Finally, a Drug Company Listens to People with Hearing Loss

In a day and age when it feels like there are drugs for everything—from restless legs to toenail fungus to stage fright—it’s strange the drug industry has almost completely ignored one of our most important organs: our ears. Given that 15 percent of people in the U.S. report at least some level of hearing loss, you’d think drug makers would be doing more to figure out how they can help. Well, now there’s at least one company that is. Cambridge, Massachusetts-based Decibel Therapeutics went public in 2021 to help raise money to fund its research on ways to treat a specific form of deafness caused by a rare genetic mutation. Decibel is testing a gene therapy that would be administered only to cells in the inner ear and would provide patients with a correct, working copy of the otoferlin gene, which is inactive in about 10 percent of kids born with auditory neuropathy. Harry‘s guest this week is Decibel’s CEO Laurence Reid, who explains how the company’s research is going, and how Decibel hopes to make up for all those decades when the pharmaceutical business had basically zero help to offer for people with hearing loss.

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Harry Glorikian: Hello. I’m Harry Glorikian, and this is The Harry Glorikian Show, where we explore how technology is changing everything we know about healthcare.

These days, it feels like there’s a medicine for almost everything.

There are drugs to calm your restless legs. There are drugs to treat fungal infections under your toenails or fingernails. There are even drugs to calm down performers who suffer from stage fright.

So it feels odd that the drug industry has almost completely ignored one of our most important organs: our ears.

15 percent of people in the U.S. report at least some level of hearing loss, so you’d think drug makers would be doing more to figure out how they can help.

Well, now there’s at least one company that is.

It’s a six-year-old company based in Cambridge, Massachusetts called Decibel Therapeutics.

Decibel went public in 2021 to help raise money to fund its research on ways to treat a specific form of deafness caused by a rare genetic mutation.

It turns out that in about 10 percent of children who are born with auditory neuropathy, the problem is a mutation in the gene for a protein called otoferlin.

It’s involved in the formation of tiny bubbles or vesicles that carry neurotransmitters across the synapses between the inner hair cells that pick up sound and auditory neurons in the brain.

Decibel is testing a gene therapy that would be administered only to cells in the inner ear and would provide patients with a correct, working copy of the otoferlin gene.

Otoferlin wasn’t even discovered until 1999. So the fact that there’s a drug company working to correct mutations in the gene for the protein is a great example of how genomics is enabling big advances in medicine.

My guest today is Decibel’s CEO Laurence Reid.

And in our conversation he explained how the company’s work is coming along, and how Decibel hopes to make up for all those decades when the pharmaceutical business had basically zero help to offer for people with hearing loss.

Harry Glorikian: Laurence, welcome to the show. It’s great to have you here.

Laurence Reid: Yeah. Hey, good morning, Harry. Great to see you again. Thank you. Thanks very much for the opportunity to join you. I’m looking forward to it.

Harry Glorikian: Yeah, I mean, we’ve known each other for, my God. I remember. Like, I want to go back in time to Warp or one of those companies way back when you were there.

Laurence Reid: Like ten or 15 years ago, I think I think we’re both compressing our compressing our memories. I think it was a while before that. But, you know, you’ve been a student of personalized medicine, of course, a leader. Those ideas and I know a lot of those ideas for me started at least personally when I was at Millennium. And I think we were pretty you know, there was a lot of fantastic thinking that some of what was ahead of where we really were technologically. But I think that’s when you and I first met. So, no, it’s great to reconnect.

Harry Glorikian: Yeah. And now you’re CEO of a company called Decibel, which is ironic because I remember when the company literally was coming out, they called me to help them think through diagnostics.

Laurence Reid: Oh, interesting. I wasn’t aware of that. Yeah, the company got incubated at Third Rock and got launched in 2016. So we’re about six years old now. And, you know, we believe that the time is is now for sort of molecular innovation coming to hearing loss. And I’d love to talk more about that. But the diagnosis remains, there’s an interesting, there’s almost a dichotomy because at least in the in the Western world, we put our babies religiously through a hearing test within 24, 48, 96 hours of being born. And then and then beyond that, like we sort of like almost, we don’t quite ignore it, that would be unfair, but the caliber of follow up care, never mind when you’re our kind of ages, is really poor. So we’re like we’re really good out of the gate. And then after that and part of that is diagnosis. I mean, we think a lot about it, which, you know, you would love, is trying to think about improved molecular diagnostics, particularly with respect to the genetic components of hearing loss. So love to talk more about that.

Harry Glorikian: Yeah. I mean, you know, you were talking to Kevin Davies on on another show. I mean, I think you mentioned you said something like “Hearing is a backwater of the pharmaceutical industry.” And most of the focus is is what I would call a device, not necessarily a drug. So, you know, if we let’s I mean, starting there, where do you see or how do you see that changing? And, you know, how have genomic tools and and these things made a difference in the direction that we’re going. And I think that’s what Decibel was sort of formed around, if I remember correctly.

Laurence Reid: Yeah, no, you’re exactly right. But those are, those are the central questions. So where we are today is there are, so, so, both. And we think about both hearing loss and balance disorders, because they’re both mediated by evolutionarily related organs that sit inside inside the inner ear. And, you know, the hearing loss afflicts literally hundreds of millions of people around the globe at all ages. It can come on, you can whether it’s congenital or it’s sort of later in life or noise induced. So it’s a massive unmet need. And, you know, and there are no approved therapies. So it’s it’s a field of medicine today that is that is completely served, to the degree it is served, by assistive devices, namely hearing aids and then cochlear implants. And there are no approved therapies. And I think the pharmaceutical industry has been really, is just not invested in the field at all. Astellas works with our friends at Frequency and has been committed and a couple of other big companies have sort of dabbled and then and then exited. Translation has been has been a challenge. We should talk about that preclinical work not really replicating once you get to you know, human beings. And so it’s been a quite a difficult field for for many years. And and so the pharmaceutical industry has really not dived in and, you know, in Third Rock was really incubating decibel which is how they how they start companies. It was one of their ones that was was a slow burn.

Laurence Reid: And they had they looked at assets out of one or two pharmaceutical companies and were really trying to get their heads around, is the time really now. And they they pulled the trigger in 2016 and went into it with a belief that that molecular innovation was coming and is coming and that that would that would give rise to therapies. So here we are six years later. And the playing field, as I like to say, is really, you know, dominated by small companies. We like to think about Decibel as a leader there, but there are other companies doing fine science, but they’re small companies. And but that’s going to change. It has to change. And it’s going to be exciting from many aspects. When it changes, it affects how you build a company, when pharmaceutical companies are sort of watching, but they’re not committed and they’re not they’re certainly not investing yet. But I think that’s going to change. And I think we’re going to see it change, I don’t know, in the next couple of years. And I think 5 to 10 years from now, all the major pharmaceutical companies would have to be playing in this because, you know, there’s the aging component, there’s the cognitive health later in life. You could talk more about the specifics of why hearing is so important to our existence as human beings. And that’s really not just a quality of life issue. And that’s going to change. To have that happen.

Harry Glorikian: That’s why I was going to I was going to say I mean, I think if I remember correctly and it was fascinating to me when I went into Decibel, like, you know, when it was first getting started and how it was having conversations, it was like the number of people that are losing, you know, certain parts of their hearing earlier in life because of all the headphones and how loud they listen to things and so forth, was staggering. And then the economic impact of that was even more staggering. And so you would think that it’s not just the pharma industry that would be interested, but anybody that—-like I’ve got my AirPods in now. So I mean, Apple should be interested.

Laurence Reid: Those guys, those guys are working around the field. Bose, of course, a fine Massachusetts company with some of the best sound equipment. They’ve been investing in the hearing aid technology field for in recent years and have just launched a new generation of technology under that umbrella and come out with some pretty sophisticated marketing, trying to really get people to think about the quality of their hearing and why it’s important. And so, as you say, so new people coming at it despite perhaps their contributions to it. And so, you know, so I think I think that’s really very, very interesting. And but it is now devices, as you say. It’s devices. So today, you know, a lot of it is treated nominally with hearing aids and then for very severe forms, particularly in in in young kids, but in adults as well. There’s a technology which has been around for about 20 years now, known as a cochlear implant, where you have a surgical implantation of a very sophisticated device into your cochlea. And essentially it essentially hard wires, really a microphone directly to the onto the auditory nerve.

Laurence Reid: And so there’s a device inside your head and then there’s a detection device that is visible outside. But both of these we view as assistive devices. And I mean, with some of the things that we’re thinking about for molecular therapies, you know, we really think we can be disease modifying. And the devices are, they’re an attempt to sort of palliate, effectively, the manifestations of hearing loss. They don’t work 24/7 because they can’t and kids in particular hate wearing them. But, you know, our parents hate wearing them as well, particularly the hearing aids. And so the compliance is very poor. But I think more importantly, they can only be so effective, and particularly if you’re very severely deaf, the difference between that status and, you know, what the kid next to you in the classroom is hearing and picking up and how that’s affecting their development is really massive and to me is one of the big drivers certainly why I got excited about the field personally.

Harry Glorikian: Oh yeah. I mean, you know, if you’re in a crowded restaurant and you can’t hear the person across from you, there’s all of a sudden it changes the entire dynamics of what’s going on. I mean, that you know, that said, I think if my wife could implant a microphone that was directly wired into my brain, she would probably take advantage of that to make sure I hear everything.

Laurence Reid: And hard wired up straight into her larynx. And then then everything would be would be beautifully aligned. Yeah, I know. It’s really interesting. So my beloved mother is 84 and you have a one on one conversation with her and it’s fine. You know, it’s absolutely it’s completely normal, like you and I chatting or talking to a 20 year old. But you put her in a crowded restaurant and it’s very hard for her to participate at all. And so it’s a really interesting. So on one level that’s trivial, right? It’s a night out in a restaurant. But it’s indicative of the challenge. So I always think most easily comes to me with thinking about congenital deafness and then deafness or loss of hearing in in older people. But that restaurant is sort of an analog for in the case of the older people losing, you know, we talk a lot about connection, losing connection with their loved ones or their coworkers or their family. And, you know, hearing loss is the number one risk factor in cognitive decline later in life. And nobody is suggesting it’s necessarily causative. But that loss of connectivity clearly in some way is contributing to, you know, to a cognitive decline. And I think that’s really the way to think about it. For me, I think about hearing loss as why, why does it matter? And it’s not because I think it’s, if you haven’t dealt with it, you probably think about it in terms of a social discourse. But actually why it really matters is the impact on, I use the phrase cognitive health, which is probably not a phrase of professional would use. It’s really how is your overall ability to interact with people, to process information and and to share it? And if you’re disconnected, it’s clearly contributing to that lack of of of interaction and ability to, you know, to have discourse with our with our with our families. And so you see that. Pivoting to loss of interactions later in life. And then for a kid.

Harry Glorikian: And how it affects the economy. I mean, if you’re not going out to dinner or you’re not or you don’t hear everything at work or things like that, I think the impact is is dramatic. But you know how many I know you guys are working on different therapeutic approaches to solve this problem. So, you know. How many different forms of deafness right now, or maybe balance disorders, are monogenic or or caused by mutations of a single gene that, say, we can get in there and do something about it, because I think that’s where you guys are starting.

Laurence Reid: That’s where we’re starting. And that’s exactly the right way to think about it. So let me let me step back and then I’ll answer your specific question. So the strategy that we’ve taken and other people have different views of this is really that the most robust understanding in 2022 of the molecular etiology of any form of hearing loss is, is that it’s driven by overtly by monogenic conditions. So two mutated genes inherited from mom and dad that good old recessive genetics and that therefore we’re able to understand precisely what’s causing it and we’re able to understand the impact of that of a child born with bi-allelic mutations in the otoferlin gene for example. And and the promise of gene therapy is the ultimate to put back a a functioning copy of the gene very early in life and put a child back to a physiological state of of hearing that mimics the kid down the street. And that’s and that’s the ambition. And what we think will that will enable is both these modifying treatments, maybe even cures for for those sections of the population. But it’ll teach us about how to do gene therapy safely in the ear. We think the ear is a wonderful organ in which to do gene therapy. We should probably talk about that in a moment.

Harry Glorikian: Yeah, absolutely.

Laurence Reid: But that over time, the Holy Grail. So as you get into the bigger populations, it’s a classic, you know, genetics and environment, viruses, noise, lots of chemicals or lots of things  that damage areas over the course of life. And we just naturally lose the sensory hair cells in areas over the course of life. Everybody approximately linearly is losing that, that sensitive and that sensitivity. So eventually you hit a threshold and we all suffer from some form of hearing loss or balance, you know, lack of equilibrium as we get to be a little bit older and. For for many different causes. So the Holy Grail is can we really have regenerative medicines that regenerate the sensory the sensory hair cells, as they’re called, in the inner ear, potentially as a treatment for hearing loss or balance disorders. And so the way we think about this is our strategy is really to to start with the monogenic forms of hearing loss have a chance for very clear diagnosis, driving, very precise clinical trials, driving potentially therapies that are directly addressing mechanism and with very high potential molecular upside. And to build from there into a pipeline of gene therapies that will start to go into broader populations, populations of much older people, and that will be gene therapies that are regenerative medicine. So that’s our sort of long term vision of how this will how this will evolve. But it’s starting with the monogenic conditions which which are which are rare diseases, orphan diseases by all definitions. And I think for the reasons that rare diseases have been such an intellectual driver of our industry in the past 20 to 30 years, is because you can link mechanism and etiology and a potential molecular cure in a very linear fashion. But it teaches you so much about how to manipulate an organ and how to develop therapies that eventually will treat broader populations.

Harry Glorikian: Yeah. Laurence, you need to move faster, because I think I went to one too many rock concerts when I was younger. And, you know, I could tell you that.

Laurence Reid: I had friends, when I was in high school who were who were into certain, you know, I hated heavy metal when I was a kid, but I had friends and they would come back and they’d been to a concert and they’d they’d stuck their head inside the speaker and they they couldn’t hear for like a day or two. And I, I think back to those I worry about where those guys are now because they’re hearing I’m sure they’re otherwise.

Harry Glorikian: Yeah. I mean, when you’re when you’re when your ear is ringing like a day afterwards, you probably recognized that was probably, it was a lot of fun at the time. But you pay for it later. But but stepping back, though, even if we were able to match every form of deafness to a specific genetic cause. Right. Very few infants or children get the kind of tests that would be needed. Like how widely available are these genetic tests for the hearing neuropathies today or.

Laurence Reid: Oh, it’s. I’m sorry. Go ahead.

Harry Glorikian: No, no, no, go ahead. Because that would be my first question.

Laurence Reid: It’s the minority. And so by definition and I appreciate you’ve worked and thought a lot about this over the last years. You know, good diagnosis is is gating to everything that can follow. And so part of our broader I mean, at some level actually even step back from molecular diagnosis, which I know is where you’d want to go, that just overall how we manage hearing how is is almost rudimentary compared to how we think about about our eyes for example. And just I had my annual physical a couple of days ago and and a new physician and and the doctor was like, oh, you know, you go and get your eyes tested on, on an annual basis and which I do. And we talked about all the the good things that are cutting edge, you know, ophthalmologists does these days to look at your optic health. And then I was like, you know, the real question you should be asking me is, when did I get my hearing tested? And but when did you last get. We just we just it just doesn’t it’s just not part of adult health care in a routine way unless you get really I mean, my wife and I joke about it occasionally. I’m like, oh, well, let’s go together and get our hearing tested.

Laurence Reid: Not that, not that it’s at all funny, it’s not. It’s a serious issue, but it’s just not part of routine health care for helping adults think about about how how they manage their health. So. So we sort of we start with a, a broader set of educational issues. And then and then we dive down pretty quickly into how do we educate people about about the need and potential power of molecular diagnostics for children who, when we begin to figure out that they’re hearing is developing, you know, in the early either days or early years of their life and as as in in the developed world, most children have a basic hearing test, you know, within hours of being born, literally, often while they’re still in the hospital. And it’s like, you know, in many, many places they catch them while mom is still, you know, literally in the hospital and and they do a basic hearing test so we can catch a lot of it like that. If it if you start if the hearing degenerates after that, it is still very challenging for that to get properly understood and picked up and diagnosed and managed even in, you know, developed cities and, you know, in the United States.

Laurence Reid: And the the ability to to reflex to molecular testing is is very variable. If you talk to our our audiology team, it starts to be very dependent on which city do you live in and what’s the ability? I mean, we’re sort of privileged in Boston, Mass Eye and Ear is obviously one of the world’s leading hospitals. But but how do you get from a an early “Yeah there’s an issue here” to any form of molecular. What that path looks like of your pediatrician driving you to real audiological analysis, driving you to a molecular diagnosis. It’s a pretty fraught path. You think about it in in in cities like Boston. Fair enough. And aren’t we privileged to live here? We’re lucky to live here from that perspective, but it’s very heterogeneous. And so part of our work is really we have a collaboration with our friends at Invitae, part of which is trying to just it’s almost educational. It’s offering a free genetic testing service for important genes related to your hearing health. But part of the purpose is, is educational, really.

Harry Glorikian: Yeah. Yeah, I was going to I was going to ask about that. I mean, in making it available, I mean, this is somewhat of a crusade, right, to educate people and get them on board, right. Because if you just don’t know what’s available, you may not think about it for your child. And if a parent knows they can help their child, I think most parents would go out of their way to do something positive. But just for everybody who’s on the phone, you know, can you walk us through an example of, let’s say, a single gene mutation can cause deafness? I mean, maybe you can concentrate on the example of, I think it’s otoferlin, if I’m saying correctly, which you know, basically, if I’ve understood it correctly, it’s the formation of the synaptic vesicles that carry neurotransmitters across the synapse, which is very, very tiny. And if the hair pulls away just enough, you start losing that ability to hear at that level because the chemical can’t jump across to make that connection, which is, I think what’s happening to me as I get older.

Laurence Reid: Yeah. Very good. Yeah. And I’d love to talk about otoferlin. So otoferlin is our first program where we and other people are thinking about this as well. Our friends are also are working hard on this problem as well. But it’s the vanguard program for Decibel and the field in terms of gene therapy for modern forms of hearing loss. And so obviously, we we know the gene that causes this particular subset of severe hearing loss. The children are born profoundly deaf. They really have almost no no signaling capability whatsoever. Despite that, when you study their ears and when you look at animal animal genetic models of the condition, the ear, functionally, structurally appears to be normally constituted. So what you see start with a belief that we may be able to instate normal hearing in these people by in these children, by, by by providing a a wild type, a normal copy of the gene. And there are other forms of of genetic hearing loss where by the time the kids are born, the children are born, their ear has not developed properly, structurally and functionally. And I think that’s a much harder problem and may be impossible to to solve postnatally. So so as we think about areas where we think we can have an impact with the first generations, we’re looking for clear genetics. We’re looking for an ear that appears to develop normally and in which we therefore have the chance to instate normal hearing. Otoferlin is a calcium sensor and it functions at the interface between the hair cells in the cochlea, the inner hair cells, as they’re called, which are the cells that transduce… Sound is effectively a mechanical signal. It comes to us as a sound wave, and it disturbs structures and eventually molecular structures inside your inner ear and creates a molecular signal that is transmitted by the hair cell through the synapse. As you say, to the auditory nodes, there’s a direct interface between these cells that are that are detecting the sound wave into the into the auditory nerve. And if you lack otoferlin your calcium sensing functionality and that synapse is not present and and there’s essentially no signal. So we measure this with something called an auditory brainstem response, which is a test you could run in a human or an animal. And there essentially it’s a flat line, which from a from a restoration of a normal signal, it’s a really excellent clinical endpoint because we’re going to, we hope, instate, a signal, a quantitative signal with quantitative richness as well, that we’re going to be able to measure relatively early after we administer our therapy. But the children have this is what we call an auditory neuropathy. They have no ability to signal from the cell into the brain. And as I say, the structures appeared to be intact. And what we know is that in an animal, if you create an animal model of this genetic animal model, that we can go into that now with DB-OTO, as we call it, which is which is a adeno associated virus vector to to basically deliver a normal form of the gene. And we can do that within weeks of this mouse being born. But interestingly, we could also go to those animals as long as a year after they’re born, which which for a small furry animal is is about half of their life.

Laurence Reid: So it’s a big piece of their life. And and we can go in we can intervene at that at that one year point and still rescue the phenotype. So the is structurally intact. And when we provide the signaling molecule, we fairly quickly instate a normal signal. So that’s that’s exciting. Right. And A), it’s a fantastic signal to measure in an animal. B) it gives us a lot of optimism that if we can get the gene to the right cells and get it turned on, then decent chance to to to solve to solve the signalling problem. So that’s sort of our reason to believe. And actually maybe the last component, and then I’ll breathe, is we think the ear is, is a fantastic place for gene therapy broadly because your inner ear is this tiny enclosed compartment. So we need a surgical route to get there, but we can then go directly to the site where one is trying to elicit a molecular effect and deposit a tiny amount of drug compared to what’s required — three or four orders of magnitude less drug than is required for systemic gene therapy — directly at the site where we’re looking to elicit the biological effect. And then almost none of it leaks out into the into the systemic circulation. So the ear, we think, is a fantastic order or organ for gene therapy, and we think we know some great genes to go after us, our first generation.

Harry Glorikian: Yeah. I mean, you know, whenever if if people have followed any type of gene therapy, like the eye has been in optimal place to sort of start with. And so, you know, I think you guys are learning from what has been done in ophthalmology to sort of transition this to the ear, which, you know, I always say to people like we always start on the outside because it’s a lot easier and then we then we figure out how to go deeper in because it’s a lot harder. But, you know, what kind of results are you seeing so far when you transfer genes into, maybe nonhuman primates.

Laurence Reid: Yeah. Yeah. No. So we’ve just in the last year or two, transitioned from rodent studies to non-human primates. You are correct that the characteristics of the ear that make us so excited about the possibility here, a lot of them are very much learning from why the eye has been really such a primary site of our efforts in gene therapy in the last ten years or so. And so as we move from small animals to larger animals to human beings, we start with, as I mentioned, genetic rodent models that we can knock genes out in the mouse that replicate the human genetics. The ear, it turns out, is it is evolutionarily highly conserved. So the the ear of a rodent is a lot smaller than than your ear in my ear. But structurally and molecularly and cellularly it’s very analogous. And we can come back to your point about genomics and how it’s opened up our understanding of these cells. But nonetheless, the basic structure and physiology is highly conserved from from lower mammals to to higher mammals. So so we start with genetic models that we can manipulate the genome and create what we believe is a pretty interesting analog rodent analog of the human condition. We don’t have genetic models in non-human primates, so we end up doing studies in non-human primates where we we we mimic exactly the surgical procedure by which we will access the inner ear, and then we end up either using a surrogate marker, GFP, or we end up detecting the human otoferln, in the non-human primate, which is quite hard.

Laurence Reid: But we’ve sort of figured out how to do that now. And really what you’re looking at is, is, is really is efficiency of the delivery and expression process. And then when you can’t measure a fixing of the genetic burden and so at Decibel, we spend a lot of time using our genomics platform to really be able to define molecular control of our gene therapy. So we’re really trying to express the transgene selectively in the cell types where nature intended it to function. So, you know, calcium sensor in the wrong in the wrong cell type one might fear, and we have data that suggests, that that may be a problem. So Decibel is really invested very significantly in sophisticated molecular control of our gene therapies. And so when we do the experimentation in the non-human primate we’re looking at, are we getting good delivery throughout the cochlea? Are we getting good infectivity throughout the cochlea and then expression of basically a surrogate marker? Because we we can’t change the physiology of a of a normal non-human primate. So it’s really all about about surgery, delivery expression. And then obviously you then got a stable transgene expression, it turns out, rises over the over the weeks and months after after after the transduction. And so we’re measuring that. And that’s going to play ultimately into clinical trial design, both in terms of safety and an end points that will measure in human being.

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Harry Glorikian: Let’s pause the conversation for a minute to talk about one small but important thing you can do, to help keep the podcast going. And that’s leave a rating and a review for the show on Apple Podcasts.

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It’ll only take a minute, but you’ll be doing a lot to help other listeners discover the show.

And one more thing. If you like the interviews we do here on the show I know you’ll like my new book, The Future YouHow Artificial Intelligence Can Help You Get Healthier, Stress Less, and Live Longer.

It’s a friendly and accessible tour of all the ways today’s information technologies are helping us diagnose diseases faster, treat them more precisely, and create personalized diet and exercise programs to prevent them in the first place.

The book is now available in print and ebook formats. Just go to Amazon or Barnes & Noble and search for The Future You by Harry Glorikian.

And now, back to the show.

[musical interlude]


Harry Glorikian: I would assume that some level of spatial genomics, the new technologies that are out there, must be hugely helpful to see the different cell types, where they are and what type they are. And you know is actually lighting up and changing versus what you don’t want to light up and change. So yeah. So I had a great interview with Resolve on their system, which I think is going to be the next frontier, because what you’re saying is, what cell type, where it is, and did I make the change in the exact one that I wanted?

Laurence Reid: That’s exactly right. So my my colleagues, long before I was here, invested in building a platform that we think is still, we have a database of over 3 million molecular profiles of the cells of the inner ear, which we think is a unique asset. And basically applying the tools of single cell genomics, which is the ability at the level of individual cells in the organ of an individual animal to analyze comprehensive gene expression. And so what we’ve been able to do, and I think this is part of just changing our attitude to how do we understand the cells of the inner ear and therefore how can we think about manipulating them pharmacologically to open up the field? And so we have a complete molecular characterization of, there are about 30 or so important cells in the inner ear and there’s two or three subsets of those cells, starting with the cells that I talked about that are probably the critical therapeutic targets. And so we have a detailed molecular understanding of the composition of the level of gene expression of each of these different cell types. And we look at them a lot as they as they as they differentiate and form in a natural process, because we think that holds the answer ultimately to regenerating them as part of this next part of our strategy. But it’s also taught us about how individual cells control gene expression. And I mean, otoferlin is expressed essentially in an adult animal only in the so-called inner hair cells. And that’s what we then aim to replicate with our gene therapy. And so we’ve been able to take our genomics platform to define genetic regulatory elements that drive our trans genes in our gene therapies to express selectively in the most important cell type where you need it and not elsewhere. We know from our animal studies that that has a beneficial impact on on on the therapy and that the durability of the therapy. So that’s our overall molecular goal, but it leverages this platform of single cell genomics.

Harry Glorikian: So I’ve seen company presentations. Like you guys are, you know, you intend to initiate a phase one, clinical trial of of DB-OTO. I mean, how is that going? I mean, what are the big technical or medical barriers, where you’re thinking about testing gene therapy? Like, I mean, you know, where are you guys in all that?

Laurence Reid: Yeah. So so we what we’ve and I’m going to be precise as a public company, I need to be careful with my disclosures. So apologies in advance. But what we said is that we’ll initiate will file an IND or a CTA in Europe this year and and move into our first in human study this year. And so we’re in the you know, we’re deep in all the almost classical, you know, pre-IND work of making material and, you know, and testing it in, in the final, you know, GMP tox studies and making material of a caliber that’ll that’ll go into human beings, which is very exciting. And that’s, you know, that’s that’s what we’re working on. Those are the two sort of basic barriers. I mean, we have published and talk publicly about a lot of our animal data, what I sort of recited a few minutes ago, small animals to large animals. I think we understand the basic pharmacology and now it’s okay, scale up, make the material for human being, you know, GMP material for human beings, test the material, you know, in more prolonged formal toxicology studies, you know, and move it into human beings so that that work is ongoing. The other part that’s really fascinating that you would appreciate is, you know, in a rare disease like this, a lot of very interesting discussions about about what’s the exact patient cadre in which one starts a clinical trial.

Laurence Reid: And we spend a lot of time building relationships with with clinicians, particularly in Europe, but also in the US, who really invested in understanding the genetic basis of of children in their region with genetic forms of auditory neuropathy. And we have a fantastic collaboration with our colleagues in Madrid at the Roman y Cajal, who have a database that is essentially all of the all of the known diagnoses of otoferlin deficiency in Spain. And so they’ve done so we have been able to help them do a lot of natural history work. What is what is the progression of the condition and how do we find these kids? And so we ultimately not necessarily immediately, but the ultimate goal is to treat children very early in life. These kids are now once they’re diagnosed, they would get a cochlear implant really probably around the end of their first year of life. It used to be more like two, but that age has come down from a medical perspective. Being born profoundly deaf is the phrase is is a neurodevelopmental emergency. And I talked a lot about about old people. But for a kid, the the or a baby, the issue is that hearing lack of hearing impacts that their initial social interactions that their generation of language skills and their ability there and that and that feeds into their cognitive development.

Laurence Reid: So there’s a there’s a whole set of emotional interactions that are happening very early in life. And of course, with so much cognitive development going on and the hearing is, is the absolute gate to a lot of that happening. And so it’s widely, widely agreed that this phrase, a neurodevelopmental emergency, is what physicians use. So so ultimately, we need to be treating these kids in the first year or two of their life. And you know, how soon we’ll get there remains to be seen. And it is an ongoing discussion. But that’s that’s where that’s where ideally we would end up. While at the same time, as I said, we know we can intervene in animals later in their lives. So we’re optimistic that we’re going to be able to take adolescents and and children beyond the first year or two of life and still be able to have a positive impact on them. Well, that’s the vision for sort of the broader applicability, not just in a newborn baby.

Harry Glorikian: Yeah. I mean, you know, I mean, a child’s, you know, the neuroplasticity or how easily that their brain or their system adapts and changes. I could see, you know, the drug having a much more profound effect in that population. I mean, in older people, I like to believe that we still have neuroplasticity, because I’m constantly evolving and changing. But, you know, I also sometimes think we’re sort of stuck and maybe maybe don’t have. But, you know, the human body is an amazing machine. But, you know, it brings me like one of the biggest themes on this show is like data, data, data and how that intersects biology. And, you know, what you’re talking about is identifying the right sets of data, the right patients to have this work done on so that you can achieve a level of success. We all know that if you pick the wrong patients. Like you’re utterly almost doomed for failure, or you’re going to have an effect that you really didn’t want to have. So how much of of Decibel’s work or approach is is rooted in “Here’s the data, here’s the patient.” How much are you guys using that to drive every decision that you’re making?

Laurence Reid: It’s a it’s a really great question, actually. And the answer is a lot. In fact, as I think about Decibel and where I think the team that my predecessor built, Steve Holtzman, who of course, you know, is really, really exceptional, is is effectively translation in its broadest sense. Right. I think what differentiates Decibel is an outstanding understanding of the biology of the inner ear and that we’ve invested in in turning that into a genomic molecular understanding of every cell type. But it’s then, okay, who’s my patient? What, their molecular profile. And how do I link that back, feed that back into my discovery process? What are my animal models look like and how am I looking forward, you know, into ultimately into a clinical trial? And with people suffering from from congenital hearing loss age, which we try and intervene, becomes a big variable, as you’re suggesting. And so, you know, if you’re in the pharmaceutical R&D, it’s like, okay, that’s translational medicine he’s talking about. And and it is I just think we do it really well. And it’s really the essence of the scientific core of Decibel is linking our molecular work in the cells of the inner ear to a fantastic understanding of the patients, their individual phenotypes and how we look to bridge that gap between preclinical research and the clinic. And the the the truth is, I mean, there are no approved therapies and there hasn’t been a lot of work, as I said, up front.

Laurence Reid: But but it’s not like we’re we’re complete, we’re not we’re not going to be the first people either to do a gene therapy in the ear, nor to try and develop a therapy. But the translation has been really poor. And I think that our ability to understand the mechanistic pharmacology, preclinical and clinically and then be confident that that was going to work in a human being has been really poor. And obviously genetics from a simplistic perspective is a fantastic way to bridge that gap. Right. We know which gene we’re trying to fix. And therefore, is the ear able to be fixed in a child of one two years old? And can we get the gene there safely and effectively and turn it on in the right place? Right. But those are problems that you can break down and solve and you can analyze them in smaller animals and larger animals. Whereas I think historically, the preclinical data, how do you validate it in a human being or do we really know those mechanisms are going to work in a human being? Well, the outcomes have shown us that we didn’t have all the understandings of that. And I think you look back on it and the ability to translate has been has been weak. And that’s why the genetics is is so appealing as a formative place to to start and try and build a pipeline of therapeutics, at least in our opinion.

Harry Glorikian: Yeah. It’s funny because we’re always coming back to this genetic part of it. And I remember like somebody saying to me way back, No, it wasn’t that long ago, relatively speaking, but why would you want to sequence anything? Right? And now it’s like it’s the cornerstone of everything we’re doing. Yeah, but. But you guys have another drug, right?

Laurence Reid: We do.

Harry Glorikian: That prevents ototoxicity, right. Damage to the inner ear.

Laurence Reid: Yep.

Harry Glorikian: And it’s that’s one of the most common side effects of chemotherapeutic drugs like cisplatin. I mean, for those people that are listening, right, these little hairs, it’s the same thing as like maybe the hair on your head.

Laurence Reid: Please don’t go there. It confuses people.

Harry Glorikian: But essentially, you’ve got a drug that you’re working on this in this space.

Laurence Reid: Yes, we do. So firstly, how are you just upset because of our relative quantity of hair here. The hair cells in your hair are very different than the hair cells on top of your head or other parts of your body. Their role is to transducer signals on the inside of your cochlea into the brain. So but the cisplatin based chemotherapy is still very, very commonly used around around the world and is quite efficacious in certain types of tumors. It’s widely used, for example, in testicular cancer, just one example. And it comes but it comes with a couple of of fairly severe toxicities, one of which is it kills the hair cells in your ear. And it also damages their interactions with the nervous system. And earlier in Decibel’s life when we were sort of using our biological thinking before we. That’s what I would say when we started as a biology company and we explored different molecular molecular modalities as the right way to treat it. And now we are significantly focused on gene therapy. As we’ve been talking about, this program was home grown and we’re pretty excited about it despite our core investment in gene therapy now. And what we have is a proprietary formulation of a molecule of sodium sulfate, which is a natural metabolite, and it chemically inactivates cisplatin. And so we actually administer this by an injection into the middle ear and then the active ingredient leaches into the inner ear. And we administer that about 3 hours or so in advance of the Cisplatin IV, so that by the time the cisplatin gets to the ear, the inner ear is already bathed in sodium sulfate. And so and then you have a chemical reaction in situ inactivates the cisplatin.

Laurence Reid: And you know, it’s interesting because some people don’t find that very sort of biotech sexy, but it’s actually an incredibly elegant way to to to stop the side effects of a molecule that has multiple, multiple molecular forms of damage that are probably being imposed on different cell types. So solving that biologically or biochemically is a very hard, diverse problem, whereas solving it chemically in situ we think is is very powerful. The principle to give some credit was validated by a company called Fennec, but they have an IV administration and they are constantly fighting between achieving good things in. As you might imagine, preventing against that toxicity without inhibiting the efficacy of the drug. And it’s correct. And that’s that is a very and they hopefully eventually will get approval for a fairly narrow pediatric population because it’s been very hard to sort of thread the needle of can I protect without inhibiting the efficacy? Now if you go directly to the organ where the damage is being done, local administration of a proprietary formulation, so it sits in the ear, it’s there in advance. Essentially, none of it leaches out into the circulation. So we have, we believe, negligible risk of inhibiting in any way the cancer benefit of the circulating cisplatin. So we’re achieving a local protection and we’re looking where we will be reporting some human proof of concept data. We’ve said in the first half of this year. So pretty excited about that, actually.

Harry Glorikian: Yeah. I mean, you know, I don’t need sexy. I just need something to, like, work, right? I mean, sexy is nice, but, you know, if it’s working, it’s working sometimes, you know.

Laurence Reid: Right. So, so not not to compare protection of hearing against protection from people who are going to die of cancer. But it’s an interesting example of where hearing health or ear health gets neglected. So in the context, you know, cisplatin is used in many cases with what people refer to as an intent to cure and so people can get cured. Young men, I think the cure rate is something like 95%. So you’re talking about a young man, maybe 20 years old. He’s going to live for 100 years, right? Maybe more. Maybe more. And nowadays and so the the importance of protecting his hearing at that age. And there are female cancers as well. But his hearing at that age for his long term health is incredibly important. But it gets it gets, unsurprisingly, neglected because the focus is on is on the cancer, which is which is understandable. But but we think that there’s a really important opportunity to, you know, to provide a better overall solution for for those people that’s going to have an incredible impact later in their life as their hearing would be naturally degenerating anyway. And and I think because of the the understandable stress when you’re going through chemotherapy, you know, worrying about the hearing decrement, is it’s just not top of mind. And so we’ve got some awareness. We’ve got some work to do to increase awareness there and hoping that some of our animal data might replicate in human beings because we think this could be fairly effective and really hopefully get it into the minds of oncology physicians. Is the goal that you should be thinking about this. You’re trying to cure this patient. You’re trying to whether it’s a woman with ovarian cancer in her fifties or a young man with testicular cancer, they’re going to live for decades to come. And we think it’s important that they’re hearing health is protected and we can help you do that potentially in a very powerful, rather simple way, actually.

Harry Glorikian: So. I’m going to assume and you can correct me if I’m wrong, that if this gets through sooner than the gene therapy and can generate some revenue in the short term, you can then utilize that revenue to continue to fund the gene therapy programs.

Laurence Reid: We’re all always looking for money to do this, right, Harry?

Harry Glorikian: So, unfortunately, that’s the business we’re in.

Laurence Reid: That’s the nature of the beast. Certainly, after we have our data in hand on the proof of concept, we’ll be looking for an FDA interaction to define the path to registration, which we think could be relatively efficient. We have, you know, the medicine that effectively becomes an oncology supportive care medicine. It needs to be administered probably in the chemotherapy suite right in advance of a patient receiving their chemotherapy. So it needs to be marketed to an oncologist with a lot of education in the audiology community so that they’re leaning on their oncology colleagues to you need to do this and you need to think about this as you’re putting your patient through through chemotherapy. Ultimately, I think that that marketing to the oncologists, I don’t think that’s what’s going to do that in itself. We’re going to eventually bring a partner partner in to do that who is a specialist in marketing to the oncology community. And we want to be involved in rethinking about making sure that the ideological education and understanding is transferred into the cancer into the cancer world. And so that’s that’s a commercial strategy and structure that will will put together, you know, potentially starting when the data is in hand, but certainly some time between now and approval of the drug.

Harry Glorikian: Well, Laurence, you know, I can only wish you the greatest success because and working in older people would be great, because I’m sure that I’m going to need this at some point, and some of my friends may also need it. But it was great to catch up with you. Great to talk. You know, I hope, you know, it’s not as many years past again before we we get a chance to connect. So great to have you on the show.

Laurence Reid: Thanks, Harry. I really appreciate it. And hopefully I’ve been able to provide some of the color and why we’re so excited and think we’re opening up a new area of therapy here for people with hearing loss and balance disorders beyond that. So really appreciate the opportunity. Thanks very much and great to see you.

Harry Glorikian: Thank you.

Harry Glorikian: That’s it for this week’s episode.

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