RARE Daily

Restoring Hearing through Gene Therapies

April 20, 2023

About 10 percent of children who are diagnosed with hearing loss at birth have an auditory neuropathy that is usually due to a genetic cause. One of the most common genetic causes of hearing loss is due to a mutation of the otoferlin gene, which encodes for a protein that enables communication between the sensory cells of the inner ear and the auditory nerve. Decibel Therapeutics is developing an experimental gene therapy intended to restore hearing in patients with a mutation of the otoferlin gene. It is part of a larger collaboration with Regeneron Pharmaceuticals. We spoke to Laurence Reid, CEO of Decibel, about the unmet need in genetic hearing loss, how these conditions can affect early development of children, and the case for gene therapies to treat these conditions.

Daniel Levine: Laurence, thanks for joining us.

Laurence Reid: Oh, good afternoon. Thanks very much for having me. I’m excited to talk to you.

Daniel Levine: Decibel is working on therapies to address hearing and balance loss. Some of these are related to aging, some of these to the use of cancer treatments. I want to focus our discussion today on the company’s efforts to develop gene therapies for genetic hearing conditions. There’s been a fair bit of attention and activity around gene therapies for vision loss, but we don’t hear a lot about diseases of genetic hearing loss and the need there. How large a group of conditions might this include and how big is the need?

Laurence Reid: Yeah, that’s a great question to get us rolling here, right into the substance. Just before we dive too deeply in I just want to note for the record, as I’m obligated, I’m the CEO of a public company, Decibel Therapeutics, and excited to be here. I will make some forward-looking statements about our programs. And I have to note, in terms of biotech drug development, there’s risk associated with all those programs. And people should also take a glance at our regulatory filings in terms of understanding the risks and opportunities involved in this type of business. So, with that formality aside, yeah, let’s talk about genetic hearing loss, which we think is a very important, really emerging medical opportunity from a therapeutics perspective. So, severe hearing loss is a very significant global unaddressed need in terms of therapeutics. It’s a field today that is largely addressed by assistive devices, either hearing aids with which I’m sure everybody’s familiar, but also devices called cochlear implants. Some of your audience may be less familiar with those, and we’ll talk about them maybe a little bit later in the conversation. There are no approved therapies for any form of hearing loss. And we believe this is a major discrepancy or major paradox in terms of modern medical care. And we look forward to being in the vanguard of beginning to solve that issue in years to come. So, around the world, somewhere around 400 or 500 million people are estimated to suffer from some degree of hearing loss.

Those are numbers from the World Health Organization and others. Within that, obviously genetic forms of hearing loss are more rare, but scientific knowledge today tells us that they’re about a hundred different forms of genetic-based hearing loss. And we’ve come to understand those much better at the molecular level in the last, you know, 10 to 20 years, along with a lot better understanding of so many forms of common diseases. But also, it’s really just in the last few years that the root by which we can finally begin to address some of these has really begun to appear for us. And we believe in the foreseeable future. That’s the opportunity for gene therapy in the ear. Of those many different forms of hearing loss, we estimate these numbers are a little soft. We estimate that about 1.7 or so per thousand children born in the U.S. suffer from some form of genetic hearing loss, one of those 100 different forms. And that rolls up sort of as you think about it in total, that in the western world, often these are the numbers that tend to be most available—that in the U.S. and Western Europe, we estimate that somewhere north of a million people suffer from some form of genetic hearing loss. And we’ll talk more about different opportunities, but at Decibel, we believe we’re working on products that might have the opportunity to address perhaps up to about a half of that total population. So, that’s sort of the playing field from a quantitative basis. I’ll keep going and sort of try and put some color on the impact of hearing loss, particularly on children who are born deaf.

Daniel Levine: Well, I did want to ask you about that because with a condition like this, it’s not just a matter of lifestyle impact or a quality of life issue, but young children have a developmental impact, I imagine, from hearing loss. What’s the impact of hearing loss on young children who are most likely to suffer from a genetic form of this?

Laurence Reid: Yeah, that’s a great question and I think it really puts the fingertip on a really important set of issues. So, for a child born with a profound congenital lack of hearing, the medical community refers to that as a neurodevelopmental emergency, quote, unquote, meaning that it needs to be addressed really as early as possible during the first formative months and years of a child’s life. And, for example, for a cochlear implant in significant parts of the Western world, the goal is to administer that cochlear implant within the first nine to 12 months of an infant’s life if they are born with profound hearing loss. If you step back and think about the early years of a child’s life, we know that most of one’s language acquisition skills are occurring or being developed during the first three years, and so if you think about the role of hearing and language in the early years of a child’s life, one’s ability to hear completely informs the ability of a child to participate in a verbal linguistic exchange with their parents, with their siblings, ultimately with their teachers and classmates, just to name, perhaps the most obvious categories of people. And it’s during those very early months and years that very strong social and emotional connections are being formed between an infant and their parents, for example, and that they’re beginning to acquire those sounds. If you think about a child starting to make sort of intelligible verbal emotions around the latter part of their first year of life and sort of turning that corner about a year of age. And so those connections that are being made during those early months and years are incredibly formative. Children who fall behind on that front eventually they can catch up. Children’s brains are very plastic. For example, with a cochlear implant a little later in life, they’re able to close some of those gaps. But the devices that we use are imperfect and are unable to restore a complete physiological sense of hearing capability to a child of that kind of age or any kind of age. So, we think it’s an incredibly important part of the overall hearing loss landscape and a big part of the reason why we and others have chosen to start with gene therapy for treating these genetic forms of hearing loss.

Daniel Levine: You mentioned cochlear implants and hearing aids. Are these generally effective ways to treat someone with a genetic hearing loss? And are there other treatments available?

Laurence Reid: So, the only forms of treatment today if one chooses to provide a treatment to a child are these devices, either cochlear implants or hearing aids. They are fundamentally different types of devices in that a hearing aid is, in simple terms, merely a way to amplify the signal that a child or an adult more often detects, and that it relies on a remaining ability for your brain to hear a signal from your ear based on detection of a sound from the outside environment. And a hearing aid can amplify that. There are some forms of genetic hearing loss that result in a more moderate degree of hearing loss, such as GJB2 mutations in the stereocilin gene, which is a target of interest to us at Decibel. And in that case today, those children are treated and helped to a degree by hearing aid. In other forms of genetic hearing loss, there is a complete blockade of the ability of the inner ear to signal to the brain, for example, our lead program addresses hearing loss due mutations in the otoferlin (OTOF) gene, and those mutations cause a complete blockade in signaling from the ear to the brain. It’s referred to as an auditory neuropathy. A cochlear implant effectively bypasses. A cochlear implant is embedded into the cochlear, directly into the cochlear of somebody with a severe form of hearing loss and it basically bypasses the function of the inner ear and transmits sound coming from the outside world directly into the nervous system. And so that is able to provide some degree of restoration of a coarse form of hearing, for example, to a child who is profoundly lacking hearing. So, they’re fundamentally different in terms of how they’re used, in terms of the severity of hearing loss in the patient population that they addressed.

Daniel Levine: You’ve got a partnership with Regeneron, which is unusual in that Regeneron is providing access to its technologies as well as funding. While Decibel retains worldwide development and commercialization rights to its therapies, Regeneron will get tiered royalties on any new sales on products that result from the collaboration. I don’t think I’ve seen another deal structured like this one. Did I describe the terms correctly and how did it come about?

Laurence Reid: You did a very nice job of summarizing the key parts the business terms of the relationship. And you’re right, to our knowledge, it is very unique, or a unique deal structure. I think you have to understand Regeneron a little bit and their very unusual culture as a large biotech company today to have a sense of how it came about. So, Regeneron obviously is one of the leading science driven biotechnology companies in the industry. And even as they’ve matured to become a very sophisticated and a successful product development commercial organization, they are still—I think it’s objective to say—they’re still fundamentally driven by their research capabilities and by the scientific ethos that comes from their founders who still run the company today and the outstanding R&D department that they’ve built over the last 40 years or so. And so, that company looks at medical opportunities from a scientific and medical basis first and foremost, and how they can impact those with their capabilities, with their science, with their technologies, and then analyzes the commercial opportunities from that very much downstream. So, Decibel approached Regeneron back in 2017, and the company was just getting started in terms of really building out Decibel in terms of really building out its pipeline and opportunities. And the companies at the time were very interested in some of the particular signaling mechanisms between the ear and the brain that appeared to be related to areas of neurobiology and molecular neuroscience in which Regeneron has been particularly expert in the past several years. And then over time, they’ve matured or evolved more towards an interest in gene therapy and Regeneron, broadly speaking, has a very significant commitment to genomic medicines, really to complement their obviously huge expertise in antibodies and protein based therapies. They’re really building out a commitment to genomic medicines, and they have very significant investments in oligonucleotide based therapies, new investments in genome editing and also in AAV-based gene therapy. And so, for them, Decibel represents an investment into a new frontier for gene therapy, namely the inner ear. And so they’ve been very engaged with us in the science of how we deliver new gene therapies to the inner ear. So, it falls under their strategic commitment to genomic medicines as a major driver of their growth in years to come. But fundamentally, I would say it’s very much driven by their scientific appreciation of what we do at Decibel, the caliber of opportunities and the opportunity to really deploy gene therapy into effectively a new area of medicine, namely therapies for hearing loss.

Daniel Levine: How closely are the two companies working, and how big a boost has this been to your efforts?

Laurence Reid: Well, so we work really quite closely together. In addition to the usual governance committees meeting on a quarterly basis, we have very collaborative program teams around the individual projects we focus on today. All of the efforts of the collaboration go into three principal programs, all of which are seeking to address and develop gene therapies for the treatment of genetic-based hearing of three different forms of genetic-based hearing loss. So, we have project teams that meet almost on a weekly basis updating on data and ideas. And so it’s a very interactive type of relationship. And we’ve really benefited, I would say, particularly, they’re a very mature R&D organization with huge sophistication and development of sophisticated complex biologics and other forms of medicines. And we get the benefit of their advice and experience as we develop our programs, as we write regulatory documents and think about really the scientific and medical impact of our products. So, it’s a very interactive type of relationship that, I think as a small company during its formative years, having a big brother, big sister, if you will, to provide advice and support along the way and obviously also make a financial contribution to the costs of developing these products. Yeah, it’s a very strategic and important part of our existence. They also own about 9 percent of the company, so it’s a very strategic relationship and it’s been a very important part of Decibel and our growth in the early years of our company. Now, to just round out the picture, you did also note that it has this unusual aspect that in the long term Decibel retains control of the products in terms of ultimately their development and commercialization, which is also a really important component for us to continue to mature and grow as an independent biotech company. That’s really important to us in terms of generating value for Decibel and its shareholders over the longer term.

Daniel Levine: Decibel is developing AAV gene therapies. What’s the case for using this type of vector for the ear?

Laurence Reid: Yeah, that’s a really important question that we are quite excited to talk about today, recognizing we’re on the verge now of going into human beings. A lot of our evidence is based on our animal studies and also just the fundamental characteristics of AAV and the characteristics of the inner ear. So, human data to follow and as we move forward in the next the next few years, we’ll really be looking to de-risk this approach based on subsequent efficacy and of course safety studies in terms of delivering gene therapy to the inner ear. But the opportunity we believe is very important and really quite exciting, and we really think that gene therapy for hearing loss is on the verge of being one of the vanguards of the gene therapy field more broadly defined in years to come. So, the inner area is effectively a tiny, essentially enclosed space. And the inner area is encased in bone really quite dense bone that protects those structures. And that means we have to think very carefully about how we access that space. But the advantages of those characteristics are firstly that most of the drug that we administer stays in the ear. So we’re able to deliver it very directly to the cells that we are looking to infect. And the vast majority of the drug doesn’t get out of the ear. So, we have no systemic exposure in the circulation, which has been a big challenge to the development of gene therapies for other tissues—that the drugs have to be administered in very significant quantities and circulate systemically. We are developing therapies that are delivered directly to the tissue in need and that because of the space we’re going into and the cell population and the tiny nature of those structures, we have a very small drug dose, some numbers of perhaps three to four logs less of dose than is used for systemic gene therapy. And that we’re able to, as I said, directly deliver it and achieve very high rates of infectivity of all the key cells that are of therapeutic relevance in the ear. We’re able to infect very effectively with our AAV-based gene therapy. And we access the ear by a surgical procedure that allows injection of the gene therapy, essentially directly into the cochlea. And that’s a surgical procedure that’s used today on a daily basis throughout the developed world as part of the surgical routine by which a child or a patient receives a cochlear implant. So, we’re leveraging that set of surgical knowledge, which we think is really important in terms of just trying to remove the number of variables that are involved in such a novel therapy for a new field of medicine.

Daniel Levine: The company’s lead therapeutic candidate is in development for OTOF-related hearing loss. What is OTOF-related hearing loss?

Laurence Reid:

Yeah, as you say, it’s our le our lead program. So OTOF is an abbreviation of otoferlin. And OTOF-related hearing loss is a profound form of hearing loss. It’s an auditory neuropathy where signaling from the inner ear to the brain is essentially completely blocked. And so, these children are born with a profound hearing loss that’s caused by receiving two mutant forms of otoferlin, one from each of the child’s parents. It’s a simple monogenic form of hearing loss and it causes a complete block on signaling from the hair cells of the inner ear to the auditory nerve that takes the signal, the heard sound into the brain in terms of detection and interpretation of the sound from the outside world.

Daniel Levine: How is it diagnosed and what age are people generally diagnosed with the condition?

Laurence Reid: Yeah, that’s a great question and represents an evolving part of the opportunity here. In the western world, children receive a basic hearing test, and there are different kinds of hearing tests, but a simple hearing test usually at the hospital where a child is born and within hours to a very small number of days of being born. So, that’s a basic hearing test that we’re able to assess, in a very simple way, what’s the capability of a child. Human beings are born with the capacity to hear in the vast majority of cases. And so, a basic lack of hearing capability can be picked up very early, literally within hours of a child being born. The next step is a little bit more complicated in that you have to reflex from that basic hearing test ultimately to get to a genetic test. And for us, that’s essential. We need to know that the children that we’re interested in treating or are able to treat today are carrying mutations in the otoferlin gene that underlie that form of hearing loss. And that’s achieved by genetic testing. And there are panels for most of the common forms of genetic forms of hearing loss. They’re available in almost any genetic testing situation today. But the frequency or the fluidity with which children are moved from getting a signal that they may have an issue on day two of their lives to getting that genetic analysis, that can be a little different, very heterogeneous, even within the U.S. depending on the city or medical system in which one happens to be living. So, that’s something that we’re working on—an education route to try and encourage a smoother transition of all children who fail a hearing test early in life onto a genetic test. Sometimes it can take a few months to get a child to a definitive genetic diagnosis and really understanding what the basis of their hearing loss is. In years to come, subject to our ongoing programs and subject to our clinical trials, et cetera, when we hope to be able to offer therapies to these children, that genetic diagnosis will be an essential part of that process. So, we’re really trying to educate on the importance of that transition from the basic diagnosis to the genetic diagnosis today. And the genetic diagnosis, even in the absence of therapies, can still be quite informative in helping parents understand the likely trajectory and prognosis of their child’s hearing loss. And there are some of the genetic forms of hearing loss that they know that are profound and are not going to change. Others are more moderate, but there may be a degenerative effect over time. So, there’s a variability of prognosis so this value comes out of the genetic test today. And then, of course, in the future, it really is the root by which we will get to the patients who are really the candidates for our gene therapies.

Daniel Levine: One of the question marks around gene therapy is the durability of these treatments, the cells you’re targeting are non-dividing cells, and I’m wondering what that might suggest about the durability of your treatment.

Laurence Reid: Yeah, that’s a really great question. So, let’s just back up a moment. The key sensory cells in your inner ear are on our hair cells. they have nothing to do with the hair cells on the top of your head. They have sensory structures that detect movement of fluids through your ear in response to an external noise stimulus. That signal is then transmitted from those cells directly to the auditory nerve. And otoferlin the gene, the otoferlin gene codes—actually functions right at that interface of the hair with the auditory nerve. And then you are correct, we are born with a finite number of hair cells, which is unfortunate because they degenerate over the course of our lives, and we all ultimately hit some kind of threshold at which our hearing capability in terms of hair cells in the cochlea or our balance in terms of hair cells in the vestibule. We hit a threshold at which we lose the acuity of our hearing or our balance response, respectively. So, those cells, it is a finite population. They essentially don’t divide after birth. That’s an issue in terms of health of the ear, particularly for those of us as we start to age a little bit. But it does mean that we believe, and this needs to be confirmed, obviously, in human beings, but our animal studies are consistent with your suggestion, namely, that because these cells are nondividing, we have the possibility to be able to achieve a stable infection of our AAV into those cells to set up a stable genetic system within that cell expressing, for example, otoferlin in otoferlin-mutant children, and that system would then be stable and not washed out by those cells dividing in years to come. So that creates a reason to be optimistic about durability. We’ve certainly seen durable effects in animal studies over many months. And so that sets us up to do much longer-term studies in human beings. So, that’s the reason to be optimistic about durability. And of course, all to be proven in human studies in the months and years to come.

Daniel Levine: In many genetic rare diseases, there is progressive damage that requires early intervention with the gene therapy to get its full benefits. Is this true in the case of hearing loss? Would early intervention with the gene therapy work better to restore hearing?

Laurence Reid: Yeah, that’s a great question and we’ll be analyzing it, obviously, in our clinical trials in years to come. If you go back to where we started a few minutes ago, there’s also a strong impetus for the reasons I hopefully I explained that we want to intervene early in these children’s lives just to make sure that they are starting to have the types of cognitive development and social and emotional interactions that we talked about. But yes, as a general statement where a tissue is or a cell is unable to function due to a genetic defect, the functionality of that cell can be lost over time. We believe that for otoferlin, just to stay there for a moment, that one of the reasons that otoferlin was picked as our first target is that the hearing structures appear to be intact in a child born lacking otoferlin mutations. Same is true of the animal models of the condition that we’ve developed. And so, we believe there’s a window, a postnatal window, in which we’re going to be able to intervene and, again to be proven, that we expect that we’ll be able to be successful intervening in a window postnatally. Now it remains to be demonstrated how long is that window measured in years after a child is born and to define a time after which we may not be able to intervene and restore hearing. We know that in an animal, a small animal, we can intervene as late as a year after the birth of that animal and still achieve a very significant degree of hearing restoration. And a year, that’s a long time in the life of a rodent, and it’s perhaps 50 percent of its life. So that gives us, again, reason to believe that in years to come, we’re going to be able to intervene for some extended period of time successfully after the birth of a child, but eventually, we will be testing that in our clinical trials in terms of what that age distribution looks like. So, there are good physiological and neurodevelopmental reasons to get to a child early in their life and administer a therapy like this. And then there’s also the concern or the risk that that therapeutic window, if you will, will be closing in months and years to come. So, we’ve tried to pick targets, excuse me, based on a clear ability to intervene, based on animal models, and based on our understanding of the trajectory of hearing in these children. But those windows need to be validated ultimately in human studies in years to come.

Daniel Levine: And with regard to your lead experimental therapy, what’s the development path forward?

Laurence Reid: Well, we announced at the end of last year that we cleared an IND in the U.S. to start our phase 1/2 clinical study of our candidate product, which we call DB-OTO. And then in January we received clearance from the MHRA in the U.K. to start studies there as well. And so, we’re now in the process of working with particular clinical sites across the U.S. and a number of sites in the U.K. to start a clinical trial. And what we said publicly, those sites will be up and running and the trial will be initiated during the first half of this year. We also have a regulatory application under review in Spain and which has been a key country in terms of studies in that country, and experts in the genetic basis of hearing loss. So, we’re excited to work with investigators in Spain as well. And we hope that our CTA there will be cleared in the not too distant future. So, moving ahead with a phase 1/2 study in pediatric patients who are diagnosed with an auditory neuropathy that’s due to otoferlin mutations and looking forward to dosing those patients during this year. And we’ve also talked a little bit about expecting to be able to share initial data from some of the first patients in the trial very early next year, 2024.

Daniel Levine: It’s been a tough time for public biotech companies. Decibel raised $127 million in an IPO in 2021 at $18 a share. It’s now trading around $3.50 to $4. What’s the conversation like with investors these days?

Laurence Reid: Yeah, that’s a great question. As a public company we go out and we tell people the story and why we think Decibel is trying to do important things. And when you go public, you lay out that strategy and goals. And I believe Decibel has made very significant advances in the two years or so since we went public. The biotech stock market generally has been completely beaten up during those two years. And the gene therapy sector also, until recently as a sub-sector within biotech, has been disproportionately beaten up. There were a lot of concerns, I think, about some of the safety concerns around systemic gene therapy, recognizing that we think gene therapy in the year has a different proposition in years to come for reasons that I tried to explain. And so I think generally there’s a degree of appreciation that we’re in a challenging stock market, and Decibel is an early stage company with all the risks that go along with that. And we look like quite a number of other companies out there. So, that’s sort of the overall backdrop. As people look forward now, both in Decibel specifically [and] in the market more generally, I think there’s a mood of quiet optimism or cautious optimism that the biotech stock market will be improving perhaps later this year. It seems to be sort of the mood, obviously, who knows what will actually happen. And I think that in terms of investors who look at Decibel today, there’s an appreciation that therapies for hearing loss still represents very significant opportunities and people are looking forward to the early clinical data that’s going to be coming from us and hopefully other companies in the gene therapy field over the next few years and that clinical data will be important in terms of really helping the field mature as a human therapeutic field. So, it’s been tough times. I think people have a general understanding of that. And then they’re very much looking forward to companies like Decibel to, okay, you raise money, you need to execute, you need to hit some of these goals that you’ve laid out in front of us. And I would say that overall we feel people remain open and positive on the opportunity, and it’s up to us now to deliver product candidates that can begin to validate some of that trust and hopefully open up the opportunity for these therapies, and take them into the clinic and really gain the type of clinical data in the future that, subject to all the obvious bumps in the road and risks of those kinds of processes, can get us to a situation where we can really begin to demonstrate in human beings the potential for these approaches.

Daniel Levine: How far will existing cash take you and what’s the plan for raising additional capital?

Laurence Reid: Yeah, so as a young biotechnology company, of course, one is always thinking about accessing capital and that sort of ongoing part of our strategy. What we say publicly is that we have runway into the first half of 2024. And we will be using that money to ensure that we get to those very key initial data readouts from our otoferlin trial. And we’ve stated that we’ll release some of that data very early next year. So that’s within our current financial footprint and [we’re] very committed to making sure we get there, and as we move down that path, as I said, constantly looking for the right avenues and timings to access additional money to help continue to build the company. And we’re very excited about the pipeline. Our colleagues at Regeneron are very excited about our pipeline. So, we think there’s a lot of potential here and need to navigate through these financial times and make sure that we focus on the key aspects of our company that are really going to help us continue to advance as what we think we can be a leader in this field in opening up new therapeutic opportunities for people, children in the short term, but hopefully also people of more maturing years, you know, in the future of our company,

Daniel Levine: Laurence Reed, CEO of Decibel Therapeutics. Laurence, thanks so much for your time today.

Laurence Reid: Thank you. Really appreciate the opportunity to be here.

This transcript has been edited for clarity and readability.

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