Excellent. All right. Thank you everyone for joining us this afternoon. My name is Whitney Ijem. I am one of the biotech analysts here at Canaccord, and it is my pleasure to be joined by Ocugen this afternoon, and the Chairman, CEO, Co-Founder, Shankar Musunuri. Thank you so much for being here.
Thank you for having me.
Starting with the high-level overview. Sorry, and I have been told to talk to the microphone, so I am going to face this way. What does the company look like today, and what are you hoping to build over the next five years?
Great question. I think, we, as Ocugen today, I believe we lead ophthalmology gene therapies. Why? We have three programs in late stage. If you take the vision loss diseases today with significant unmet medical needs, IRDs, which are inherited diseases, retinitis pigmentosa and Stargardt, and on the age-related macular degeneration, dry AMD is much bigger, right? It is 90% of the AMD compared to wet AMD is 10%. All these diseases have significant unmet medical needs, and these are blindness diseases today with very limited therapies or no therapies across the globe. Today, I am proud to say Ocugen is in late stages, all three of them. We are targeting two BLAs next year, for both retinitis pigmentosa and Stargardt and AMD in 2028. So that is what Ocugen is.
If we are able to get the approvals in all the major markets, U.S. and EU, including Japan, in the next three years and launch these therapies, that will be a monumental task because that can change the paradigm of all these unmet medical needs across the globe for blindness diseases. Millions of patients can get benefited. Today, as we are talking, a lot of the patients across the globe are becoming legally blind, right? That's what Ocugen wants to do. Not only take these gene therapies in the next two years, work hard to file those BLAs or market authors in Europe, across the globe, get them approvals, but we want to work even harder to provide market access to patients who need them globally.
Not after five or 10 years, in a parallel process.
Mm-hmm. Okay. That's important, I think, too. For a lot of investors who think about gene therapy for eye diseases, they might be thinking about these really niche-y, gene-specific approaches that are slow and you got to go multiple to get a larger opportunity. But you all are doing something different. You're thinking broader, I guess, with your gene modifier technology, which uses nuclear hormone receptors. What is a nuclear hormone receptor? Where did the IP come from? How did you identify it, and why was it interesting to you?
Yeah. Nuclear hormone receptors, these are modifier genes. Simple concept is genes don't work in isolation. They work as a network. When somebody has a genetic defect, it's there from birth. So you have the misfolded or toxic protein it's producing, right? And that has an impact on network of genes. So there are genes which are transcription factors responsible in retina for key functions, phototransduction, cell development, metabolisms, cell survival. Some of these key functioning genes are impacted by defective gene, irrespective of what defect it is, right? The technology, it identified the missing link. For something like retinitis pigmentosa, mostly a disease that impacts phototransduction pathways. There's a modifier gene, Nr2e3, that's invented by Dr. Neena Haider at Harvard, and she invented these modifier genes. Why? She is a genetics person. She worked on human genome before.
She spent about 20 years inventing these genes. The invention was, you take RP, you take multiple mutations. Every time there is a mutation, she is tracking it back. Oh, these transcription factors are getting impacted. They provide key functions. Then, Nr2e3 is a link. How about we upregulate Nr2e3? Everything comes to sync in a cellular homeostasis. She also worked on RORA, which is another modifier gene, because when you take diseases such as Stargardt or AMD, one is inherited, another one is age-related. But they both have same complex pathways for progression of the disease, right? Oxidative stress, lipid metabolism, inflammation, complement system. This other gene regulates all those pathways. It also creates a healthy environment for retinal cells, including RP, to survive, which is very important in the case of this. RP has to be protected.
The technology came from Harvard, from Dr. Neena Haider's lab. She did the original work. Then, of course, Ocugen took it, and they exponentially grew that technology platform. Today, not only the IP covers the ability of our modified genes in ophthalmology space, we also cover neurospace. That's the future.
Got it. Good. Okay. Very helpful. I am going a little bit out of order here, and we are going to start with OCU410 in Stargardt disease. I guess, can you review the product here? You briefly alluded to the transgene, but talk about the vector, the transgene, and how it's administered.
Yeah. In Stargardt and GA, geographic atrophy, which is a late stage of dry age-related macular degeneration, in both the cases, of course, you have the macular central vision issues, you have lesion. There are complex pathways. If you take current therapies, the two products approved for GA in U.S., they target complement system. Right? Many companies worked on that. If you take that pathway, that's a final frontier you can call it. It's the last pathway, but the origination is caused by oxidative stress and drusen formation, which is lipid metabolism. Then you got inflammation. A lot of these are important too. Very important. This RORA regulates all these pathways, and we have data in one of those nature publications.
We demonstrated that. Not only it regulates all those pathways, it also has ability to reset cellular homeostasis
and create a healthy environment for these cells to survive. There are certain cells in our human system, right?
You take our retinal cells or you take like a neuron, and some of them, and even cardiac, some of the key things we are looking at, and these are all non-dividing cells. If you take these non-dividing, that's why as we age, we have issues, right? Everybody has these age-related diseases. If there is anything we can trigger to reset them at the cellular level, that'll be phenomenal, right? That's what the genes do, your anti-aging kind of a trigger.
Reset the cellular homeostasis, and then you are creating a healthy environment for these cells to survive. That means at least you should not go down where you are. That's a concept.
Right? In some patients, if you are able to stop the progression, that is great. If you are able to reverse it, that is even phenomenal, and we are seeing that
Right
with both the genes.
Right.
Nr2e3, some of the patients are improving further and further, not only what they have. Some people who got loss of peripheral vision, they are getting it back. Some people who have central vision issues, RP, they are getting it back.
RP patients are getting central vision back. They are seeing much clearer now. I think in all these cases, it is reversing it, too.
That's a difference. Any modality you take for GA, even for Stargardt, oral therapies, they may hit on that one pathway, oxidative stress.
Right.
It may slow down disease progression, but those modalities cannot offer you stopping the progression or reversing it.
It's only possible because this modifier gene therapy platform has the ability to do that.
Mm-hmm. Okay, perfect. Just to dive into Stargardt a little bit more, I talk about Stargardt first. We tend to focus on that one because there's a direct comp here. There's another company.
Sure.
Different mechanism, a different route of administration, but targeting Stargardt, they have filed. That is like a $6 billion company. I think sometimes I bring up Stargardt and you are a gene therapy company, so people will say, "Well, what niche of Stargardt are they going after? What is the small subset of patients they are going after?" Can you talk about that? Are there specific subsets or aspects of the disease or patients you are enrolling, or is this also a broad Stargardt?
Stargardt is a very complex disease.
Obviously, if you look at our phase III, we go from 3+ pediatric all the way to adult.
Early to advanced stage.
Within that segment, of course, if you look at the oral therapy you are talking about, the lesion size, too. They went on a very low lesion size, seven and below. There is a difference, and also their clinical trial focuses on age group of 12+ .
There must be a reason for that, right?
Yeah.
Obviously, agencies look at all these safety issues when you go to pediatric population, so they are restricted up to a certain age group.
We were asked to actually go down to 3 + to cover the population.
Yeah.
We also have a Rare Pediatric Disease Designation with our Stargardt. The Stargardt, we have a combined. The study got, it's a U.S. study, but it got endorsed by EMA.
They like the design. We did only small phase I because of unmet medical need and promising data we saw in phase I. FDA allowed us to convert our phase II into phase II/III total trial.
EMA said, "That's fine. You don't need any other clinical trials," right? The clear difference, again, I'm going back. They are focusing on the oxidative path, right? That modality, I'm not saying it's bad. It's one of the key factors. But you have to take it oral medication every day.
If it slows down a disease progression compared to control, that's fine. When you don't have anything, that's great. But you have to be compliant. You have to take it all your life, right?
And whereas we come back and show after our therapy, because our modifier gene is based on all the nature publications, all the data we are getting from all these programs over the years, if we are able to not only slow down, in some patients it is stopping it. Some patients it is reversing it, and it is one and done. That is it.
You take one injection back of the eye, you are done.
So that is a huge difference. Also, depending on the effect, the efficacy and safety are very important when you launch any. Let the data dictate. If the data comes out, all the things I am talking about,
this is going to be a paradigm shift. It could create a gold standard of care where anybody else with other modalities will have tough time crossing that.
Right? So that's a differentiation.
For sure. Okay, perfect. Phase II/III running, as you said. Pivotal study with a masked interim coming up that could help de-risk the ultimate outcome. Remind us when are we expecting top-line data from the final study?
Yeah. The Phase II/III, we're anticipating second quarter of next year.
The top-line results, and right after that, within few months, we'll do the BLA filing and market authorization parallel.
Okay.
That's the plan. So that means if everything goes according to the plan, sometime in 2028, you should get approval
and launch.
Yep. Perfect. Okay. Then same gene, but moving over to geographic atrophy. Briefly, I guess, can you talk about the differences between OCU410ST, the Stargardt program, and OCU410 for GA? Are there meaningful differences between the constructs, or is it a nomenclature thing?
The construct is the same. Obviously, Stargardt is a rare disease. It has its own path. The VGs, I think, the amount of gene therapy, the RORA we use, the concentration is different.
It's a different dose. Stargardt has a different dose than GA.
That's the difference. Obviously they have their own regulatory path.
One is a broad disease. The good thing is, probably we're the first company to get Regenerative Medicine Advanced Therapy for AMD.
It's a huge disease, and based on the promising data from phase II and unmet medical need, before FDA gave a green signal for us to go into phase III, same week, they gave us RMAT designation, which will be very beneficial. Why? Because typically the PDUFA dates for any big therapies, which are not orphan, is 10 months. In reality, they take longer than 10 months because they're regular products, right? Not orphan significant. So in this case, having that RMAT is almost like an inclusive of Fast Track and Breakthrough encompassing for gene therapies, and it'll allow us to get an accelerated approval.
when you do the filing in six months, which is very important.
Right?
Yep.
There are a lot of other things, benefits you get, post marketing commitments to channeling with FDA during the phase III clinical trial. Anytime you want to have meetings, because of unmet medical need, RMAT, they jump on calls with you. So they're supposed to collaborate with you
to take this therapy to the market
because of unmet medical need and the promise.
Yeah.
I think those are all the elements we have in GA.
We are trying to embark on a phase III, about to get started this quarter.
It's a single trial. We already got green light from FDA. We're working with the EMA.
Hopefully in the next few weeks to months we'll be able to align, so it'll be a single global trial.
Mm-hmm. Okay, perfect. We will be looking for updates on that. Last but not least, as far as the product discussions go, is OCU400, which we could start with as well because that's the nearest term pivotal readout coming in the first quarter of next year. For OCU400 in RP, what's different about the transgene here? You mentioned Nr2e3. Why does that make more sense in RP versus RORA for the other two?
Yeah. Nr2e3 works mostly on the transduction pathways. When you take RP, you start with rods. I think regulating those phototransduction is important for RP patients because they lose the peripheral vision, night vision first, then the central vision. Whereas GA and Stargardt, it's almost like a macular. You got central vision issues. I think RORA is better regulating those pathways. That's how we differentiated it.
Got you.
We have good evidence in those nature publications. They're very methodically done.
Then we went to the clinic.
Yep. Okay. On the clinic, can you talk about the key takeaways from the phase I/II study? I guess what is new or different in the phase III design versus the phase I/II? I'll stop there.
Yeah.
I'll talk to you later.
The phase I/II study obviously is still a controlled study, but the contralateral eye is the control. We had 18 patients with multiple mutations, and the rhodopsin is one of the big ones because typically most of the rhodopsin mutations are autosomal dominant. That means if you try to give a traditional gene therapy, you can get a gain of function, which is actually a gain of dysfunction, right? Because the defective gene is so powerful they can turn the functioning gene signal into more negative. Right? That's why a lot of traditional companies didn't attempt, because that could be safety impact. If you take entire RP, rhodopsin is the biggest of all the mutations, 10%-12% of RP population. So we took that tough population in phase I/II. We showed very promising results. Right?
We also used the same, similar, I can't say it's same, mobility test. It's a functional test because these patients lose peripheral vision, night vision, so if they can walk through a maze with obstacles, that's the first product got approved using the same endpoint. With agencies, if you use the endpoints where they give approvals, you have a low barrier to pass, right. So at least you're aligned. You're not trying to get a new endpoint and prove it's clinically meaningful and all that. So that's good. We took that, and when we looked at the phase I/II obviously, sometimes, because it's a safety study, you got a very high-risk population, too. And some of them are on the almost like a ceiling effect you can call it, on that mobility test there. That means we stopped at, let's say, at 1 lux level.
You're already at 1 lux level. You may be improving as a patient. You can come back and say, "Oh, I can see something in the peripheral," but I can't test you on the primary endpoint, right. We had patients like that, and so if you take the demographic of patients who will fit into phase III, ability to pass few levels, and phase III also went to 0.04 levels. We made it more specific and sensitive by working with FDA. They helped us out. It's a very good design. We had about 63% of the patients in phase I/II who were eligible for phase III pass two levels compared to untreated eye, which is zero. So that's a good result, right. Then for designing phase III, obviously, we refined that test further, make it more sensitive and specific, too, based on FDA input.
Then we decreased that buffer. We put some buffer in there like, okay, if you have 50%, if you hit responders, and then even though control population, like contralateral eye didn't hit, none of them actually have two levels. Okay. Assume there are 10% failure, right. Or 10% of control, if at all they reach. So based on that, we came up with 95% power reaching passing two levels, responder rates, right. So in real life, if control subjects don't pass, they're zero. You don't even need to get 40, 50%. Much lower number responder rate, it'll pass. Why that's important? LUXTURNA got approval with 30 patients. Okay. Our phase II had 18.
Our phase III has 140 patients with 2:1 ratio, and we had more than 30 mutations covered in the phase III, so most comprehensive, early to advanced stage, pediatric to adult, most complex genetic medicine trial to date globally, period. Why? All the genetic medicine FDA approved to date, they're less than 50 patients. That's it. So this is most comprehensive. Then in phase III, we took 30 patients. LUXTURNA got approved with 30 patients, actual patients. We validated the course. It's very robust. The variability in the course is almost zero. That means a patient walks on certain level multiple times, changes everything, it'll only fit on that level. So I think it's very robust. So that's what we are using in phase III. So those are all good elements of our clinical trial-
which is a validated course and also refined course by closely working with FDA and data supported by phase I/ II. Going into phase III, we built some buffer into that.
We took all those precautions. In addition, we will continue to monitor low luminance visual acuity as a secondary, and there are some PGA, score of patient quality, all those things we are collecting.
LLVA is very important because this mobility test is very complex. Tomorrow, when you get the product approved or even the current phase I/ II patients, we track them for three years. We are going to have four years data next year before we do the BLA filing. It is very difficult to do mobility test because it is very complex. But on annual basis, when they go to doctor's office, low luminance visual acuity, LLVA, is easier test. It is more accurate and more sensitive for these patients because most of these patients with these IRDs, even for dry AMD, the low light visual acuity is a first target. Definitely BCVA will have impact in the longer term, but LLVA is a good measure for all these patients. It is easier to measure in doctor's office. So that is a long-term measure.
Got it.
In fact, in RP we showed most of these patients are about two line improvement on the treated eyes using LLVA consistently three years, which is good.
Yeah.
We also showed durability. Another thing with all our therapies, they are subretinal, right? It is a small vitrectomy, and going directly into the retina because you want to express the gene where the effect is needed. In RP as well as Stargardt and GA. Stargardt and GA, you can have multiple blebs, so you got a more surface area for gene expression, so you get the impact. All these targets we have going into I lost the thought. So with going into RP with the phase III clinical trial, LLVA becomes a long-term measure.
Okay, for payers. That is what I want to bring it back because you want a easier measure.
Right.
That is why we are doing LLVA.
Right. Yeah.
Because mobility test is very complex. For approval up to one year, we will monitor.
Because all the gene therapy, the reason I brought all the gene therapy programs, we have obligation to agencies to monitor for safety
Right
for five years.
Right.
Okay? After one year is for approval, but even phase I/ II, we will continue to monitor. We also treated more than 325 patients across all the clinical trials
including expanded access program for RP. We have more than 50 patients in EAP.
A lot of data coming up.
Right.
Almost like more than 200 patient treated for RP.
We do not have any SAEs
Yeah
serious adverse events related to our gene therapy
Right
in all these populations. We have good safety database.
Right. Right. Strong safety database. Okay. That is super helpful. Phase III data coming in the first quarter, as I said. Talk to us about the BLA filing. I think you are on track to start that actually ahead of the data. Is that still the case?
Yeah. Yeah. Good point. A lot of gene therapy companies, I think CMC is very complex, so we are ahead of the curve. Most of all our phase III clinical trials, we did whatever is needed, not taking a lot of favors. We introduced two commercial scale lots for both RP and Stargardt in our phase III, and then we have successfully completed our PPQs, validation runs needed for BLA submission for RP, and that same material, the supplies can be used for commercial.
We already have launched supplies for RP. We are in a good shape. Non-clinical and CMC sections are ready to go, the modules.
Perfect.
Under RMAT, we have eligibility to file rolling submission. We had to work with FDA, their timing and their clock and the resources. We agreed, and FDA suggested when the top line comes in, talk to us
at the pre-BLA meeting. At that time, maybe we will allow you the sections already, and that will still give them about several weeks head start before we drop the clinical module.
Gotcha.
I think that's where we left off.
Yes, under RMAT you're eligible, but you still have to work with the agency.
Gotcha. Gotcha. Okay.
The target is first quarter top line.
Within months after that, we will file the BLA completion. The rolling BLA submission does not have any impact on completing BLA filing approval clock. Approval clock starts with final BLA module. That is clinical. Six months from there.
Right.
If you do it in second quarter, fourth quarter is potential approval.
Right. Right. Okay. Got it. In the last 15 seconds, you recently converted $130 million convertible note financing, extended the runway into 2028. We have talked a little bit about that, but just quickly review what are the key milestones that that capital gets you through, and how should investors think about spend, particularly as you start the OCU410 phase III?
Yep. The good thing is the spend will not increase that much next year because we got two phase IIIs this year. We completed recruitment, and those things next year, they are completing them, right? So their spend is going to come down, and the GA is going to take over. So mostly our financials are going to stay the same. The $130 million should get us into 2028, and obviously, we announced another regional partnership. On the BD side, we are very active. In U.S., we want to be very opportunistic, because there is a lot of value in U.S. for our gene therapies. We will work with payers. Ex-U.S., even though a lot of us came from big pharma, we can do global commercialization, but it takes a lot of effort and time to establish infrastructure. We are evaluating partnerships.
Based on how much money we can raise non-dilutive funding through partnerships, we are going to evaluate next year. Then if we need to raise, we want to be sensitive to our shareholders, and if we need any more equity raise, we will raise it to support our commercialization in U.S. That is the plan.
Okay. Perfect. Very helpful. Very interesting story. We are out of time, but thank you very much for that overview, and thank you everybody for coming to listen.
Thank you.