Inside Regeneron’s Groundbreaking Hearing Loss Gene Therapy Treatment Program

Hello, and welcome to another episode of This Week in Hearing. I’m your host, Brian Taylor. And our topic this week is hearing therapeutics. Our guest today is Dr. Jonathan Whitton, who is the Auditory Global Program Head at Regeneron. Jon I hope it’s okay that we use first names. Absolutely. Brian. Yeah. Great to be with you. Weve been trying to have you as a guest for a long time, so we’re happy to. That you could take some time out of your busy schedule to be with us. I’m pleased. I’m pleased to be with you. So it’s not often that we get an audiologist that’s both an AuD and a PhD on our program as a guest. So I was hoping you can kind of tell us a little bit about your career path and what your role is at Regeneron. Sure. I’m happy to. So if we go. Go back a number of years now, maybe you can tell because of my gray hair. But if we go back a while you know, I came into audiology with a deep interest in language and linguistics. Really, that’s how I sort of came into the field and was very excited to be able to work on you know, therapies for people who had different forms of hearing loss. And so, really, my trajectory of, like, about 20 years of my life actually started pretty early during clinical rotation. So I did my AuD at the University of Louisville and the program at the time got the the AuD students involved in clinical rotations very early. And so it was really in my first year, frankly as an AuD student, where I started rotating through a pediatric clinic. And it was my first time to start interacting with patients who were using different types of prostheses, you know, so cochlear implants and hearing aids. And you know, I came into the field pretty naive. I thought, you know, you. You fit a device, and then it’s done. Everything is good after that. And it’s pretty exciting for me, like, that I was going to get to be the person to work with these devices. And I think what I learned pretty quickly was that hey, there’s still a lot of challenges here for people who have hearing loss. And particularly I was working with children who might be using cochlear implants, for instance, in their families. And so at that time, I sort of decided, hey, if I’m going to stay in this profession I really want to be working not only on what technologies we have now, but I want to be able to tell patients when I see them, you know, that I’m working on something else for you. And I didn’t know what that something else would be at the time, but it was, it was basically as simple as that. I want to be working on something else. And so as I continue my clinical training, it became clear to me that while I had the heart for that, I still didn’t have the skills to actually do something else to help. And so that’s what actually sort of created my interest in neuroscience. I thought, I’m going to need to go do some more scientific training if I want to work on what’s going to be the next generation of approaches that we might be able to offer to patients. And so that led me down a couple of roads. So one is I had a great opportunity to go work with some really talented scientists at Vanderbilt as part of the T35 program for research training for clinicians. And that was a hugely impactful time in my career. And then after that I had an opportunity to go do my PhD training. And so that followed my, my clinical residency at Cincinnati Children’s Hospital, which was again, another fantastic experience for me. But then I went off and I went to Massachusetts Institute of Technology to work in neuroscience and do some engineering work as well, again with the interest of, I want to be a clinician scientist, I want to work with patients, and I want to work on the next generation of therapies for patients. And so I did my scientific training there. It was transformational experience for me. And I was planning to go off into an academic career. Really, that was my intention. And that’s where I sort of had my first job offers and really actually started on that path. And right at about the time that I was getting started, actually I was introduced to an opportunity to be an early member in a new biotechnology company called Decibel Therapeutics that was being started in Boston. And that really sent me down a road of working on gene therapies, which I’ve been on now for a while and remain on working on gene therapies for different hearing conditions. So the, the decision point for me was really that I sort of thinking about everything I was going to be able to do in my career and thinking about how much difference do I think I can make in the next 10 years if I’m working by myself in my lab and then sort of I have my activities in the clinic versus if I go work together with a big group of people, really talented scientists. We’re all going to focus on one thing which is that we’re going to try to develop new therapeutics for patients. And so I made that decision then and have been on that path, I guess for, I don’t know, about 10 years now and I’m pretty excited with the progress that we’ve been able to make thus far in developing these new types of therapies. Well, before we get into the therapies, my next question is about the specific type of hearing loss, otoferlin related hearing loss. I don’t think a lot of audiologists are all that familiar with it. You could tell us a little bit about it, how prevalent it is. Sure. So you’re right, it’s not a diagnosis that comes right to mind. Right. But let’s just step back and think about pediatric hearing loss in general and think about congenital hearing loss. So we know that congenital hearing loss is relatively common. You know, as we’re talking about maybe almost two in a thousand children who are born are born with hearing loss. And for the longest time you know, we didn’t really know exactly what was causing their hearing loss. So we could bring them into the clinic. You know, we, there’s been a lot of amazing work by people in our field to implement newborn screening programs. Those were already in place by the time I was coming in the field, so I was a beneficiary of that. And so we could get the kids in early and start doing testing and understand, hey, this child has, let’s say a profound hearing loss. We could diagnose the hearing loss severity, there’s other tests we could do, imaging, et cetera. But usually we didn’t know what was causing the hearing loss. Right. And so I think the big change in our field, which is still really like emerging was that if you go back to the late 90s really, people started studying genetic causes of hearing loss. And as we then progressed sort of through the early 00s, basically we started testing more and more and we figured out that a little more than half of those kids who we’re seeing who are born with hearing loss have a genetic cause to their hearing loss. And in these cases, basically what’s happening is that the child is born, usually they have what’s called recessive inheritance to their genetic hearing loss where they have a copy from mom and a copy from dad, basically. And both of those copies of a given gene that is supposed to make some certain protein in the body have some variant that makes the makes their process of producing the protein inefficient or may make it completely impossible. So they produce no protein, basically. So if you end up having a genetic form of hearing loss, the sort of simple way to think about it is basically you have some genetic variant that has been inherited, usually that is causing you to have the deficiency of a given protein, like one protein in your inner ear that just so happens to be very important for your inner ear to function. Right? So if we look at all the possible genes that can cause hearing loss in kids, we’re talking about over a hundred, maybe 200 genes that have been identified now. But you can look across that whole list and really there’s maybe a top 10 list, you know a top 10 list of genes that are causing about 80% of the cases that we’re diagnosing in the clinic. So one of those that falls in that list is this particular gene called otoferlin. So it codes for this protein called otoferlin. Otoferlin is really important for inner ear function. So if you think about the different sensory cell types in the ear, you have your inner hair cells and you have your outer hair cells. The inner hair cells are the primary transmitter of information to the brain. Of course, they connect to the eighth cranial nerve dendrites. So basically they’re sending most of the information from the ear to the brain at the base of the inner hair cell, where you’re going to provide a signal basically to the auditory nerve. Otoferlin is a protein that’s expressed sort of in that basal region that helps to tether synaptic vesicles to the membrane of the inner hair cells and drop neurotransmitter into the cleft so that they can signal the auditory nerve. So basically, just think about it like this. Kids who have, who are born with deficiency of this protein, their inner ear develops normally. So all this sensory cells are there, you know, all the structure, the beautiful structure that makes the mechanical tuning of inner ear work. All of that’s there when sound comes in their ear. It actually activates all that structure in the ear. It activates the outer hair cells, it activates the inner hair cells, everything at the last step, when the inner hair cell is going to drop a little signal, like a transmitter signal into the cleft so that a signal gets sent to your brain. If you don’t have otoferlin protein there, that step fails. So basically everything went right. Everything in your ear went right, but you just didn’t send the message to the brain. Basically. So this is a case where, if you see it in the clinic, if you didn’t have the genetics, all you would see is an absent abr. So you’d see an absent abr. It turns out because of what I just told you, you won’t be surprised to learn that you see normal OAEs, usually. So these kids present with an auditory neuropathy, a spectrum disorder phenotype, usually. So that child, though you don’t know what’s causing this absence of the ABR, unless you take the next step, which is do a swab of the cheek is how you can do it these days. Do a cheek swab and you order genetic testing for hearing loss. And there’s readily available panels now to do this type of testing, and you get back the result. Hey, now I can actually tell the parent the reason that your child is unable to hear is because their ear is not making this one protein that it needs to make, basically. And so the story of what we’ll tell you about the therapeutics, basically, really start with our field. Continually improving diagnostics, right? So one improvement was, I just mentioned OAEs. These kids would be not distinguishable from a lot of other kids if we weren’t measuring OAEs. But fortunately, people in our field sort of developed that technology, moved it into clinical practice, and we started figuring out, oh, hey, some of these. Children have absent ABR and present OAEs, and we started calling that auditory neuropathy. Right. And a next evolution in our diagnosis is being able to say things like, oh, yeah, this kid, they, they don’t have an ABR. They do have OAEs. It looks like an auditory neuropathy. And I did another test and I figured out it’s actually this specific cell type, the inner hair cells, not making this cell specific protein. And that’s exactly what’s causing their hearing loss. And when you start understanding the underlying biology of the disease in that way, you can now start imagining other ways to deliver therapeutics. You have to know all that to design something like what I’ll, I’ll tell you about with DB-OTO, a therapeutic that would focus on a specific protein like that. Yeah. And that’s a very comprehensive explanation. Thanks, John, for doing that. I mean, that reminds me of back 30 years ago when I first started Chuck Berlin, the late Chuck Berlin, Linda Hood, talked an awful lot about auditory neuropathy. And now we sort of know the underlying basis for that in many cases. It sounds like. Yeah, it’s, it’s a beautiful story. Right? That’s, I think, of, of these folks who really led the way in the field and really set the stage for this next step of, of us to sort of work on like, hey, what’s the next step we can take in better understanding patients? Because the better we understand patients, we’re gonna keep being able to come up with better and better solutions, basically. So, one thing I didn’t mention, Brian, you asked me about the number. This is very rare, actually. So if you think about all the kids who are being born with hearing loss, I’ll give you a number for the U.S. in the U.S. we think it’s less than 50 children a year who are born with hearing loss specifically from this cause. Basically. Theres others that are more common. So, you know, I don’t know about you, but when I was doing my clinical training, I never heard of otoferlin. But I did. I did see a couple reports where kids had diagnoses with GJB2 deficiency or connexin 26, because that one’s a relatively common. So usually if any clinician has heard of a genetic cause of hearing loss, it’s usually something like Connexin 26. And in that case, you know, you’re talking about more like maybe 1400 kids a year who are born with, in the US with deafness because of that specific gene mutation. So this one in particular, very rare, actually less than 50 kids a year who are gonna get this diagnosis in the U.S. we believe right now. Well, that’s good to know. Well, let’s talk about these therapeutics. You mentioned DB-OTO, the DB-OTO program. Could you give us an overview of that? Sure, yeah. So, you know, going back to what we understand about what’s causing the hearing loss. So basically we understand that these children may have a profound hearing loss, be born with a profound hearing loss, because in their inner hair cell they’re not making this specific protein. So if you understand that about an individual patient, then you can ask a question. Hey, is there more, is there, there a more elegant solution to be able to provide hearing to a child who is missing the single protein? And the approach that we started working on now about eight years ago was to say, hey, what, There are technologies that exist that can deliver a little piece of DNA into a cell and can produce a protein that that cell is missing. And so these technologies are called Adeno Associated Viral Vectors. So per the name, they’re viruses, basically. These are naturally occurring viruses. And for a few decades ago, basically, scientists figured out how we could basically leverage the power of these viruses to deliver engineered payloads. So instead of delivering what a virus normally would, which is its own DNA, to our cells, basically that’s how viruses work. Instead of doing that, we can actually steal the technology from nature and say we’re going to take that technology and we’re going to deliver things that we want to deliver to a cell. So that’s basically how it works. So think about these viral vectors as being sort of a little box, basically, so this little package, and inside we’re going to design something that we want to deliver to cells. And so we’ll design features of the box to make it go to the cells that we want it to go to. So that’s an important thing to do, do. And then we’ll also spend time designing that little package that we’re going to deliver to the cells, basically. And so we did a lot of that work going back, you know, eight years ago, designing the technology to deliver what we wanted to deliver. So what we’re, what we’re actually delivering to the cell. The idea is that we deliver this box, it goes into the inner ear, it’s going to touch, imagine it touching up against an inner hair cell. So it’ll touch receptors on the inner hair cell and it’ll get pulled inside of the cell. So now once the box is inside of the cell, it’s actually going to open up and let its contents out. And its contents are going to go into the cell’s nucleus, Right? So that’s the nucleus of the cell. This is normally where all your chromosomal DNA is. This is where all the magic is happening, where the cell is going to have this DNA that’s going to make RNA and then ultimately turn into proteins that get sent out all over in your cells and do really important stuff. So we’re going to deliver this box into the cell. It’s going to go in the cell, it’s going to open up, let its contents out, and those are going to go into the cell’s nucleus. The contents that we deliver there are going to be the main pieces are going to be two things. One is going to be the instructions to make the otoferlin protein. Because what we know is that for these kids, their inner hair cells don’t have the right instructions. That’s why they’re not making the protein. So we’re going to deliver a right instruction copy of the instructions to sit in the cell nucleus. To make the protein also connected to those instructions, we actually put an extra set of instructions. So we said, hey, if this box happens to go in any other cell, so let’s say that the box, instead of going into an inner hair cell, it happens to connect to a receptor and it goes into one of our supporting cells. So think about, like your diter cells or some other type cell type in your inner ear that it’s not your inner hair cell. We said we want to put some instructions there. So if you go into another cell, we don’t want you to make this protein because this protein is not normally expressed in those other cells. So we actually only want this protein to be expressed in the cell type that it’s supposed to be expressed in, which are the inner hair cells. So that’s the design. So once the instructions are in the cell, they’re going to just start making protein. And you can kind of think about them like a little protein factory that we’ve built. We built a little protein factory in your cell. It’s going to start making the protein as the protein builds up. What we’re hoping is that if the protein’s there now, since the inner hair cell structure was there, the auditory nerve was already connected to it. The rest of the ear was already there and working that once the protein is there, maybe the child, instead of having no hearing, maybe with the protein being present, they’ll actually start being able to hear because all those great messages that their ear was processing will finally be able to get sent via the auditory nerve to the brain. That was like the therapeutic concept. That was the hope. One thing I’ll try to make really clear, because our field has spent so much time talking about regeneration, sometimes when I talk about this technology, people think I’m talking about regenerating cells. They think, oh, the child was deaf and you’re going to regrow their hair cells or something like that. I just want to be really clear that that’s not what’s happening. We’re working on a very simple biological problem, which is the cell is already there. All I need to do is make a protein. Now. I don’t have to rebuild a cell, which is hard. Instead what I’m going to do is just make a little protein factory. That’s all I’m doing. So the intervention is that simple, really. At the end of the day, it takes a lot of really smart people to, like, build the technology for sure. But you can think about it as being that simple from a, a clinical perspective, I think. Great explanation. I’m curious how, once the protein factory is in place, how long does it start? How long before you notice an improvement in hearing thresholds? Okay, so I thought you were going to ask me a different question, but that, that one is a great question too. So once it’s in place, so what we’ve seen. Brian. So when we did this, you, you. Whenever you’re doing this type of development, you start out and you’ll test it in, like, animal models. So you’ll like, create a mouse that has auditory neuropathy because of otoferlin deficiency. Like, that’s possible to do. So you can, you can model that. And we deliver this this therapeutic to the ear of the mouse. And then we would use ABR, so auditory brainstem response. Actually, you can do that in a mouse just like you do it in babies in the clinic. And we would measure, you know, how long or number one, we didn’t know, like, would it provide improvement in the, in the ABR. And then two, how long would it take to your question? So in a mouse, it took about four weeks. So basically you would see the proteins, the protein would start expressing, and then about. It varied a little bit. But two to four weeks in, we would see protein expression get to its maximum state. And that’s usually around the time that we would start seeing functional recovery on an Auditory brainstem response. I’ll tell you, we’re now in a clinical trial with this therapeutic. And within the clinical study we see a little bit of variability. So some kids within four weeks of the therapeutic are starting to respond to sound already. Some of them, it takes a little bit longer for it to be clear that they’re responding. Might take six or 12 weeks before we see a very clear response based on clinical assessments. But I’d say it’s in that range we weeks, basically after delivery that you start seeing some response. Thats good to know. I know that you recently presented some data at a scientific meeting on the DB-OTO, could you give us a little bit more insight around the results that you presented at that meeting? Yeah, let me summarize it. So I mean, just to give everybody a perspective here, so the way this works, right, you have. Imagine you’ve got a little vial with some fluid in it. That’s the AAV vector. And the way in which we deliver it to the ear is actually directly into the inner ear. So you know, we, there’s standard surgical approaches for accessing the inner ear. Currently for cochlear implants, we actually use the same surgical approach to get to the inner ear. And then what we do is we take a small catheter and we, we push it just a few millimeters through the round window membrane. So you, you know, you’ve got a couple different places you could think about trying to access the inner ear fluid. But you go right into a few millimeters into the round window membrane. And then we slowly infuse this fluid into the inner ear that contains all of these little boxes. As I mentioned, the vector with these payloads we’re trying to deliver to the inner ear. We actually put a little hole in the semicircular canal because the inner ear is encased in bone. And so we’re pushing fluid into a space that’s filled with fluid and there’s a lot of membranes around. So in order to make sure we don’t put too much pressure into the inner ear, we basically have this pressure release valve in the semicircular canal. So we’re pushing fluid in and the displaced perilymph is coming out of that sort of opening, basically. So we infuse the ear, basically get the vector in the ear. So that’s how it’s done. It’s surgically delivered, and then everything is closed up, right? And the child’s allowed to heal from the surgery. What we’ve seen, so we’ve had. We reported data, as you mentioned, Brian, at the ARO meeting just a few weeks ago. And what we reported on were the first 12. Patients who, who had received DB-OTO in the clinical study. And these are all pediatric patients. And they ranged in a, they ranged in age from 10 months of age, so very young, up to 16 years of age when they were receiving the therapy. Most of them on the younger side though. And so the things that we shared, number one, we talked about safety. You know, if you’re, if you’re introducing a new molecule for the first time, the first objective for you is to understand safety. And so what we’re seeing so far and we shared is that we have not observed any DB-OTO which is the the name of this molecule related adverse findings in the study thus far. The types of things that we’ve seen in the study from a safety perspective are, you know, the types of findings you expect from doing the surgery, which we know those really well because everybody in this field, we’ve been doing cochlear implants, you know, for a very long time. So we, we understand the, the surgical side effects basically. So first off was safety. The second thing we looked at was you know, what type of hearing responses are we seeing? And so on that side we’ve had. Our first participant in the study was a 10 month old girl and we’ve actually been able to follow her now out from, for 72 weeks in the study. So we followed her over a long timeframe. Now what we saw in her was that at the baseline, profound hearing loss. Right? So for listeners of your podcast, probably everybody understands that that means you have a vacuum cleaner next to your ear, you’re not gonna respond basically. So she could not hear. What we saw was we dosed in one ear with DB-OTO Basically only one ear received the therapy. The other ear, she actually received a cochlear implant during the same surgical procedure. And what we found was that after about four weeks she was responding to loud sounds. In fact there was a nice video her mother shared of her first moment hearing. She was testing her at home and saw her hearing for the first time with this gene therapy. But we brought her in the clinic, we did the standard testing that you and others know. We did behavioral audiometry, we did auditory brainstem response testing. And, and what we saw was that she could respond to loud sounds. By the time she got to 12 weeks, she was responding sort of to conversational level sounds. And then by the time we got to six months she was responding in the normal hearing range. So we went from we went from profound deafness to normal hearing sensitivity over about a six month period and we’ve been able to follow her out now she’s had stable hearing over this time period and now she’s two years of age. So now you can start trying to test speech and it’s really hard as you know and others to test speech perception in a two year old. But we try and so we do testing with her in the clinic and we have seen you know that we tested her with the early speech perception test and for the two syllable words she has a hundred percent recognition. Right now for monosyllable. She’s at 50% right now. So we’re excited that these seem like pretty promising early findings in the study. And we’re really interested to see where it goes as she gets older and she can you know, do more things and tell us more about her perception. Thats all. I mean I can’t imagine the parents I mean the modern miracle of medicine. It’s a, it’s a really beautiful story. It’s been just remarkable for everybody on the team, a lot of people who’ve worked on this for so long, to hear the stories from her parents. Her parents have actually shared videos at different time points, you know, to show some of her progress. So they’ve been able to show, share some videos of her at home, you know, engaging in imaginative play and listening to auditory prompts and being able to follow along. And so that’s just been really remarkable to see. So the other data we shared is that in the other participants in the study they’re at earlier time points. But what we’ve seen is that of the 11 patients that we’ve at least had that four week first check on their hearing, that 10 out of the 11 patients so far have had significant hearing improvement in the study. And obviously we’re going to continue following them to see if you know to what extent their progress is going to map the same as this first participants in terms of the ultimate you know, hearing recovery for also. Yeah, so, so those were the big findings. This sort of this is what we’re seeing over the long term. In the first participant we’re seeing about 10 out of the 11 other participants who are showing significant hearing responses and pretty exciting to see where those kids go in subsequent time points. Yeah. Tell us what’s, so what kind of, what are the next steps in this evolutionary process of, of gathering Data, clinical trials. What do you, what do you see as next steps? Well, you know, I, I’ll tell you the way we feel, Brian, and I think that our, the, the investigators in our study feel this way as well. You know, we were kind of taken aback by some of the early findings in this study the robustness that we were seeing in the data. And so we feel a lot of urgency and responsibility to try to move as quickly as we can. You know, sometimes the clinical development can take a very long time. We’re trying to explore every pathway to try to move this program forward as quickly as possible and be able to provide access to families as quickly as possible. And what that means is engaging early and often with regulators basically so the health authorities to talk about what’s the most efficient path, what do we need to do to progress this program and get this to patients as soon as possible. So I’ll tell you that it is the commitment of everyone on the team, the teams that I’ve been working with to move as quickly as we can. So that’s, that’s what’s happening right now. We are essentially laser focused. We said, you know, we’re seeing these data, they are very exciting, both from a safety and an efficacy perspective. And we have to move quickly for patients. We feel it’s our obligation. So that’s what we’re doing. So I think you can stay tuned. We’ll be trying to share our progress and, but I’ll, I’ll promise you that the team is going as fast as they can right now. Yeah, we’ll definitely be following that. I’m kind of, I had a couple follow up questions I’m curious about. One is is it more multiple injections needed? Like was this person this these children or in a few years do you think they’ll need another injection to kind of revitalize the protein factory or? That’s a great question. That was the one I thought you were going to ask me earlier actually when you asked me the timing, I, he didn’t ask me how long. So. Yeah. So let me tell you what we know. So our belief, you know, based on the preclinical data, so we, we did this experiment in mice first and so we, we delivered and we said how long will this last? So there’s reason to believe that it could last a very long time, you know, maybe a lifetime. Here’s the reason. The cells that we’re delivering to, in this case, the inner hair cells are all post mitotic, just meaning that you know, they’re not gonna divide over time. So everybody in your audience, or at least all the clinicians in your audience understand that, that the, the hair cells you’re born with are the ones you get for the rest of your life. They don’t, they don’t replenish themselves. That’s part of the reason why we have age related hearing loss, you know, like we lose them when we don’t get em back. And so so you know, this is something that’s actually very different. There’s a, there’s a big gene therapy field by the way, that’s happening right now in the liver. So people deliver boxes to your liver cells, your hepatocytes. And one of the things people spend a lot of time talking about is exactly your question, like how long does it last? And one thing that we know about liver cells is they actually do divide. And so if you have cells that are going to divide over time, because the technology I mentioned to you, I’m not, I don’t want to try to be like too much into the weeds basically. But they’re what are called non integrating viruses. So I mentioned before that, you know, think about your DNA. You have, you have DNA and your chromosomal DNA, right? And you hear people talk about gene therapy where you’re, they’re editing your DNA, et cetera. That’s not what we’re doing. Were not editing DNA. So if a cell divides, we have to create a new cell. If you edited your DNA, then it would, that, that edit would go over into the new cell. But in the case of the kind of therapy we’re doing, which is just a little protein factory, you know, there’s no change to your DNA, so it’s just gonna live only in that cell. So I’m I’m, I’m going in the weeds a little bit just to tell you this, that you’ll hear people talk about this idea that a gene therapy could be reduced over time, you could lose your efficacy over time because your cells are dividing. And if it’s, if it’s this little protein factory, it doesn’t move over in the division. So it’s like you lose it. Once that cell dies, that protein factory dies. I’m sorry, your protein factory is gone. And your new cell that you grew doesn’t have the protein factory in it basically. So that’s a big discussion in the liver. I say all that to Say, think about the ear though. Our cells are just there basically, they’re not going to divide. So there’s reason to believe as long as we have a little protein factory there and we’re not having issues with toxicity or something that kills the cell, then this it should do the protein factory should just keep producing the protein basically. And so that’s what we saw so far in our mouse experiments. So in our mice we let them age, let them get really old. And for a mouse, a mouse, if you wait about a year, that’s like halfway through their life. And so we waited all that time and we saw consistent expression and function over that whole time period. So the question is, what’s going to happen in humans in the ear, right. And so the farthest we’ve been out so far, it’s just because where we’re at in the study, as I mentioned, is 72 weeks, so about a year and a half we’ve been following and we see good stability. But you know, we’re going to keep following these patients over time and really we’re going to learn the answer to your question. So we start out with a belief it could be very long term. But the truth is we just have to learn that together in the clinic and figure out like, are we going to need, are we going to need to think about, you know, redosing at different times or something like that. But that’s, that’s, that’ll be the next question I think after. It’ll take us a few years though to know how to ask that question basically. Well, that leads me to the second question around this, which is, what about an adult and you’re some people, you know, like somebody who’s in their 30s or 40s or even older, is it possible they could come in and get this injection? And I mean, what are your thoughts on that? I think it may be so. I mean, I’ll tell you that we’ve had two 16 year olds, right? So you start thinking about what’s different, you know, about a 16 year old or a 20 year old or a 30 year old, right? So we’ve had two 16 year olds come into the study thus far and for both of them, These are both 16 year olds who had a cochlear implant in one ear when they were very young. So they had some access to sound. So think about that in terms of neural development. That’s the other component here to think about. Had access to sound at a young age in one ear. And then they received this therapy in the other ear, and within four weeks, both of them had pretty good hearing responses in this other ear. And it was really remarkable to see. They’re also interesting because they can tell you a lot of things about their hearing that a 10 month old can’t tell you right away. So I expect their experience to be different because we’re- like, think about it this way. We’re interacting with their brain at a very different place, like time point and development, basically. But what we know is it’s possible for the otoferlin to express in the hair cell in a 16 year old. It’s possible for that hair cell then to start signaling the nerve for the. First time in a 16 year old after 16 years of deafness. And it’s possible for that signal to make it up to the brain and for the child to be able to respond to sounds. That has been proven to be possible now in at least a 16 year old for adults maybe too. Right. It seems to me that it’s a worthy question basically to ask, but the 16 year olds tell you things like this, Brian. This was fun. We one of them was telling the investigator you know, a few weeks after they had received the treatment, they were taking a shower, okay. And they’re like, what is this? And they’re like perceiving something and they’re not sure what’s going on. And then they realize they’re hearing water for the first time, Brian. That’s what it is. They’re hearing water for the first time. Right. So you get these beautiful moments that the patients are sharing about their experiences growing into that older cohort. So anyhow, that’s so. So I think the answer to your question is I, I have hope. And certainly it, it should be something that we look at. Right. Well, … So we talked about otoferlin related hearing loss. Is there any other forms of hearing loss that Regeneron is exploring treatments for? Yeah, so, I mean, on both ends of the, the age spectrum. So on one hand, I mentioned earlier that congenital hearing losses, like more than half of them are caused by genetic protein deficiencies, basically. And so you can think about the same model that I just described for DB-OTO, just apply it to your favorite, you know, gene that’s causing hearing loss. And we’re looking into that. We’re trying to develop therapeutics for other forms of congenital deafness. Each one requires its special treatment type. Basically. You know, you have to, it’s real precision medicine. We’re designing for the specific protein deficiency and a very specific cell type of the ear for each one of these patient groups, basically. So that’s, that’s one side. But then obviously, as you know, there’s a whole big side here, which is acquired hearing loss. Right. So age related hearing loss, noise induced hearing loss, things like Meniere’s disease. Right. These are big public health challenges that we have. And so we’re also focused there. You know, number one, we have to really understand the biology a lot better than we do right now, as I mentioned before, really understand the disease biology. Then you can start developing the next generation of potential solutions. So it really starts with, with understanding that biology. That’s something that Regeneron as a company, like we were basically built on that. We’re built on the idea that, hey, we’re going to understand the biology in a deep way by really leveraging genetics. And at first for us it was mouse genetics. That was a big part of the original vision at Regeneron. We’ve expanded that now to include human genetics. So we use large scale sequencing studies and what we call the Regeneron genetics center to deeply understand the underlying genetics of complex diseases. We want to leverage that same kind of thinking that we’ve done for other, other disease areas. We want to leverage that for, for hearing, you know, and really drive the next generation of insights into the underlying biology of hearing loss. So that’s the other area that we’re really focused on. And those are hard problems. But the hard problems are the ones take like, worth taking on. Right. Like that’s worth spending your life like work else. I think so that both areas is the answer, Brian. We’re focused on both of them right now. It’s a good. But one question we always like to ask experts on therapeutics is how do you see it fitting into the broader hearing healthcare landscape with hearing aids and surgical interventions? What’s the role of something like DB-OTO? Yeah, I mean, well, as said before, you know, a DB-OTO for a very precision therapy like that that’s going to be able to provide benefit to this certain segment right now. And then we’re gonna have to develop therapeutics around these other areas. I think right now the way our field is sort of the way in which we’ve delivered management strategies to our field is primarily through prostheses. Right. So we’ll use hearing aids for this. For certain populations, we use cochlear implants. These things can provide a lot of help to patients basically over time. I expect, you know, that going to have a mixture of these things happening within our field. We’re going to have mixtures of devices that are providing benefits and therapeutics that are providing benefits. And in some cases we might have a mixture of both those things in the same patient actually. Right. So I think there’s going to be. I’m pretty excited, Brian. I think if you think about what this field looks like over the next couple of decades, it’s going to be very exciting because we’re introducing some really new things. We have a well established history. You know, we’re probably, I don’t know, maybe I’ll brag and say we might be the best at devices when it comes to managing patients right now. Think about the success of something like the cochlear implant from the standpoint of an implantable device. So I think we have a rich history in our field from a device perspective. We’re now introducing for the first time therapeutics into the field as well. And I imagine seeing some beautiful things that we’re going to be able to do for our patients in the coming years with a mixture of these things. I also think that having therapeutics enter into the field is going to force us to be way better at diagnosis diagnostics than we’ve ever been, because we’ve never been challenged to understand our patients in this way before. You know, have you ever been challenged to actually understand the underlying molecular cause of hearing loss in a patient? Well, there wasn’t necessarily a reason to before, but now we’re going to have to. So the clinicians of the future think about what they’re going to have to be able to understand about patients. It’s a lot more than we usually do today. That’s pretty fun. I mean, that’s like a transformation in the field. So I think that we have a couple decades of, a lot of expansion within the field, and it’s going to be exciting to be participating in this field right now. So. Wow, that’s that’s great. My final question to you, John, is this. What advice do you have for an aspiring audiologist, somebody who might be in the first year of their AuD program, somebody that’s an undergraduate thinking about getting into audiology. What career advice would you give them? My advice is twofold. I mean, one is I think about the things that are happening in our field right now. Like, on one hand, there is massive effort at improving access to devices, right? That you see that happening in the field. We’re trying to make sure more and more people get access because a lot of people who could benefit from a device don’t have access. So if you’re coming into this field, you better understand that and you better be at the forefront of trying to help get more and more access to people with devices on this other side. I think the thing that’s happening right now is what I just described, you know, more deeply understanding the underlying biology of these conditions that we’re working with in patients, because you’re going to be responsible for understanding patients in a whole new way. And that might mean that you need to understand things that are not typically taught in some of your programs. So, like, be thinking forward, like the. As, I guess, was it Wayne Gretzky who talked about going to wear the puck and working or whatever. That was Gretzky, right. So, like, you need to be doing that. You need to look at what’s happening right now. It’s. You might say, oh, it’s dibioto is. You know, you just told me otoferlin was, like, less than 50 patients a year. I don’t have to think about it yet. I think you better start thinking about understanding the underlying biology of what’s causing hearing loss. So if you see a patient with hearing loss, start asking yourself, you say I’ll say this, actually, I’ve had this discussion with clinicians before. There’s some people who look at, let’s say, like, an absent ABR and they go, all the cells are dead. Right? Or something like that. They just. You make an assumption about what’s going on in the ear that would result in a profound hearing loss. You have to change your thinking and say, I see the phenotype here. I see that the patient has a certain severity of hearing loss. What is happening at the molecular level in this patient that is causing this presentation? And maybe I don’t know the answer today, but what are all the ways in which we would try to understand the answer to that question? Because the leaders in this field will start understanding the answers to all those questions, and you should be part of that, lead the way to understand this, because then you can lead the way to developing, if you have the insight, the next generation of therapeutics for these patients. And that should be our obligation to keep making it better and better and better. Like, every year we should look back and go, like, oh, wow, we weren’t so good at providing management then. Like, we look back at the 50s or something now. Like the 1950s. Sorry, I forgot. We look like the 1950s now. So we say, oh, man, we’re so much better now than we were then. I hope that, you know, Fast forward another 30 years, and we’re looking back, and we’re like, oh, man, we’re so much better than we were then. Like, that is what we should be striving for. So I think a couple axes are important there. Access is really important. And the other axis that’s really important for new clinicians is you’re going to need to understand the disease biology in a way that maybe none of your professors ever had to when they were Sort of going through clinic. Yeah, that’s a great point. So I’ll put you on the spot here a little bit. John. What do you have any you know, for even experienced clinicians, any good resources to learn and bone up on these, on the biology, the underlying biology or genetics you know, papers, books, anything like that that you can think of off the top of your head? Trying to think of a really good clinician friendly, like version. So you know, we’ve developed some materials and I’m happy to share those that are sort of clinician friendly and some that are even family friendly materials to just explain genetics in general. Explain genetics. Explain genetics of hearing loss. Probably there are, there are probably others that are not coming to my mind right now where others have probably created websites and things like that. I can’t think of like a great textbook per se that’s been on this. But I feel like somebody’s going to be like, has written one and they’re like John, I can’t believe what you thought. I mean, we’ll flip the link in and the notes for some of the Regeneron materials that you’ll work on that. And I’ll look, Brian, and see like there probably are some other folks who’ve created some nice websites. I’m imagining that the group out of Iowa. So the University of Iowa has been sort of one of the leaders in developing our understanding of the underlying genetics of hearing loss. And Richard Smith who is there has done a lot of this work. He’s trained a lot of people who’ve come through Iowa and they’ve created a lot of stuff. And so I would imagine that Iowa has something hosted, you know, around this. So I will look to see if they have something that could be shared with your audience as well. On that topic, Brian, thank you. I didn’t mean to put you on the spot, but Is it okay came to mind. So, any final any final thoughts, Jonathan, before I let you go? I think the future’s bright, Brian. That’s my final thought. I’m so excited to be in this field right now. It’s in my mind like new era, basically, new era of medicine. It’s exciting to get to be part of that. So yeah, Dr. Jonathan Whitton, who’s the auditory global program head at Regeneron. Thank you. I can’t thank you enough, John, for taking the time. This has really been an informative conversation. Really appreciate. Was a lot of fun for me, Brian. So Thanks. Thanks for having me on. I appreciate it. Well, no problem