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Gene Therapy for Vision Loss Explained - An Interview With AAVantgarde Ep 51
00:33:16
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A
In this episode, we are demystifying ocular gene therapy, what it could look like for those living with inherited retinal conditions. With a closer look at the trials underway at Avant Garde, I'm super excited to be joined by Dr. Jaysha Ri Sani, Chief Medical officer at Avant Garde, and a seasoned retina specialist with more than 25 years of experience leading global gene therapy programs. Together, we unveil the mystery of gene therapy, talk about what participation really looks like, and how this research could move us closer to approved treatments. Hey, guys, it's Sam and Rachel, and you're listening to the Blind Life Podcast.
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This is the companion podcast to the popular YouTube channel the Blind Life.
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Here I share tips and tricks, how
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to's, interviews with amazing VIPs in the community, and loads of assistive technology reviews.
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A
The goal of the Blind Life is to help you live your best blind life. Jaishree, thank you so much for joining me. I really appreciate it. I'm excited to talk about this demystifying gene therapy.
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B
I'm also very excited to be here, Sam, and I am looking forward to this conversation. And as I mentioned just a minute ago, I'm also very curious about your own experience. So let's see where the conversation takes us.
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A
Yeah, absolutely. Absolutely. Happy to share. Well, first of all, can you please introduce yourself and maybe talk a little bit about your role at Avant Garde?
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B
Yeah. So my name is Jaishree Sani. I'm the chief medical officer here at Avant Garde, and I have been with the company for over a year and a half. But by background, I'm an ophthalmologist and retina specialist, and I have been in this field for over 25 years. I joined the industry about 10 years ago, but prior to that, I practiced in UK in the National Health Service, and I had the opportunity to sit across several patients with inherited retinal disease, which was part of my fellowship as well. And partly that prompted my transition into industry when the opportunity came. And initially I was with the big pharma, Roche Novartis, where I learned the trade. It's a really good ground for learning robust processes. I was very fortunate to also work on Luxturna, the gene therapy at Novartis. So for me, coming to Avant Garde is like bringing everything that I have learned so far. And, you know, Stargardts is one of the most common rare diseases. So in some ways, it's just like, I'm so grateful for the opportunity to be able to put together everything that I learned so far and then work with this Amazing team at Avant garde.
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A
Yeah, that's a very good point. You know, I never really thought about it, but the more I'm in this world of vision impairment and blindness and learning more about the eye and all the complexity of the eye and all the different ways that something can go wrong with the eye, yeah, it totally makes sense that there's, you can, there's a lot of different ways you can go scientifically and medically just dealing with the eye as a whole.
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B
And the eye is unique, it is relatively immune, privileged. It doesn't have all these blood supply, heavy amount of blood supply, which is, can take also things outside and cause immune challenges. The retina and the tissue between the retina and the retinal pigment epithelium, where we deliver the drug, is quite a safe zone. We can give very low doses and it can give a massive effect without, you know, these high doses that are needed in systemic therapies. So I feel like the potential of gene therapy for retinal diseases, we're just scratching the surface.
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A
Speaking of the, the current state of gene therapy, we want to talk about that because the whole, you know, the topic of this, this episode is, is demystifying gene therapy, kind of explaining what it is. And I think, because I know I, and I think a lot of, at least here in the US I don't know about in the uk, I imagine it's probably similar, but we, we were raised on these, these, you know, these movies about the evil scientist messing around with our genes and turning us into something that we don't want to be. And so I think the, the, the words gene therapy tends to have a negative connotation. And I wanted to speak with an expert. Clearly you are and kind of get the background on exactly what gene therapy is and what the patient can expect, especially when it comes to retinal condition, inherited retinal diseases. But first, I want to really quickly touch on what you guys at Avant Garde are working on regarding clinical trials and gene therapy.
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B
Yeah, so we are what is called a clinical stage company. That means we are now in the clinic with our therapies and we go back to talking about gene genes and demystifying genes in some ways, but we are addressing, we are primarily in ophthalmology diseases. We have two, which we have already started dosing patients, which suggests that it's a clinical stage company and we have a few in the pipeline. The first disease is retinitis pigmentosa, caused by a mutation in a species, another gene called MYO7A. It's called USHER1B. And these patients or these people are born with deafness. Then over a period of time, they also have progressive loss of vision. And our we have completed the enrollment of our phase one study, which is, you know, all the participants who enter a phase one, they we go through different doses of the drug to look at whether there is any safety issues. That is the primary aim of a phase one. We have already presented the data at several conferences and we are also in touch with several patient organizations because there have been some, let's say, early encouraging signs. We still have to look forward to what happens and from a safety perspective as well. So in some ways, the first ever dual AAV gene therapy has been pioneered by us and it has already been dosed, the patients have been dosed for it. So Stargardts is the second program. And in both these diseases, the gene is quite large. So you wanted to kind of demystify and maybe we can start with that. So what is gene like? What is a gene? Genes are essentially at the basic level, they're just instructions that are given to in your body to produce proteins. And proteins are what do all the heavy lifting. But the genes are the ones who say make this protein or make that protein, and they are building blocks for your body as well. And you inherit or me, I inherit a gene from my mother, a gene from my father, and potentially I may be carrying faulty copies of Genesis, different genes that I've inherited from my mother and father. But if both my mother and father had a specific gene in which there's a faulty copy, and when I am, I'm born, I would inherit one copy, let's say for ABCA 4 or this Usher 1 autosomal recessive diseases, which is what we are targeting. That means my parent might be a carrier, but doesn't manifest the disease. That means 50% of the protein is sufficient to keep things going. But when it's 100% protein defective, there's a range. But when I get one 50% from my father, 50% from my mother, then I manifest the disease because 100% of the protein is somehow defective or malfunctional. And that's what happens in an autosomal recessive disease like Stargardt's Usher 1B. And they are what are called monogenic diseases as well, because that's one gene is faulty. Whereas the monogenic diseases, you could in theory replace that gene and then the protein is optimized, or you deliver a good copy of the gene, the functional protein is replaced, and the hypothesis Is that by replacing that protein, the problem is addressed. So that is what is gene therapy. So there is a protein production. It's a long story to say the genes give instructions to produce proteins. If you don't get the right copy of the gene from your parents in couple of some of these diseases, then you have a faulty protein production or no protein production. And essentially by delivering the full copy of the gene, we are replacing the functional protein. So your protein production of that particular gene can be restored. Is that, does that make sense?
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Yes, absolutely. I think, I think it does. I think that clears up a lot of the confusion about exactly. Not only what gene therapy is just in general, but what the process is. And so that's the goal of avant garde is to somehow, and we don't need to get into the details of how this all works, but is to go in and correct that gene.
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B
Exactly. And avant garde. I mean, there are different types of genes, of course, there's sizes of genes and the. It's like, if you think of it like a chip, the 4.7 kilo basis is the chip size of where one vehicle can transport the gene. The vehicle that we use is a virus out of which all the content of the virus has been removed. We call it a vector. But essentially it's a delivery truck that is delivering this gene. But if your gene is quite big, imagine there's a sofa that's so large that it cannot fit into two into one delivery drug. So essentially what we do is we divide that furniture into two halves. We take two delivery trucks to deliver this gene into the cell, in this case the retinal cell. Once they come in, the two halves are have little intine fragments, different proteins. They're like magnets. They find each other and then they connect and make the protein again. So we have two halves of the gene because it's too big to be fitted into one delivery vehicle. So avan that that did take many years to optimize. And our pioneer or founder is Professor Alberto Auricchio, based in Italy. And this has been his life's work. So he has been working for a very long time. And now we have two drugs that we are taking into the clinic to deliver largi.
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Well, I want to touch on. You mentioned you guys use a virus as the vehicle to get it in there. And just to clarify, because I know that's one of the trigger words that people kind of get stuck on is virus. Oh, I don't want a virus in me. Why would I do that? And I love that you mentioned that, you know, it's just. Well, you said it like a delivery truck. It's all the contents, all the negative stuff of the virus has been taken out. It's not a harmful virus anymore. It's simply a way to get the corrected gene into the body. So it, it's not a virus in the way we think of a virus anymore.
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That's correct.
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Yeah.
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The. It's called a vector even because we don't even call it a virus anymore.
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You mentioned injection, so we're going to talk about that. The process is an injection. But first I wanted to ask is, is the goal of gene therapy with regards to inherited retinal conditions? Is it to stop the progression of the disease? Is it to restore vision? Can you expand a little bit on that?
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Yes. So it depends on the stage of the disease in which and if the therapy works. So we are here in the assumption that the therapy works. Sure. And it depends on the stage of the disease that you present with. So I can give you an example from the. From Luxturna, for example. Right. In Luxturna, the patients with advanced disease, then you're trying to halt further progression. Assuming that there are cells that are left there which can be. Which can. Which are completely intact. So you want to keep those intact cells. Now there could also be some cells who are a little bit, how to say, sick. They haven't died, but they are sick. So there's a potential to even rejuvenate those cells.
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Okay.
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But there are cells which have completely. If there are no photoreceptors there, then there is no way that therapy could work. In Lakshmana's case is retinal pigment epithelial cells. So they are the cells below the photoreceptors that are responsible for it. So if they don't exist, then the gene therapy cannot really stop the progression or halt the disease or improve the things. So from my perspective, there is like a, like a range of cells, cells that are relatively healthy and haven't yet kind of demonstrated the disease. We want to preserve them. Then there are cells which are potentially sick and not yet on that way to completemize. We can resurrect them. And that's where we may see some improvement. We still have to. And we can measure that with things like sensitivity. We can look at the retinal sensitivity in those places. And then there are cells which potentially have already committed to not improving or have. Cannot be resurrected. So initially we do enroll patients in our clinical trials primarily for safety. So those with advanced disease because we want to be safe. And then as the therapy becomes more accepted and in our later stages, we will go into patients who, who are earlier in this frame of the disease. And again, taking Gluxter as an example, children as young as two have been treated in some ways. You also don't want to get too early before the disease manifests itself because there are so many other things that we are trying to learn. This is a journey for the patients, sponsors the drug, but essentially want to get there eventually earlier, before the retinal cells have damaged themselves because of the lack of. That is the ambition.
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Yeah, yeah, no, that totally makes sense. And it makes sense about the different stages of the cells and how they're going to be affected. So talking, you know, expanding a little bit more on the process and I do want to talk about the patients themselves and how they get chosen and what criteria and all of that. But the process we mentioned, injections, is this a, a single injection? Is this something that like they will need maintenance injections throughout their life.
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B
So with gene therapy and with the retina, so the retinal cells, the photoreceptor cells are cells that don't replicate. So in some ways we are fortunate. So once we give the drug and if we preserve those cells, it is a one, it's a once and done treatment. But studies still need to be done to see how durable that treatment is. So if we. That's why we need to learn once we give the treatment, this is the hope is that it is going to continue throughout the life. But we have to measure that with long term studies. So typically a gene therapy study is five years minimum. And that is both for safety as well as efficacy. Does it last five years? But for the gene therapies which have been approved not just in ophthalmology but in other diseases as well, we are seeing data up until 10, 12 years, etc, going for the durability of treatment, I, I have to say that we have to watch and wait and see how long it lasts, how we deliver the drug. There are different ways. Some people you will hear are delivering via an injection into the eye, which is what you mentioned. But what we are doing is we do a surgery, but the injection is under the retina. So you have to do a small surgery called vitrectomy. So the patient is taken into the operating theater. Depending on the sponsor and the age of the patient and different factors. It can be general anesthesia or local anesthesia. But typically we want to do general because a patient is Comfortable, the surgeon is comfortable. You can give the drug very easily. And then you do the vitrectomy to clean up the jelly of the eye to get to the tissue and then you inject under the retina. So it's a once and done treatment, but we have to kind of follow up long term.
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A
Sure. Do you do the treatment on both eyes? Do you choose just one eye? And if so, how do you make the decision?
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Again, really good questions. In the early stage studies, it's almost always the one eye and we tend to choose for the first phase especially we choose the more advanced eye, unless of course, there's a reason to choose the non advanced eye. But it's because these are primarily safety studies before approval. And then in phase three we may, we can tailor our inclusion criteria based on what we see in our phase 1 study. Before approval, we have the choice to treat both eyes and get approved, or even after approval we can do that. And that is for two reasons. One is for safety as well, because you know, you want the drug to be shown to be safe before treating somebody's both eyes. That's one reason. And the second reason is sometimes in early stage studies you can use this fellow eye as a comparator in the sense you can say this disease is progressing in such a fashion and both eyes of a patient can be used to see how the drug is working in one eye compared to the other. There are pros and cons of that because the diseases may be at different stages. So you have to take all this with the scientific discussions, with the regulators, etc. And regarding both eyes, you can either get treated at the same time when, once it gets to that stage, or also one after the other. So we will be testing all these things in future trials, but in the initial trials we do one eye at a time, preferably the worst eye. And then as we get more confident, we go into the better eyes. And also the doctors and the patients also they vote with their own how they feel about the drug. And all these discussions that we take prior to the, prior to enrolling somebody
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in a clinical trial, if someone signs up for a trial like this, does that exclude them from being able to sign up for other trials in the future?
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So there are different types of medicines that are tested. So for a gene therapy, which is what we are talking about currently, answer is at present, that is the situation. So once you have had a gene therapy in the eye, because as I mentioned, they stay in the cells. So if you're already treating these cells with the Gene therapy, you cannot remove it, so it kind of stays there and produces that protein. So for a gene therapy, yes, but let's say you're on oral therapy for Stargardts and you want to participate in a gene therapy trial. You cannot participate in two studies at the same time, but you can potentially participate after what we call a washout period. So you give it long enough, the drug is washed out of your system, and then you can participate in a gene therapy trial. There are certain other types of drugs as well, which are given into the Isin injection. Again, they have a shorter duration of action. The, the, what we're trying to achieve with gene therapy is a once and done treatment. So that's a longer duration of action. So this is why after a gene therapy, we don't typically allow people, or we suggest that people don't, because you cannot have two gene therapies into the eye for the same disease. You don't know what the interaction could be.
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Right? Yeah. Well, speaking of, of the patients, what is the criteria to choose the person for a clinical trial? Do they, do they need to be kind of in the area that the trial is being conducted? You mentioned age. I guess that's a pretty, pretty big deciding factor.
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Yes. So in our trials, I'll talk about our trials because different sponsors run it differently. So for Stargards, we are global in the sense we are currently enrolling patients in our natural history study has just finished enrollment. So that is wonderful there. We have enrolled a lot of patients and the aim of that observational study is to learn more about it, about the disease, find out patient and investigator appetite to participate in a clinical trial. Typically, as I mentioned when I was in clinical practice as well, the information on rare diseases is rare. So we need to kind of make our own assessment of the quality of data, et cetera, prior to including a patient in the study. It also allows us to design the clinical trials more appropriately based on our own learning. So we have, we are doing that. And then for the initial phase one of our clinical trial, which is called Chela Stay, our natural history study is called Stella in our clinical development plan, our Celeste, because we are an Italian based company. Really, it is Celeste in English, by the way. So it's a Italian pronunciation. It's a phase one too. And for the first part of that, we are enrolling adults because it's the first time we are trying with the gene therapy. And I mentioned we want patients with established disease. So children typically may not yet have established disease and appetite for participation of Children is also. We need to be a little bit mindful. We get some safety data before moving forward with the pediatric patients. And then we have certain inclusion exclusion criteria. So we have vision criteria. Again, we are trying not to include people with fantastic vision because we want to be safe. This is a safety study. And then we have certain criteria based on retinal images. Regarding participation, we welcome patients in Europe, US and UK to participate. They don't necessarily have to be at the trial site. We as sponsor will arrange travel, sustenance and everything else for the patient for the. For the purposes of the trial and to take them to the trial site. And we have a number of sites in uk, Europe and US for the Stargardts program.
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A
Well, good. That was going to be another question was I wanted to kind of get a brief overview of what participation looked like, the treatments. And then that was going to be a question is travel and would there be support for travel? So that's great that it sounds like there is.
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Yes, there is support for travel. We have a patient concierge service who will address everything and the sites and our operations team are really on the ball with making sure that a patient who wants to participate is given that opportunity.
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That's great. That's great. Well, what kind of time commitment is. Would participation involved? I know you said multi years, but how many visits a year? That sort of thing.
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Yeah, this is a very, very good question. It is a time commitment by the patient and I. We couldn't have. We can't do this without patients. Right. Like. So it is a huge altruistic step by the patients who are willing to participate in our first in human clinical trial or clinical trial. So we acknowledge that there are multiple screening visits. Now, that depends on the patient and the site and the way they organize their infrastructure. And. But there we do many of our tests three times at baseline because we want to get a very strong baseline. And then the patient of course needs to come in for surgery and then they stay over for a day or so because they get general anesthesia, majority of them. So there's that. And the initial few months there are more regular appointments because we are trying to make sure that there is no safety signals, that we address them as quickly as possible. And as the. And after about six to nine months the frequency reduces and after the first year it goes down. Even they don't need to come in so frequently. So. So in the first year it is a heavy time commitment and. But we try to make it as comfortable for the patient as well as the site and the carer to accompany the patient.
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I don't know if you can, you know this or how many sites are there. Like, you know, the US is so, so large. I'm just curious how far someone might have to travel if they wanted to participate.
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So we currently have sites in the center of us, I guess Texas and we somewhere in the center. We have sites in the west coast as well as we are opening some sites in the east coast.
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What types of risks that or safety concerns with the patients might, might have.
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So that again a really important question because we are administering the drug by surgery. So there are those. So let's take the kind of things where you can have ct, there's anesthesia involved. So there is that. We give some medicines to the patients to make sure that or to try to ensure that there is not significant inflammation. So we give quite high doses of steroids. So even the medicines that we give can sometimes cause some side effects. Then there are the surgical related adverse events. So they can be cataracts or high, high pressure in the eye post operatively. These are all quite known side effects of these, these kind of procedures. In our first in human study with the Usher's disease, we have had very few. But that doesn't mean that in a new drug therapy with newer, many different types of patients we will not. And the last thing is of course the drug itself, the gene therapy. So one of the most, most common complications of the gene therapy is inflammation due to immune reaction to these vectors that we put in the eye of the gene. And this is why we give the high dose of steroids. So by giving the dose of steroids we are trying to keep the inflammation at bay so that the drug can start to work. So a patient coming into the trial is given a very detailed informed consent form and they are provided all the details on the adverse events that can occur as a result of all these things. The concomitant medicines they take the anesthesia, the surgery as well as the drug. And we put everything in place by going to credible centers who have done these procedures before, selecting our patients very closely, making sure that the benefit should always outweigh the risk. Hence the early stages. We don't go into early patients or patients with good vision. So we try to put in place a lot of structure and you know, guardrails to prevent any adverse events.
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Right, right. Is there at any point during the treatment if the patient says I'm done, I don't want to deal with this anymore. Are they allowed to just opt out,
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yes, the patients, it's a patient choice. Patients that are allowed to withdraw at any time, although we do encourage that they continue to come for the safety reporting at least because it's good for them, for the program, for us, because safety is something that we want to study. But if they find that it is too much, they can step back at any time.
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I said that was going to be the last question, but it wasn't.
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Please go on. I mean, maybe I'm happy to do that.
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Well, I just remembered I wanted to ask about the cost. What is the cost to the patient for any of this?
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So for, for the clinical trial, it's more a cost of time that the time they invest. And there is, you can't put a price on that. You know, it is, it is lifetime. And also the belief and leap of faith they take with a new drug. There, there is the other cause, like I mentioned, travel and sustenance and moving. So the sponsor will take care of all those things as part of the study. So that, that is a given. But it is their time commitment.
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It is, and I've mentioned this before, that clinical trials like these, it's really, you're doing it for yourself in hopes that you're going to, you know, get to see some improvement or as we mentioned, at least halt the progression. But ultimately you're doing this for future generations too. I mean this is laying the groundwork for what will come in the future and the medical applications for future generations with vision loss. So you're really, like you said, altruistic. You're really giving of yourself to make a better world for future generations. I think it's fantastic.
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B
I do as well. I'm always ever grateful to the patients. And that makes what we do even more important. That do we do it correctly and that we give it a lot of thought and we also commit to it completely, you know, so I, my hat's off to those individuals who have participated in clinical trials. I mean, I've been doing this, like I said, for over 25 years. I used to be a principal investigator in the sites and those patients moved me to this mission. And sometimes it'll be very, very important to keep those sacrifices, if that's the right word, at forefront. Make sure that we acknowledge the huge contribution that people who are participating in these trials, not just mine or avant garde's across the globe in the hope that for not just themselves, but for the future generations, for the community at large, for science to move things forward. Yeah.
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A
With that, what are next steps? How can if someone is interested in, in contacting you, how, what's the best way they can do that?
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B
There are several ways they can do that. One, of course, I mean, I can give you the website. Our website is www.avantgard. that is a, a V for Victor. A N T G A R D e dot com. You can find the patient pages there. There's also a clinical trials@avantgard.com, the same spelling avantgard with a double AAV. And then we have another email address which is patient advocacy vanguard.com so these are all. There are two email addresses, the website site and they can also reach out to us via their doctors at any time. They can also reach out to us directly. We do have someone monitoring the emails and making sure that we get back to them in real time.
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A
Well, Joshree, thank you so much for, for joining me. I really appreciate it.
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B
No, I just want to say thank you so much for the opportunity to present here and I really enjoy your podcast. So doing a great job and if we can help in any way, let us know. You know, it's absolutely critical that people like you ask those important questions that are meaningful and also contribute to our experience on how to get the right drug to the right patient.
- [32:56]
A
A huge thank you once again to my guest, Dr. Sani from Avant Garde for helping to demystify gene therapy. I'll have all of the contact information listed either in the video description or the show notes notes for the podcast. If you'd like to learn more. Thank you guys so much for listening. This is Sam with the Blind Life and I will see you in the next episode.