look at two and three years data, that should shed some light into that. That should get good data set for us. It's supportive data. It's not a phase III, but the follow-ups we are doing from phase I, phase II, monitoring these patients for second year, third year continuously, that should help us.
Will the year two or year three analysis, will the control group continue to remain untreated at year two, or will they be allowed to cross over and receive OCU410 or other therapy?
It's a good question. In phase III, it's difficult because to recruit patients, right? These patients have to come back to crossover after one year. Of course, they'll be followed up for the long term. The data, if you look at the natural history, there's a lot of data sets out there for how the natural progression of the disease. I'm sure we'll be able to get good assessment.
Right. I'm sure you have FDA buy-in, given the lesion size as a primary endpoint. There's been past precedence with the complement inhibitors on that endpoint. How about with EMA? That's where, with the complement inhibitors, they focus, I think, on risk-benefit, and they also pointed to potential for vision. Can you talk about your conversations with the EMA authorities?
Yeah. Once again, the same package was submitted to EMA, and we're anticipating output from them in the next few weeks. That's the reason we included, obviously, practically easy, something which is measurable one year, but we also included LLVA as another secondary measure. At least, if they'll be able to see some directional, that may benefit. We didn't want to leave anything. In addition, of course, as we tell agencies, we are monitoring these patients from phase II also, two years, three years, four years, and whatever data we have, we'll be able to provide that at the time of filing. They will have some more data, not just phase III, but looking at some visual function.
Got it. I guess on the phase II, was there anything to note from a safety standpoint?
We didn't have any SAEs related to the drug. Obviously, sometimes with a vitrectomy, you may have some surgery-related issues, but most of them get resolved.
You have a second program, OCU410ST, and this is for Stargardt.
Yes.
Tell us a little bit about this program. I think you've shown some data from a phase I GARDian1 trial. What did you see from a benefit standpoint in the phase I?
From phase I, obviously, we saw a pretty big impact within one year compared to untreated eye. In phase II/III pivotal trial, of course, you have a true control arm. In this, contralateral eye is a control. In that evaluable subjects, we saw 54% reduction in lesion growth compared to untreated eyes. That's about 0.28 mm sq difference between the treated and control group. We used the data to design our phase II/III. That ended up with 51 subjects, 34 in treated and 17 in untreated arm. Once again, in this case also, we're going to continue to monitor other metrics such as EZ as well as LLVA as a secondary. Agency is very supportive of this program because significant unmet medical need. There's nothing like this out there. This is one and done.
We showed bigger effect size in one year than anything out there. Right? This is very important. Number one. Number two, similar to GA, in all our programs, we dosed about 300 patients with vitrectomy without gene therapy, same AAV5 vector, we didn't see any SAEs related to the drug today, which is good safety. Based on that, we are hoping it's, again, potential one and done therapy. Some of the advantages are same thing, resetting the cellular homeostasis and also ability to attack all those four pathways, complex pathways. Not only this therapy has potential to decrease the lesion growth, it has potential to stall in some patients and reverse it, too. We are targeting early to advanced stage, pediatric to adult, three plus. It's a broad range we are covering for Stargardt.
I don't think there is any other program out there which can really compare. It's one and done. In phase I patients, you can see when they're coming close to two years, some of them are not just slowing down disease progression, they're actually improving. That can only be possible with gene therapies, as you know.
Got it. I guess, with the GARDian3 pivotal, there's also an adaptive sample size re-estimation that's been built into that, correct?
Yes. Yes.
I think you're expecting that re-estimation to occur this quarter?
Yes. Yes.
I guess what could that re-estimation tell you and tell us regarding the trial?
Yeah. The re-estimation, again, it's an SSR blinded study, the DMC has a strict guidance. We won't have a look at the data, but they look at it, and they look at the outcome analysis, right? If the 51-patient trial, with 34 in treated and 17 in untreated, they're going to compare. If it's doing well and potentially the predictive analytics show it's going to be fine, you don't need any adjustment, that's one potential outcome. No change, we'll still get the top-line data in the second quarter next year. In a few weeks after that, mid-next year sometime, the BLA will be filed. The second option is do you need to based on actual size you are seeing, because in phase I, you have a contralateral eye, right? Here, you got a true control. You got a real data with the true control.
If you need to adjust up of re-estimation, which is good. It's minimizing any risk for the clinical trial. We had a lot of patients who want to get into our clinical trial, right? We over-recruited. We had 63 patients in the trial instead of 51. We already have the over-recruitment. If that falls within that range, you don't need any adjustment. It's still good. We already over-charged the clinical trial. The third option, once again, based on the disease progression, natural history, when I had discussions with the agency, they're very supportive. They also said, sometimes extending the timeline for 12 to 16 months, another time point may help you. All those aspects, the DMC, with a blinded team, is going to look at it, and they will perform the outcome analysis. What is the bottom line? The bottom line is no change.
Even there is a sample size re-estimation, the numbers are within the recruited patients. That's good enough. They'll get top line results in second quarter. If there is an adjustment or extending the timeline to 16 months, that'll help with the predictive analytics. That's still minimizing the risk for the program, which is really good to have, right, in a phase III. There'll be some impact on the timeline. Is it like three months, six months? That's what we are going to let the market know. What we are going to announce is outcome. Hey, this is the outcome, this is the impact on top line results and BLA filing. That's it.
Got it.
Won't be discussing any data.
Even, I guess with the 16-month, you could still hit year-end next year.
Oh, yeah. Absolutely. Yeah. That won't have a major impact. Yeah. There'll be delay of four to six months at the most. Yeah.
What would be considered clinically meaningful on the 12-month change? Is it the 54% or something less than that?
There are companies out there filing, with a different modality, with 35% in two years. We are way above that in one year, so I don't think we had to hit that high. Obviously, depending on the design and everything, we would like to see, right? The higher numbers are better.
Got it. Anything to note from, like, the safety standpoint from the phase I?
Same thing again. So far, we haven't seen anything related to SAEs related to the drug.
Got it.
The safety and tolerability look good.
You've got a third indication with RP with OCU400. Can you maybe just talk about that program? I think, phase III enrollment is completed, with top line data expected first half next year. What can we expect from that data?
I have to really reset. This is the largest genetic medicine trial in the world. 140 patients. Nobody has done that. Most of the drugs FDA approved had less than 50 patients with the genetic medicine. I'm not comparing people using AAV vector to carry as a drug delivery. I'm just talking about true genetic medicine clinical trials. 140 patients, we have over 25 genetic mutations. The most diverse and very complex trial we are conducting right now. The reason is we use NR2E3, the way our modified genes work, once again, whenever you have any defect, the defective gene has impact on key functioning genes of transcription factors, and they impact them, and they are down-regulated and NR2E3 controls.
By giving NR2E3 through AAV, it upregulates all these key transcription factors, resetting at the cellular level and creating healthy environment for cells to survive, just like RORA does in RP patients, NR2E3 is the key. That's a link. Because of that, we believe it's a gene agnostic and we have pediatric to adult, early to advanced stage. We're covering the entire population, including syndromic, non-syndromic, and patients, in fact, in our EAP program, which is going on the side, had about 50 patients because people don't want to wait until the product comes to the market. They even recruited people with even clinical diagnosis because certain percentage of RP patients were unable to do the genetic testing, right? We really want a very broad indication for this patient pool. The clinical trials are 140 patients, 2: 1 ratio.
That means you got treated populations two and half of that in the control arm. We are going to have one big group. Part of that was rhodopsin, because rhodopsin had more patients in phase I, II, and they did well because predominantly it focuses on the rod degeneration, right? Whereas in the mixed mutations, you can have rods, cones, all mixed up, 25 mutations we are using. Obviously that's a little bigger group. However, we'll be doing a pooled analysis and we're using Luminance Dependent Navigation Assessment, the functional test, which similar one MLMT, what Spark used, we made it more specific and sensitive. In fact, this test got validated for phase III with 30 patients. LUXTURNA got approval with about 30 patients. It's very robust. Okay?
In that test, what you're measuring is rate of change in the sense the improvement over a period of one year compared to control arm. That's what they're going to compare.
Great. We're about up on time. A lot going on with all three programs. Clearly a lot of updates over the next 6- 12 months anticipated from the company. Looking forward to hearing more about all three over the next year or so as you provide those critical data updates. Just want to thank you, Shankar, for taking time out this morning to share some overview of the pipeline and data expectations going into the next year.
Great. Biren, thanks for having me. I'm very excited with what Ocugen is doing. We're not targeting 200 patients or 5,000 patients. We're going after with our one-time potential treatments, targeting hundreds of thousands to millions, and that's the differentiation between Ocugen and other companies out there. We are hoping, just like you stated, two top-line results for two programs next year, the third one in 2028, three BLAs in the next two years. Thank you, Biren. Thank you for having me.
Great. Thanks, Shankar.