All right. Good morning, everyone. Thank you for attending Chardan, Chardan's 8th Genetic Medicines Conference. My name is Daniil Gataulin, and I'm one of the senior biotech analysts here at Chardan. It is my pleasure to introduce our next presenter, Arun Upadhyay, the Chief Scientific Officer from Ocugen. Arun, welcome.
Thank you. Thank you, Daniil, and thank you for giving us this opportunity-
Of course
to speak at this forum.
Yep, of course. The format for this session is the fireside chat, and as always, we welcome questions from the audience. If you have any questions, please raise your hand, and we'll get you the mic. With that, I think we'll go ahead and get started. Arun, if you could spend a few minutes in the beginning, and introduce Ocugen to the audience, please.
Yes. So, Ocugen is a fully integrated biotech company primarily focused on developing therapy for unmet medical needs and also for large public health concern. And we have a breakthrough modified gene therapy platform technology which we are developing for a large group of retinal disease and we have cell therapy targeting articular cartilage knee injury. It is in orthopedic space. And we also have a inhalation vaccine-based platform primarily we are developing for respiratory diseases including COVID and flu.
Got it. Thank you. So you mentioned your modified gene therapy platform, a differentiated approach to gene therapy. So can you talk more about that platform, the potential advantages, what that platform is, and the potential advantages, or what... more broadly, what is different between modified gene therapy and a more traditional gene therapy approach?
Very good question. So, if you look at traditional gene therapy approach, primarily, either it has been gene augmentation or gene editing, and in those approaches, normally, you target either single gene or single mutation. So in contrast to that, modified gene therapy platform is approach where, you know, you can address multiple mutation and at a time, and also, it is not just addressing, directly the genetic defect, but it modifies the disease. And through the disease modification, it provides benefit to the target patient population.
Okay. And are you aware of any other similar approaches in development?
So currently, in ophthalmic space, there is no, as such, there is no product, you know, where people are using modified gene as such. However, if you look at other disease area, disease-modifying concept and drugs have been in this place, for example, muscular dystrophy, if you look at Parkinson's disease or Alzheimer's. So disease-modifying drugs concept has been there, but using modified gene as a disease-modifying agent is quite novel, and that's where our breakthrough approach is. Yeah.
Got it. Okay, understand. So I wanted to dive into your pipeline. So OCU400, one of your lead development candidates, you're developing it for retinitis pigmentosa. Can you talk about OCU400, and specifically, why do you think it's a good candidate for RP?
Yeah, so if you look at RP, the inherited retinal disorder, retinitis pigmentosa, and there are more than 100 genes are associated with this particular condition, and it affects close to, you know, more than 100,000 people in the U.S. alone, and if you look at the global prevalence, it is in millions, so we talked about traditional gene therapy approach, like where you are targeting single gene mutation, either through gene augmentation or gene editing, so the one of the biggest challenge in this space has been, you know, developing a product targeting 100 gene, is a pretty much daunting task or almost unfeasible, but not only that, this approach is limited by the kind of patient you are targeting, the modality, and also in terms of, you know, overall safety and efficacy profile.
So in contrast to that, the modified gene therapy platform, which we are working on, it has potential to address broader RP patient population. That's one advantage. Not directly- it is not that it is directly fixing the genetic defect, but through modified approach, it addresses the disease pathophysiology. So if you look at IRD disease as such, including RP, the disease pathology is primarily centered around the imbalances in the cellular and molecular homeostasis pathway. So what modified gene does, that it brings balance in those pathway, and that is how it not only enhances the function of retinal cells, but also it enhances and preserves the survival of the photoreceptors. So that's how we are unique- we are. So one uniqueness is that it targets multiple genes and mutations.
Okay.
Other approach, it helps enhancing the cellular function, as well as, preservation of the photoreceptors.
Okay. And in terms of the landscape for RP, what is out there currently? And if successful, where would OCU400 fit in that treatment landscape?
So currently, there is only one product approved, if, for the treatment of RPE65-related retinitis pigmentosa, and if you look at the prevalence of that particular mutation, it, it's close to 1%-2% of the total RP patients. Currently, if you look at the pipeline where, like, various approaches, you know, are under development, there are some which are directly targeting, you know, gene augmentation and gene editing approaches. There are approaches where, you know, optogenetics and other approach, like neurotrophic factors. However, if you look at those approach, still that is very limited to the certain segment of the patients, you know, at the certain stage of disease and some certain group of mutations. So in contrast to those approaches, our approach is broader. It covers pretty much all the RP patient population.
So that's how we are differentiated.
Got it. Okay. So, in terms of clinical development, you've completed phase I/II trials for OCU400 in patients with RP, and I believe you're enrolling patients in the phase III liMeliGhT study. Before we talk about liMeliGhT, can you talk about the data that you've seen so far from your phase I/II program?
Yes. So our phase I/II study was for the treatment of RP and LCA patient both. So when we started phase I/II study, we started with total four different types of mutation: rhodopsin gene mutation, NR2E3 autosomal recessive and autosomal dominant, and CEP290 mutation for the LCA patients. So we had completed enrollment of patient in all these, you know, four different category of four different types of mutation. For RP patient population, we had like rhodopsin and NR2E3. So we completed the enrollment, and we have completed the 12-month follow-up, and that was the basis for us getting into the phase III study. So overall, if you look at the safety profile, you know, product was well tolerated and safe.
We had some, a few, serious adverse events in that study, but those were primarily linked to the surgical procedure and very minimal. Like, out of 18, we had only two patients in RP trial. If you look at the mutational distribution, we have total 10 rhodopsin patients and five autosomal recessive and NR2E3, and three autosomal dominant NR2E3 patients. So across all the mutations, we observed very good safety profile. The efficacy responder was, I would say, uniform across all the different mutational landscape.
Mm-hmm.
The efficacy durability for this product across these mutations were one year until we... Like, as long as we follow the study, like up to twelve months.
Okay.
Mm-hmm.
Got it. So, the phase I obviously is dose escalation, right? Three by three design, and you know, with that caveat of smaller number of patients, can you comment on the dose response that you've seen?
So as such, we didn't see any clear dose response in our study across low, medium, and high dosage. And of course, like, sample size is one of the limitation. As you can see, like, for the low and medium dose, we have, like, four and three subjects respectively. But however, like, when we look at the mechanism of action of the molecule, it's a modified gene, okay?
Mm-hmm.
It is a transcription factor. So when we started looking at data, we realized that, you know, maybe it's very hard to predict, you know, dose response in this kind of therapeutic modality, and that might have been the kind of reason not seeing the clear dose response.
Mm-hmm.
Yeah.
Okay. And in terms of durability, did all treated eyes that saw improvement initially, did they maintain that improvement over time? Did you see any patients worsen over time?
No. So, normally, like, depending on the stage of the disease and the mutation type, what we noticed that you may have, like, onset of the treatment benefit between three to nine months. However, once you see the benefit, that benefit persisted during the course of the follow-up of the study duration.
Okay.
Mm-hmm.
Got it. And moving forward, so you're looking at patients with RHO mutations, right?
Mm.
RHO mutations.
Mm-hmm.
As well as a subset of patients that are mutation agnostic. In your early results, were you able to see any significant differences in terms of response between the RHO patients and those who did not have RHO mutation but had some others?
As I mentioned, like our phase I/II study in the RP, we have two different genes, NR2E3, and in that gene, we have, like, recessive and dominant, and we have rhodopsin gene mutation. So if you look at our modified gene, OCU400, it is NR2E3 itself. So for NR2E3 patients, it is more like a gene augmentation approach. However, for rhodopsin patient, it is gene agnostic approach because product is not Rhodopsin gene. Okay? So when we look at the efficacy across these two mutation, it was similar response. We didn't see any as such significant difference in terms of efficacy or safety readout.
Okay. Got it. And moving on to your ongoing phase III trial, liMeliGhT, can you talk about the study design, how many patients you're looking to enroll? What's enrollment progress has been to date? And, yeah, any other updates on the program, as well as if you can mention, you know, the key endpoints.
Sure. Our OCU400 phase III study is currently we are actively enrolling patients. Enrollment has started. If you look at the overall study design, it is we are targeting to enroll total of 150 subjects, and we are going to have pediatric population as well as adult population. This study has been divided into two arms, so 150 subjects will be, you know, equally distributed between rhodopsin arm and the gene-agnostic arm, and in each arm, we are going to have 75 subjects. And within each arm, the patients will be further randomized into 2:1 ratio, to receive either the treatment, OCU400, or untreated control.
The primary endpoint for this study is based on our phase I/II read out and alignment with the FDA, and it is based on the mobility course, which is basically LDNA, what we call it, Luminance Dependent Navigation Assessment. From the overall timeline perspective, we are planning to complete the enrollment for phase three study sometime in early, you know, early quarter next year.
Mm.
We are planning for the BLA in 2026. That's our high-level timeline for this program.
Okay, got it. And just to confirm, in terms of study design, so one arm you said is RHO, another one is mutation agnostic. Say, one of those arms reads out positive and the other one does not, just hypothetically. Would that be sufficient for regulatory approval or regulatory submission for the arm that is positive?
Yes, that's correct. That was the very reason we designed this study in a way.
Mm.
So if, say, we pass in rhodopsin arm, but we fail in gene agnostic. So with that, we... yeah, we can get approval for the rhodopsin arm. Yeah.
Got it. Okay. And you mentioned the primary endpoint is LDN assessment. Can you talk a little bit more about LDNA and how does it differ from mobility tests used by other companies for similar trials?
Okay. So, as you know, like, this mobility course was introduced by Spark Therapeutics, and that was the basis for the approval for the Luxturna. So in that, if you look at the mobility course, the light levels they used in that trial was from one lux level to the 400 lux level, okay? So the way our LDNA course is different, that, when we were running the phase one two study, we realized that there are a lot of RP patient who still have a very good vision, and they were able to successfully navigate through the course at one lux level.
So if we really want to demonstrate the treatment benefit in those patients, then we need to design a course and set up a light density, intensity in such a way that you have window to show the improvement and address the ceiling effect, primarily what we call it. So the LDNA is designed in such a way, right now, we have the range of from 0.04 lux up to 500 lux level. And another changes we made is that initially, when the course was designed, the spacing between the lux level to show the improvement was not uniform, okay?
So here, like between 0.04 lux to 500 lux level, we created a uniform distribution across different lux level, so that if there is a treatment benefit of two lux level or more, it is not impacted by the baseline lux level signal. Yeah.
Got it. Okay. So in addition to RP, OCU400 is also in development for LCA, right? Leber congenital amaurosis.
Mm-hmm.
Can you give us, you know, a quick update on that program, and why do you think OCU400 could be a, you know, a promising candidate in that indication?
So LCA, like we completed enrolling four subjects, two pediatric and two adult, and we are waiting for the twelve-month follow-up data. So our current plan for that program is that once we have the twelve-month readout available, we'll review the data and we'll reach out to the regulators, and accordingly, we'll plan for the next phase of development. Considering like what our thought process around based on the mechanism of action, so in our preclinical study, we did involve like CEP290, you know, mouse model, and we had a good efficacy. Also, considering the RP phase I/II data, where we have rhodopsin gene, and we saw the gene agnostic effect.
Mm.
We are hopeful that, you know, OCU400 should have some therapeutic effect in LCA patients as well.
Okay, got it. Okay, I want to move on to your 410 franchise.
Mm-hmm.
So you have two programs for OCU410. OCU410 itself and OCU410ST. They're in development for geographic atrophy and Stargardt disease, respectively. So with respect to geographic atrophy and OCU410, can you talk about that indication and specifically what do you hope to achieve with OCU410?
As you all are aware, that geographic atrophy is advanced stage of age-related macular degeneration. Currently, we have two approved product for the geographic atrophy. However, there are certain limitations with those products, and those limitations are on both sides, you know, safety as well as efficacy as such. The efficacy for the currently approved products are very limited, and I would say marginal efficacy, but still, that is much needed for the patients. Most of the products, when we see in the pipeline for the geographic atrophy, is targeting primarily the complement pathway.
So the way OCU 410 is differentiated, that it is not just targeting the complement pathway, but it also targets the pathway which are associated with the pathogenesis of geographic atrophy, such as lipid peroxidation, which lead to the lipofuscin and drusen formation. It also targets the inflammatory pathway and oxidative pathway. So this is how I think OCU 410 is differentiated from the currently approved product and other products in the pipeline. So, as I mentioned also, this disease is multifactorial in nature. It means that it. There's no one particular cause which lead to this disease.
So any therapeutic approach, which is multifactorial in nature, targeting multiple pathway and addressing the disease, you know, a disease evolution to begin with at molecular level, will have a greater potential to provide, you know, better therapeutic benefit compared to current product in pipeline.
Okay.
Mm-hmm.
To dive in a little bit deeper, so OCU410, it encodes RORA gene.
Mm-hmm.
Can you talk about what RORA is, and what is its role in dry AMD or geographic atrophy? Maybe high-level preclinical data that you know that gives you confidence.
Sure. So RORA is another candidate in, I would say, modified gene therapy platform. It is a nuclear hormone receptor gene. At the molecular level, you can call it, it is a transcription factor, which regulates multiple cellular pathway within the retina. This molecule also known to play a role outside the retina, so this is more like a universal kind of molecule as such.
So in our preclinical study, in macular degeneration mice model, ABCA4 knockout we noticed that RORA gene therapy was able to reduce the drusen formation. That is one of the, you can say, biomarker for geographic atrophy. However, in addition to that, we also noticed that it is upregulating the entire complement protein, CD59, which is also being developed as a target by some company in this space, and they are in the later stage of clinical development. And then, the preclinical, in vitro cell culture model, in RPE cells and other, cells of neurological origin, what we noticed that it has a strong anti-inflammatory, anti-oxidative property. So RORA, as such, targets four different pathway, which are linked to the geographic atrophy pathogenesis, oxidative stress, drusen formation, inflammation, and complement pathway.
Okay. Got it and in terms of clinical development, so you have phase I/II trial of OCU410 that is ongoing right now. Can you walk us through the trial design briefly, and when do you think we can expect the initial data readout?
Okay. So our OCU400 phase I/II trial, you know, of course, divided into two part. Phase I is primarily primary objective is safety, so it's a dose escalation study, 3 + 3 design. So we have completed dosing subject in phase I portion of the study, low, medium, and high dosage. And so far, safety profile looks very good. And that was the basis for safety committee, you know, giving recommendation to get into the phase 2.
So right now, we are in the phase II. So phase II GA trial is a control trial, where we have two different dose levels for the product, and also we have a control arm. So it is 1:1:1 randomization. We have total 45 subjects, 15 in each arm. In terms of, like, our next, like, milestone, we are hoping to have some preliminary efficacy and safety data available by sometime end of this year.
Okay.
Mm-hmm.
Got it. And, as you mentioned earlier, there are a couple of options approved for geographic atrophy. What are you hearing from KOLs and from patient groups in terms of the need for a new therapeutic for geographic atrophy?
Yes. So, I think, as clinicians started using this product, I think there is quite a bit of learning in past one year, I would say. And now, slowly, I think, the clinician has just started understanding that there are certain set of patient, you know, which respond better to this treatment compared to other, okay?
And considering the overall benefit/risk profile, there is a large section of patient, you know, and as well as clinician, both are hesitant to take this product, you know when they look at overall benefit/risk profile.
So considering that, I believe there is still a significant need in this space, and clinicians are looking for a new product, okay, which can help this patient better. And another challenge, I think, another thing, what we are hearing in various conferences and meeting, that these products are, you know, that intravitreal injection and which we given, like, multiple injection at certain frequency, either every month or every other month. And considering if you look at the GA patient, primarily, it is your old age patients, you know, people in seventies, eighties, nineties, you know? So these patients, you know, you know, meeting the compliance and taking the dosage at the regular interval i s pretty challenging, you know?
And it is also changing from some of the clinicians, you know. I was at the EURETINA. They were also mentioning that them planning and scheduling the patients for every month, you know. You are basically kind of stuck, you know, with their schedule. You know, you cannot take vacation. Someone was talking about, you know, when you have multiple trials and multiple patients visiting, managing them with the, you know, monthly injection is pretty tough task.
Okay.
Mm-hmm.
Got it. I want to pause for a second and see if there are any questions in the audience. Okay, I have a couple more quick ones.
Mm-hmm.
First, can you give us a quick update on the OCU410ST program?
Yeah. So OCU410ST, we completed the phase I for 410ST as well. This is for Stargardt disease. It is based on the same platform, like RORA gene. And, right now, basically, we are waiting for, yo u know, we are following up these patients and waiting for the preliminary readout you know, six-month follow-up, minimum, and based on that, our plan is to, you know, take that data and talk to regulator and come up with the phase II design, which could be potentially used for the approval of the product. That's our plan.
Okay.
Yep.
Got it. And, one last quick question: I know you guys have been busy with building out your manufacturing capacity at Malvern facility. Can you talk about that facility, and what you expect to accomplish there?
The facility construction, primarily, we built that facility to support our cell therapy program, NeoCart, as well as gene therapy assets. Facility is ready from construction perspective and initial qualification. As you know, for NeoCart, I think we are looking for the partnership. Once that is in place, we will make the facility fully operational. For our OCU400 modified gene therapy platform, for initial launch, we are working with our partner, CanSino BIO, in China. That will be our primary manufacturer. When we are planning our build in 2026, our plan is to, you know, have, like, another manufacturing facility, which is our own facility, as a supplemental, as the product advances.
Got it.
Mm-hmm.
Okay. All right, I think this brings us to the end of the session. Arun, thank you very much. I appreciate you coming over. Thank you, everyone.
Thanks. Thanks for having me.