How a gene-agnostic approach opens doors to new therapeutics

We live in an era of unprecedented progress in novel ocular treatments, including gene and cell therapies. Groundbreaking treatments are giving patients hope about vision-threatening diseases. If you speak with Arun Upadhyay, PhD, though, you'll see that the last few decades of progress are just the beginning, especially in the area of retina care.

Dr Upadhyay, who is the Chief Scientific Officer at Ocugen, sat down with Ophthalmology Times Europe to explain ongoing trials of OCU400, a modifier gene therapy product candidate targeting retinitis pigmentosa. Here, he speaks about a gene-agnostic approach to retinal disease, and explains why age-related macular degeneration, Stargardt disease and other conditions may not be as simple as we think.

Editor's note: The below transcript has been lightly edited for clarity.

Hattie Hayes: Hi. My name is Hattie, and I'm the editor of Ophthalmology Times Europe. Joining me today, I have Dr Arun Upadhyay. Dr Upadhyay, thank you so much for sitting down with me. I'm so excited to talk to you about gene therapy and what's going on at Ocugen.

Arun Upadhyay, PhD: Thank you so much. We attended the EURETINA 2024 meeting, and in that meeting we presented data related to the OCU400 Phase I/II study for retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA)disease. And also, we talked about our ongoing OCU400 Phase III study design. For OCU400, we started with the Phase I/II study for retinitis pigmentosa and Leber congenital amaurosis. In the retinitis pigmentosa part of the study, we enrolled a total of 18 subjects distributed into Phase I and Phase II…Phase I was a dose escalation study, 3+3 design, and Phase II was our expansion phase, where we enrolled additional [RP] subjects who received high doses of the product. During the Phase II portion of the study, we also expanded this trial into the Leber congenital amaurosis patients, and in that arm, we dosed adult patients as well as paediatric patients.

The Phase I/II study, basically, was the basis for us in advancing to the Phase III clinical study. In the Phase I/II, OCU400 was generally safe and well tolerated. We had a very good safety profile. In addition, we also looked at the exploratory efficacy data from those patients. In the RP patient population, we saw many patients responding [to] various functional vision parameters such as mobility, best corrected visual acuity, and low luminescence visual acuity [LLVA]. And the majority of patients responded either, you know, showing the stabilisation of the disease or improvement on those parameters.

So, our ongoing Phase III study is basically focused on the retinitis pigmentosa patient, and in this trial, we have total of 150 patients who will be taking part in this study, distributed [equally] into two arms, the rhodopsin arm and gene-agnostic arm. And in each arm, these 75 patients will be further randomised in a 2-to-1 ratio, to either receive the OCU400 product or remain as an untreated control. This phase of study will consist of only one dose level, so just a single-dose study, and it involves both paediatric as well as adult participants. And as you know, this is the subretinal procedure, so injection is in the subretinal route. The primary endpoint for this study is going to be mobility, what we call LDNA, luminance dependent navigation assessment. And in this primary endpoint, basically we are looking at change in the Lux level from the baseline, up to12 months of the follow-up visit. So the way we are defining “responders” on this primary endpoint is, any patient who received the treatment and showed the improvement of two Lux or more on this mobility course will be defined as a responder. The criteria for meeting the primary endpoint [is] comparing the responders in the treatment arm versus the untreated controls.

HH: What's the philosophy behind a gene-agnostic therapeutic approach, for those who aren't as familiar?

AU: Very good question. So, if you look at the inherited retinal disease space as such, as you know, there are now more than 300 genes known to cause inherited retinal disorders. If you look at RP, there are close to 100 genes involved [which contribute] to this disease condition. So, from a disease perspective, retinitis pigmentosa has highly heterogeneous stages, when you look at whether a clinical or genetic cause. And one of the biggest challenges in this space is that there are some mutations which are rare in nature, but there are many mutations which are ultra-rare in nature, and the patient population is not that large.

So, when we look at the traditional gene therapy approach, which is either gene augmentation or gene editing, though they have potential to fix certain gene genetic defects, when you look at the overall clinical development landscape so far, after Luxturna [voretigene neparvovec-rzyl, Spark Therapeutics], we don't have any products approved in this space. Not only that, if you look at the kind of pipeline we have in this space, it is still targeting only few sets of mutation using those approaches. And still, we are not seeing much success, and the reason for that is that when you look at the disease pathophysiology, these diseases are not as simple as we have been thinking. It is very complex in nature…Even though they are genetic disease, [genetics are] not the only factor which really determines the onset of disease, severity of disease or progression of the disease. There are other factors which contribute to the overall pathogenesis, clinical symptoms, manifestation and how disease is going to impact a patient. It is not just genetic mutation.

What we’ve learned that there is something more going on, and, what, exactly, happens? What exactly happens in this disease which leads to the vision loss? It is basically degeneration of the photoreceptors. So if we can find a way to preserve the photoreceptors, and enhance the function of existing photoreceptors, then there is a way that we may be able to provide benefit to the larger group of patients in this space. That is where our gene-agnostic, modifier gene therapy concept comes into the picture.

So in our pre-clinical development and early discovery studies by our inventor, Dr Neena Haider, we learned that there are groups of genes which belong to the nuclear hormone receptor class. They are nothing but a transcription factor. They are a regulatory molecule. They regulate various pathways in the retina which are crucial for maintaining the health of the retina, as well as the function of retina. What we noticed is that, in the animal models, irrespective of their genetic mutations…there was suppression of some key transcription factors or key regulators. Some of those key regulators were nuclear hormone receptor genes, and NR2E3, or OCU400, was one of them. So when these animals were given OCU400, what we observed is that it brought back the level of all those suppressed, downregulated, master regulator genes to the normal physiological level. That is what mechanism of action is around.

Our gene agnostic approach is more like, you know, delivering a molecule, OCU400, which can bring homeostasis in the altered cellular and molecular pathway within the retina, which are crucial to preserve the function and structure of the photoreceptors. And by doing so, we will be able to…halt the progression of disease, or maybe even in some situations, [see] reversal in the functional part, based on what we are seeing in our Phase I/II study. Visual acuity gain in LLVA, and an improvement in vision on the mobility course. So that's what our larger gene agnostic approach is, and it has potential to provide benefit to the broader group of RP patients, irrespective of patients’ genetic backgrounds.

HH: Speaking really broadly about gene therapy, what are some of the biggest opportunities and what are some of the biggest challenges?

AU: So first I'll just look at the developmental challenges, and then the potential of this gene therapy approach. If you look at the developmental challenges, of course, gene therapy products are complex biologics, you know. So if you look at the evolution of the different classes of medicine, we started with a small molecule, then biologics, and then we have a gene therapy product. And this evolution…from a development perspective, you know, the Chemistry, Manufacturing, and Controls [CMC] quality, controlling the critical quality attributes, targeting and formulation stability, all those things are the areas which challenge [investigators], because if we are addressing only the rare disease space, then we don't see that as a bigger challenge. But still, that is a significant challenge when we start diversifying this gene therapy technology to other disease areas, or larger disease areas, where the product demand is very high. Those could be developmental challenges we may face.

But when I look at the potential of the gene therapy…look at, traditionally, when we started gene therapy, the goal was to fix something which is defective, by supplying either the normal copy of that defective gene, or finding a way to fix the defective gene within the cell, tissue or organ which is affected. And that's great, but now we have started exploring whether we can use a gene therapy in the place of earlier biologics, like mAbs or other factors. Rather than delivering protein, can we use a gene therapy approach to deliver the same molecule, using our own system as a biological factory? One of the biggest challenges is regulation. How we are going to control the level of that molecule [inside cells]? How we are going to make sure that that those bio factories which are inside, in vivo bio factories, how they are going to control the level of those molecules, when we are taking the gene therapy approach? So I see there is a lot of promise for gene therapy. It is not just addressing the individual genetic defect or mutation, but also utilising this technology to address more complex diseases. Where genes can be used to deliver a factor or molecule, which addresses the complex cellular, [and] molecular pathway within the body.

HH: This therapy product is, is based on, as you said, NR2E3, and that is kind of associated with a lot of different functions in the retina. Is that something that broadens the scope of applications, outcomes or patients who could benefit from these gene therapy candidates?

AU: As we started learning about modifier genes within the retina, we realized it is not just NR2E3, but there are other set of genes which play similar kinds of roles, but in different disease conditions.

One of the modifier genes which we identified is RORA. We have another product candidate based on that RORA modifier gene, and we have two programmes ongoing using that product. We have OCU410, which we are developing for geographic atrophy, and we have another programme, OCU410ST, that is for the treatment of Stargardt disease. When you look at geographic atrophy, I think briefly I touched about the complexity of these diseases. And similar [complexities] apply for this other retinal disease that is geographic atrophy. We have made significant progress in this space and are trying to find a therapy which may provide a benefit to these patients. But still, we are not able to find a therapeutic which really, really can provide, what you call good benefits to these geographic atrophy patients. One of the biggest hurdles has been the disease itself. This disease is also multifactorial in nature. It's a very complex disease which [involves] genetic factors, environmental factors, and aging, as we talk about age-related macular degeneration. Pinpointing a single target in this disease has become very challenging, and a lot of development, if you look [at geographic atrophy treatments industry-wide], has been primarily focused on targeting a single target. When you are trying to address a multifactorial disease, where you know causes are diverse in nature and complex in nature, targeting one single pathway may not be the efficient way to provide the optimal benefit to these patients.

So that is where this gene-agnostic, multifactorial modifier gene therapy RORA molecule provides hope. When we did the pre-clinical study using this RORA molecule in the macular degeneration animal model and other various in vitro cell culture-based models, we observed that it is not just only one pathway, but this molecule targets multiple pathways linked to the pathophysiology of geographic atrophy. For example, not only just complements which [we in the field] have been targeting, many companies have been in this space, targeting that particular pathway. But also, it regulates the proinflammatory pathways, which are basically inducers for the disease. Targeting oxidative pathways, and the pathways which are linked to lipid peroxidation and modification, which eventually lead to the lipid deposits in GA, what we call drusen. So RORA targets all three pathways at the same time, multiple pathways at the same time. We believe that taking this multifactorial approach for the multifactorial disease is the right way to go. Right now, with this [OCU410] programme, we are in Phase II. We completed Phase I portion of the study…We are hoping to provide some safety and efficacy updates to the market sometime in near future.

Coming back to Stargardt disease. It's an ABCA4 gene mutation disease, and there is no treatment available for Stargardt. So the same molecule, because Stargardt, if you look at the disease pathophysiology and degeneration pattern for Stargardt, is similar to GA. Of course…there are some differentiations, but again, lipid deposits, what we call lipofuscin, and complements also play a role in Stargardt disease. So, in that animal model, we saw good efficacy, for RORA, in controlling lesion growth and drusen deposits, and upregulating the anti-complement protein. This programme is also in Phase I/II clinical development. We completed the Phase I portion of that study as well, and we are hoping to provide updates to the market sometime soon about preliminary safety and efficacy data.

HH: It sounds like it's been a really big year for you, and [Ocugen] also hit some regulatory milestones. Do you want to talk a little bit more about what you've been celebrating?

AU: Yeah, that’s great, actually. I think this year has been very remarkable for us in terms of regulatory milestones, especially for our gene therapy programmes. So to start with, the two major things I consider we achieved, from a regulatory perspective, was getting the FDA approval to initiate our Phase III study. In addition, we received alignment from the EMA for a marketing authorisation application, so we [aren’t] required to do an additional Phase III study to get approval of this product in the European market. So that was a huge achievement.

In addition to that, OCU400 has also received orphan drug designation from both the FDA and EMA for broader RP and LCA disease, it's not mutation specific. And we also received the Regenerative Medicine Advanced Therapy [RMAT] designation from FDA. It's given to the company or product which has shown some clinical benefit to the patient.

We also received [FDA approval for] an Expanded Access programme for the treatment of RP patients with OCU400. A few things which it highlights about the product: This indicates that the product has shown sufficient evidence of the safety and efficacy, which gives regulators confidence to allow the use of this product outside the clinical study protocol. RP is [associated with] significant unmet medical needs. So there will be patients who may not be able to meet some of the inclusion/exclusion criteria [in the ongoing phase 3 study]. And if those patients are willing to take this product, they can get this product, through the Expanded Access Programme. In addition to that, I would like to update you that we are already in a Phase III study. We are planning to complete the Phase III enrollment by sometime early next year, and we are targeting to submit the Biological License Application (BLA) and marketing authorisation application in 2026.