Name: Close to the Edge Episode 6: Laurence Reid

Description: Close to the Edge Episode 6: Laurence Reid

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Upload Date: 2023-10-19T00:00:00.0000000

Transcript: Language: EN.
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[MUSIC PLAYING]
KEVIN DAVIES: Welcome, everyone, to Close to the Edge, the new show from GEN Edge, the premium subscription channel from genetic engineering and biotechnology news in which we interview the CEOs of some truly pioneering biotech and pharma companies. I'm Kevin Davies, editor at large with GEN and the author of Editing Humanity-- The CRISPR Revolution and the New Era of Genome Editing. My regular co-host Alex Philippidis is taking some well-earned vacation this week.
KEVIN DAVIES: But the show must go on, as they say. So here we are. Our guest today on episode six of Close to the Edge is Laurence Reid, the CEO of Decibel Therapeutics. Hello, Laurence. Great to see you again, and thanks for coming on the show.
LAURENCE REID: Yeah, hey. Good morning, Kevin. Great to see you again. Thanks very much. I'm excited to be here. I'm thrilled to follow you. You've had a highly illustrious group of people to kick you off. So I feel privileged to follow that.
KEVIN DAVIES: Very good. Yeah, we've had some great guests so far. And you'll be no exception. We've only rescheduled this recording once. But that's life in the fast lane for you, I guess, and one reason we're not doing this live but prerecording it. So, Laurence, welcome to the program. We might edit this first question out. But my first burning question is have you recovered from England's excruciating loss in the Euro 2020 final?
LAURENCE REID: It was a sad end to, I thought, generally a pretty good set of performances. The lack of courage in the final, I thought. Could have gone at it more wholeheartedly and with a little bit more adventure, and it might have been a different outcome.
KEVIN DAVIES: Yeah, I keep seeing soccer on your resumes and LinkedIn profiles and whatever. Are you a coach or a player or both?
LAURENCE REID: I am. No, it's still an important part of my life. I coach a teenage girls' soccer team and get a lot of pleasure out of that, actually. It's a very distracting and relaxing hobby. It keeps me close to the beautiful game, as we all say.
KEVIN DAVIES: Yeah, yeah.
LAURENCE REID: No, it's still an important part of my life, actually.
KEVIN DAVIES: Are you playing a back four or a back three?
LAURENCE REID: I always play a back four.
KEVIN DAVIES: We could go on. But we should probably get to the main substance of the program. So 18 months into your role as chief executive officer of a now public company, Decibel.
LAURENCE REID: Yup.
KEVIN DAVIES: So let's get the abstract of the paper out first. How are things going at Decibel overall?
LAURENCE REID: Oh, generally, I think things at Decibel are going incredibly well. I've just had the privilege of working with this team now for about 18 months. New field for me, as we'll talk about it. But really excited to learn about the wonders of the mechanics of the inner ear and what we really see as a whole new field of therapy for the inner ear and for pathologies that arise from the inner ear.
LAURENCE REID: So a very exciting long-term proposition, a great team. And we really repositioned the company at the beginning of last year, a path that eventually took us to a new financing route and to becoming a public company in February. So it's been a great trajectory. Put the company [INAUDIBLE] on a very positive path forward to turn a lot of our science into really a new generation of therapies completely changing, I think, how we all think about the health of people with conditions resulting from pathology in the inn ear.
LAURENCE REID: And we've been a public company now for, I guess, going on six months, a little bit over six months. The public market has not been completely kind to us. Perhaps we'll talk about that. But we are resilient in the face of that and confident that that will turn around as particularly some of our clinical data comes into view over the next one to two years.
KEVIN DAVIES: Great. Well, I look forward to digging into many of those topics maybe a little bit later in the program. But I thought it'd be interesting, because I know a little bit about your beginnings in the industry, and I thought it'd be interesting to give you the opportunity to share what you maybe took away from some of your various stopping off points as you worked at some big companies, including Millennium in the '90s, Alnylam, Warp Drive, and so on.
KEVIN DAVIES: Our careers, there are a couple of commonality points. We both did our PhDs in London, both moved to do postdocs in the US, and both-- at least, I think I'm speaking, perhaps, for you as well-- realized at some point that becoming a rock star molecular biologist at the bench probably wasn't in the cards. And we both took the opportunity to move to editorial positions at science journals.
KEVIN DAVIES: I went to [? NH, ?] and you went to Cell to work with the great Ben Lewin. So take us back to that decision. And what did you learn from working for I think it was three plus years at one of the great molecular biology journals.
LAURENCE REID: Yes, you remember those days very well. I remember some of our discussions at the time about different career paths. The fundamental thing for me was I still love basic molecular science. Even today, I get an incredible thrill out of seeing really great, new molecular biology with a promise to change people's lives. Back then, I was transitioning from being an academic scientist and, I think, really coming to, as a young man in my early to mid-20s, the realization that while I still fundamentally loved science and was excited by the potential of the work we did in the lab-- I worked at MIT and the broader community-- that being a lab research directly was not going to be the most rewarding career for me.
LAURENCE REID: I contrast myself to my wife who gets a lot of pleasure out of now tending our garden but previously working in the lab with her hands. I hated that. It was a means to an end. I don't have green fingers. The lab work, my results were always the ugliest. And it wasn't inherently rewarding. But I loved the science.
LAURENCE REID: So it created something of a paradox for me at that stage of my career. I think moving to America, moving to MIT, probably caused me to reflect more on that. And so after I'd been a postdoc for about a year and a half or so, slightly opportunistic-- there's a big lesson here a little bit in following one's nose-- an opportunity arose at Cell, which was based two miles up the road in Harvard Square.
LAURENCE REID: And I think one of the things that-- I've always had a very eclectic set of interests, which is still true today. There's lots of different therapies, different biotechnologies that get me very excited today. And we'll touch on various ones that I've been thrilled to be involved and to be excited about at different points in my career. Then, it was just a more Catholic view of what was interesting to me in different forms of science.
LAURENCE REID: And so I threw my hat in at Cell and met Benjamin, which was an experience in itself, quite a character in our time and a very visionary man in himself. We'll talk about vision for companies, I'm sure.
KEVIN DAVIES: Yeah.
LAURENCE REID: And got the job and made a career change that some of my friends were like, yeah. We understand why Laurence wants to do that. That makes sense. Other people were like, seriously? What are you doing? And, I think, took me off their Christmas card list. But it turned out to be the beginning of a transition into being involved in the deployment of science without actually being the person at the lab bench or driving the laboratory science, which was [INAUDIBLE].
KEVIN DAVIES: And seeing a much broader picture of what's going on in sciences.
LAURENCE REID: That's exactly right. And so you drop into an environment like Cell, and suddenly, this was in an era when transcription factors were all the rage, when Drosophila genetics and how a multicellular organism matures and develops were really fields that were exploding open. Cellular immunology was beginning to advance. So across the course of a day of working there, one was having the chance to think about multiple different forms.
LAURENCE REID: All very molecular, but molecular forms of biology a la early 1990s. And also, really, the privilege of interacting with lots of authors. Some were angry from time to time. But a lot of them were interested in a genuine intellectual discussion about how you publish papers and bring information to people in a clear way and dealing with reviewers and the debate of what's cutting edge.
LAURENCE REID: It was a fascinating time. It didn't turn into a long-term pursuit for me. But it was three incredibly informative and fun years.
KEVIN DAVIES: Yeah. Yeah, and your first point of departure was to join Millennium Pharmaceuticals. So speaking of fields that were taking off, this was the beginning of the genomics revolution. Millennium was one of at least half a dozen--
LAURENCE REID: That's right.
KEVIN DAVIES: --probably many, many more very cool, very well-funded, very ambitious companies. And you did a number of positions in your decade at Millennium. So I wonder if you could briefly talk about that period. And was there a point where you thought, you know what? I'm enjoying my role in industry so much I want to go all the way to the top, or did that just happen serendipitously?
LAURENCE REID: Yeah, so let's separate that. I mean, it was a fantastic 10 years. Millennium rode an escalator up with the genomics revolution and then worked through some real transitions and challenges, particularly in the early to mid-2000s. I was there for a little bit over 10 years, complete opening of my mind to industry. My undergraduate degree was in genetics, and so the notion of genomics and understanding the molecular etiology of diseases at such a fundamental level, that was incredibly intellectually inspiring to me and remains so today.
LAURENCE REID: We're going to talk about genetic bases of hearing loss in a little while. Having said which, some of those ideas were, if not ahead of their time, they were certainly at the cutting edge of where the technology and infrastructure was. And we worked through some of those challenges. So to me, it was a transition. I became one of Millennium's interfaces with the outside world, particularly in shaping our collaborations with academic institutions who had access to families with certain types of polygenic human diseases-- type 2 diabetes was the first area we tried to work in-- and really bootstrap my way from there into a career fundamentally in business development for many years based on understanding what our interactions with the outside world needed to be and getting into some basic training of, how do you structure a relationship with a third party that ideally is mutually beneficial, whether you're talking about money or intellectual property or funding for research?
LAURENCE REID: That was how I started and imparted a lot of my background into that type of role and moved from there into a broader business development function. And yeah, certainly no sort of understanding or aspirations then about, gosh, could, one day, I be the CEO of one of these companies? I think those probably developed a little bit later on along the path. But it was an amazing ten years.
LAURENCE REID: Some incredible people, remarkable vision, outstanding business people, some really fantastic science. One can debate technology perhaps ahead of its time. Obviously, a lot of that genomics technology didn't materialize into real drug opportunities during those early years of the genomics revolutions, whether at Millennium or at the other genomics companies. They certainly laid a platform. So many ideas that were floating around at that time have become reality as we've sequenced the genome and built our real understanding of genetic variation and the technologies to analyze that.
LAURENCE REID: But it was an incredible revolution in its early years. And then, how did you transition that and build a real company on the back? Which can be a separate discussion sometimes.
KEVIN DAVIES: Yeah, yeah, yeah. So after a decade there, you did, in fact, get a brief taste of chief executive with an outfit called Laser Pharmaceuticals.
LAURENCE REID: Yeah.
KEVIN DAVIES: I confess, I must have missed-- I don't know what I was doing at that point, that year.
LAURENCE REID: You did. You did.
KEVIN DAVIES: So tell us about that.
LAURENCE REID: Yeah, so that was an adventure. After 10 and a half years at Millennium, I wrapped up with a period back in the UK. But Millennium was going through all kinds of transitions at the end of 2003. The company significantly reduced in size between 2003 and probably about 2005. Came back from the UK. There wasn't really a role to come back to, which is a not unusual story.
LAURENCE REID: And it was time for me to do something different.
KEVIN DAVIES: Yeah.
LAURENCE REID: I got involved with a venture group on the West Coast. I think, looking back on it, I probably wasn't ready to be a CEO at that point. And logistically, it wasn't ideal. The idea was to go out and find new technologies and working with some very high caliber investors on the West Coast. A number of challenges about logistics. Also, interesting in terms of people around the table who had very different ideas of an alignment to what we were trying to do, and all people working completely in good faith, honest people, just are you aligned in what your vision is or what you're trying to achieve?
LAURENCE REID: It was a pretty big lesson, actually, from that perspective, of how as you get into collaboration, business partnership with people, what are you really trying to do? And are your interests aligned? They don't have to be the same as yours. But they have to be complementary and aligned. And actually, the group we had involved in Laser, we had different ideas.
LAURENCE REID: And it created some tension. But there were people involved who I'm still in touch with, actually. Jim Tananbaum, who was a Prospect at the time now runs an organization called Foresite. And they're an investor in Decibel.
KEVIN DAVIES: Oh, right.
LAURENCE REID: So a small world. And these relationships, they never go away. They linger. Even I hadn't really been in touch with Jim for many years. But excited to have him and his colleagues as investors in Decibel.
KEVIN DAVIES: You then went on to a business development role at Ensemble, which, if I recall correctly, is a David Lew production, right? One of his early companies. Of course, best known now for his brilliant work on precision genome editing.
LAURENCE REID: Yeah.
KEVIN DAVIES: Yeah, so what happened to Ensemble?
LAURENCE REID: Well, so that's very interesting. So I think a couple of things. It was David's. I met David in 2006. It was the first company he'd been involved in. And this was the field of really using DNA to template DNA encoded libraries, DNA templated libraries. We called David's version of technology DNA program chemistry.
LAURENCE REID: And it was the early years of that technology. A number of people had realized the potential power of chemistry and water, which is not how organic chemists often behave. And using DNA to control reactions and to tag compounds just in terms of a way of handling large combinatorial sets of compounds, David, had this, being David, of course, incredibly elegant technology.
LAURENCE REID: I think the technology that Ensemble developed probably had more control over the quality of the chemistry and understanding the fidelity and purity of what was produced. But I think it's fair to say that, ultimately, that was a numbers game. And there were other technologies that claim that they were producing probably a few logs more compounds-- and we're talking about billions of compounds versus millions of compounds-- than we were able to produce at Ensemble.
LAURENCE REID: And certainly, the early generations of that technology beginning to succeed really went to the guys who drove the numbers, even though, I think, it's pretty objective to say, maybe there were a billion compounds in the pot. Maybe there were two. Maybe there were half. Did they really know? Was it really as pure as some of the work we were doing?
LAURENCE REID: Probably not. But the numbers prevail. And the technology was developed. There were groups. [? Prices ?] became part of GSK. Those guys still practice that technology today. It's become somewhat commoditized. But it's still an active part of the whole armamentarium of how people use small molecule technologies against challenging targets.
LAURENCE REID: And I think that Ensemble was a technology bet. And it was very much a platform bet as well. I think that with these companies, depending on the financing environment, depending on the technology, depending on the timing, was a balance between investing in platform versus trying to drive forward to products. Ensemble was built with a platform mentality, lived through 2008 and the financing crisis and the financing crisis that created to give us small, public biotech companies.
LAURENCE REID: And so it had a lot of challenges. And ultimately, there were some molecules came out of that that didn't make it. And I think the company went away about five years later, maybe about 2015. So technology, a good technology in a competitive world, perhaps not the best technology.
KEVIN DAVIES: Yeah, so perhaps Ensemble, a name unfamiliar to some viewers. But your next post was at a really high profile and hard charging company Alnylam.
LAURENCE REID: Yup.
KEVIN DAVIES: So what did you do there? And tell us about that.
LAURENCE REID: So at the time, I was thinking about where to go next with my career. I'd known the people at Alnylam, the founding [? people ?] at Alnylam, there was a lot of X Millennium roots there, and more lessons in small world, et cetera. And John Maraganore-- he was the CEO-- approached me and offered me the chance to be chief business officer at Alnylam in, this was, 2010, which is only relevant because it's sort of interesting to think about where RNAi was-- The bloom had begun to come off that rose.
LAURENCE REID: And the company was public. And I think they were in the real trenches of how do we keep driving this technology forward, solve the delivery problems, really enable the power of RNAi? And I was fortunate enough to be there during some of the downside of those challenges and then, as the pendulum began to swing back that way, 2012, 2013, 2014, which was incredibly exciting.
LAURENCE REID: It's a remarkable company. I'm still a fan, still a shareholder. It's an incredible company.
KEVIN DAVIES: Yeah. Yeah, and then your next gig as a chief executive officer at Warp Drive Bio, which will soon bring us up to the present day.
LAURENCE REID: Yes, and so that was the transition that you touched on of getting to a stage in my career. I'd been a business development executive for a long time at that time. Had a great run at Alnylam and put together some really exciting deals reflecting the power of the evolution of RNAi, that sort of second generation of thinking or second going on third generation of thinking.
KEVIN DAVIES: Yeah.
LAURENCE REID: And I felt that with the right opportunity and where I was in my career and my life that trying to set out and take a shot at being CEO felt like the right thing. And hoping that I could bring some experiences, some of the great hair, to bear in that role. And did that very much with the support of Alnylam, an amicable parting of the ways. And jumped into a Third Rock company called Warp Drive, which was a very visionary chemistry company.
LAURENCE REID: I mean, the theme through all of these companies, I would say, for me, has been is there a piece, a new piece, of innovative science-- which, to me, it can be a piece of technology. It can be a new piece of biology-- that really has the potential to develop a new medicine that can really change patients' lives? Warp Drive was a chemistry platform that Greg Verdine had really inspired.
LAURENCE REID: Greg's an incredibly entrepreneurial, incredibly creative chemist who's had his efforts into a number of companies with great success.
KEVIN DAVIES: Yeah.
LAURENCE REID: And this was really his idea to bring really new technologies to bear on the power of natural products. How do we really exploit natural products using different ways of thinking about manipulating their chemistry? And they've obviously been an elusive part of the pharmaceutical leaders. They've been very powerful. But they've been finite in their use.
LAURENCE REID: And how could we expand that? Was really Greg's fundamental vision. And so we went at that at Warp Drive in a couple of very different ways that took us into new oncolytics and into new antibiotics.
KEVIN DAVIES: And what was the final chapter of the Warp Drive story? Maybe it didn't end quite the way that you might have hoped or your business team might have hoped.
LAURENCE REID: Well, so Warp Drive got merged in the summer of 2018, fall of 2018, into a company called Revolution Medicines, which was also a company with some overlapping sets of investors, also a company inspired by natural products in some of the chemistry and thinking that they were doing. And the Warp Drive platform, we were mainly working at that time on a very exciting new way to open up inhibition of K-ras, of course the king of all oncogenes.
LAURENCE REID: And they were working elsewhere in that pathway. They had a more mature company than Warp Drive. They had built a more expansive team. They had a program that was about to go in the clinic. So they built a development organization. We were looking to finance Warp Drive at the time, mainly driven around a K-ras platform, which was beginning to really get a lot of attention based on work at companies like Amgen and Moratti.
LAURENCE REID: And to cut a prolonged discussion to the bottom line, we decided-- and this was a good decision. I think it's really played out in what's happened with Rev Med subsequently-- that putting two smallish private companies together, which is very hard to do, often from a social perspective, really was an opportunity to make a much better company with a more diverse set of technologies, a more mature team.
LAURENCE REID: And that really powered Rev Med, the combination, I would say it's fair to say, of things that they were already working on, their SHIP2 inhibitor and then our Ras work, I think, combined very powerfully to really enable them to go public last year. And they've also been experiencing some of the joys of the public markets. But I think to rebuild a very powerful company with multiple points of intervention in the Ras pathway and the Warp Drive, the [INAUDIBLE] technology continues apace within Rev Med.
LAURENCE REID: And looking forward to seeing that in the clinic in months to come. So the right business decision. Maybe not the most exciting from an organizational perspective. I don't want to suggest otherwise. But in terms of putting technologies and opportunities together and one and one making more than two, I think it is a really good opportunity. And it's very hard to do in private companies.
LAURENCE REID: Often, egos or non-overlapping investor sets can get in the way of what might be better decisions. I suspect there are a lot of other opportunities out there that just never really get properly explored of-- put a couple of technologies together or a couple of people together. And you could make a much more powerful whole. But it doesn't get done for sometimes what are maybe not the right reasons.
KEVIN DAVIES: OK. Well, let's get to the Decibel. You took to helm of the company in early 2020, taking over from someone you knew pretty well, I would imagine, Steve Holtzman. So how did that opportunity come about?
LAURENCE REID: Yeah, so Steve decided to retire at the end of 2019. He'd been the, not quite the [INAUDIBLE].. He'd been the first CEO of the company, built it. And Steve's a real builder in addition to--
KEVIN DAVIES: Who you knew at Millennium.
LAURENCE REID: --a brilliant businessman. Yeah, no. Steven and I worked quite closely together at Millennium 20 plus years ago. And so when he was retiring, I was about to re-engage with Third Rock. I was to go back to being an entrepreneur in residence there again. And a little bit like the previous time I did that, they're like, we really see Decibel as an opportunity here.
LAURENCE REID: And so I dropped into some strategic discussions that were going on at Decibel at the end of 2019, really trying to decide of the multiple paths that they'd opened up which might be the most exciting and really have a strategic focusing of the company. And I jumped in as acting CEO at the beginning of 2020 pretty quickly but became convinced that there remained huge opportunity, huge value, a great team that Steve had built, which we've augmented.
LAURENCE REID: But the founding and the basic team that had been created there. Most key people have been with the company several years now. And learned a lot more about the ear, about the challenges of significant hearing loss and significant balance disorders. Whole new field for me, which has been pretty exciting, I have to say, at this stage of my career. But also that there really are huge opportunities here to use pharmaceuticals to change people's lives on a scale.
LAURENCE REID: It's almost like a backwater of the industry or the pharmaceutical industry. It's a field that is largely dominated today by devices. And a really significant opportunity to do something really in a very new way in a field that is-- often describe it as an open playing field. And the only people on the field right now are small, innovative companies. So very exciting.
LAURENCE REID: And so I jumped in pretty wholeheartedly and took over permanently later in the year.
KEVIN DAVIES: Yeah. Have you changed course at all from the direction that Steve had established? Any--
LAURENCE REID: I think fundamentally, no. But we're more focused than the company had been historically. Decibel started with a belief that the time for biology-driven innovation in addressing hearing loss was right. This was in sort of 2015. And explored a number of different biological pathways and had worked on opportunities that might have turned into drug candidates that were small molecules.
LAURENCE REID: And we still have a small molecule in clinical development that, hopefully, we'll get a chance to talk about. We've done some biologics work, including with our colleagues at Regeneron with whom we have quite a close collaboration. But what I think was really becoming clear was that the genomics platform that Decibel had built, really for exploration of the molecular composition of all the cells in the inner ear, linking that to gene therapy, was really a route that was the right time and that we had the ability to leverage our technology to produce what we'll call precision gene therapy.
LAURENCE REID: Let's talk about that. But also, an understanding that the gene therapy in the inner ear, we believe passionately, is a really exciting match of a technology and an organ. And that creates multiple pharmaceutical opportunities. And it was a little bit of a feeling of OK, we've explored a number of different ways to change the lives of people with hearing loss or balance disorders.
LAURENCE REID: This is the best way a la 2021. Years to come, I'm sure we'll go back to more small molecules, et cetera. But right now, we think that gene therapy and the inner ear is a really beautiful match of a technology and an organ, creating some really fantastic pharmaceutical opportunities.
KEVIN DAVIES: So much of your effort is about tackling patients with hereditary forms of deafness. But you talked about balance disorders. And I'm fuzzy on to what extent they are familial or hereditary or whether so. Can you help--
LAURENCE REID: Yeah, sure.
KEVIN DAVIES: Many people watching are probably not experts in deafness. So I think a quick tutorial is in order.
LAURENCE REID: Yes, of course. You'll be gentle with me as a newbie to the field. But it's been an exciting learning opportunity. So first, I think, you come to these fields. And I was fortunate, at least so far, not to be afflicted with particular friends or relatives who suffered from these conditions. And so it's easy to underestimate A, how devastating they can be and B, how prevalent they are. The World Health Organization estimates that probably over 450 million people worldwide, maybe 48 million in the US are afflicted with some form of hearing loss.
LAURENCE REID: And those numbers are going up, mainly because some of our millennial friends have probably been injecting too much sound directly into their ears over the past 10 to 20 years. Huge global costs in terms of devices, care, and loss of economic productivity. Genetics is a big part of that. It's not the majority part of that. We estimate somewhere between one and a half to two per thousand births come with some form of congenital hearing loss and that approximately 80% of that or so is genetic.
LAURENCE REID: And so significant numbers. There are known to be perhaps around 100 genes or so that are understood to cause hearing loss. So a lot of variability in terms of the molecular etiology but a very significant problem. Balance disorders, there is not the explicit genetic linkage. Or if there is, it's not yet understood in terms of, we'll talk about, some of the targets in the hearing loss space.
LAURENCE REID: There isn't the monogenic simple genetic basis of hearing loss. Nonetheless, the numbers are also staggering. Maybe eight million people in this country who suffer from some form of balance disorder. And the common link here, a little bit of biology, are these cells in the inner ear. Our principal hearing organ is the cochlea. Our principal balance order organ is the vestibule. Function in collaboration with your eyes but is the principle.
LAURENCE REID: Both located in the inner ear. They have an evolutionary commonality. And the fundamental mechanism are what are called hair cells, which basically transduce a mechanical signal from the outside world, whether it's a sound wave or it's a movement of your head, transduce that signal ultimately into a neurological signal that you detect in your brain as the concept of hearing or balance.
LAURENCE REID: Those cells, turns out, are rather fragile. We all lose them almost linearly over the course of our lives, which is why at some age, variable, we all start to be afflicted with more or less acuity of hearing and sensitivity of balance. And then, moreover, those cells can be damaged by things like extreme sounds, certain types of pharmaceuticals, and genetics, in the case of the cochlear. But these hair cells line both the cochlea and the vestibule and fundamentally transduce these mechanical signals into our brain.
LAURENCE REID: So they're sort of the biological root of everything that we do to try and address different forms of hearing and balance.
KEVIN DAVIES: Yeah, if we just focus for a minute on the forms of Mendelian deafness that you're interested in, what's the total universe of Mendelian disorders that we know so far? And which ones have you chosen to focus on and why?
LAURENCE REID: So different people have different estimates of this. We think about there about 90 different monogenic, likely recessive forms of hearing loss. And so the two fundamental issues that one thinks about is A, the ear develops significantly in utero. Human beings are born being able to hear. Many animals, it's delayed a few days after their live birth. But fundamentally, it's an in utero process.
LAURENCE REID: And so one fundamental question is can we intervene postnatally? I mean, maybe one day we'll talk about prenatally. But that's obviously incredibly complex. Everything we do is postnatal. So is the ear in a functional state postnatal such that you can expect to intervene and have a positive benefit? So you're analyzing mutations based on that. And then we're also inevitably looking to maximize impact on numbers of people.
LAURENCE REID: Some of these genetic disorders are understood but are incredibly small populations. And so we've tended to combine our otoferlin program. We think there are about 20,000 people in the Western world who are deaf due to otoferlin mutations. It appears to be a situation where, when you study, both in animals and in humans, the ear that, an understanding the molecular function of otoferlin, we think there's a very good chance that postnatal administration of a wild type copy of the gene has a really good shot at rescuing the functionality of that and enabling the child-- this is going to go on in infants to babies-- enabling the child to get back on a normal trajectory of hearing linguistics and develop.
LAURENCE REID: Maybe just one point, if I may. One of the things that was most compelling to me as I jumped into this field was the understanding of the importance of hearing in the development of a child, that hearing leads to language, that it drives so much of our social interactions, whether with one's siblings or one's parents. And then, I think, obviously an increasingly and incredibly importantly into a school environment.
LAURENCE REID: And the challenges for a child of going through a normal schooling, or what other people would call a normal schooling, with a reduced or lack of hearing is just incredibly challenging and leads to both social isolation. And an inability to completely participate in the scholastic process and limitations, therefore, in the ability, literally, to learn. And of course, the cognitive development that goes with that social interaction and that learning.
LAURENCE REID: And so the vision of this really is, can we bring these children back to a trajectory that looks like a full physiological form of natural hearing that today we just can't achieve with devices and put them on the trajectory to achieve the connections in their lives and the potential for all the social and educational potential that, hopefully, they were otherwise born with is really the vision of what we're trying to achieve here.
KEVIN DAVIES: Yeah. You mentioned, Laurence, that many of your programs-- not all of them, but perhaps most of them-- are taking a gene therapy approach. Why is gene therapy so well tailored to treating this class of genetic disorders? And have you settled on a particular vector, viral or non-viral, to deliver the appropriate target?
LAURENCE REID: Yeah, great question. So why the ear? So of course, gene therapy of recent years, some of the most striking successes have been in the eye. The ear shares certain characteristics. So we're talking about a tiny, enclosed compartment. So we're able to work with very low doses. And we're delivering doses, sort of microliters and incredibly low doses relative to what's required for systemic chemotherapy.
LAURENCE REID: So that's one really important. Secondly, the compartment is essentially enclosed. So we deliver the drug to the inner ear. The vast majority of it stays in the inner ear and accesses the cells that we're aiming to access. Doesn't get to the systemic exposure. So we believe, therefore, in terms of systemic implications that might have negative or side effects, that we believe the risk there-- obviously, to be proven, of course-- but the risk there, I think there's a good chance to believe that it's probably significantly lower than more systemic forms of gene therapy.
LAURENCE REID: Secondly, the ear, like the eye, enjoys a degree of immunoprivilege. It's not like it's an immune-zero sort of zone. But there's clearly less immune activity. And we're targeting these hair cells. It's a very finite population. We can deliver very precisely to their environment. They're non-dividing cells, so you have a decent belief that if you can infect them, transfect them, that they will be stable.
LAURENCE REID: And one can therefore achieve a prolonged, durable biological response, which, of course, is the Holy Grail of gene therapy. So a lot of different advantages. The inner ear is a tiny compartment. It's largely encased in bone. We access it with a surgical incision that today is used routinely in children around the developed world for implanting a device known as a cochlear implant.
LAURENCE REID: And that takes us directly and exactly to the location. So the advantages, once we get to the site where we want to go, in terms of a precise delivery, really, I think the ear is an incredibly exciting location. And so you max that opportunity using an established surgical procedure, using hardware that surgeons are very comfortable with, deliver a gene therapy for some of these monogenic conditions that we've defined.
LAURENCE REID: Today, the field is largely driven by AAV. For reasons I don't think we completely understand, AAV is the most efficient way to deliver genes into the cells of the inner ear, more so than antiviral approaches, more so, so far, than nanoparticles or other synthetic routes of delivery. Some of the classic AAV capsids-- we use AAV1 in our lead program.
LAURENCE REID: Very broadly infective in the inner ear. So we think we can use the technology, a lot of the existing technology that others have developed before us, to get into the cells of the ear. And at Decibel, what we really try and impose on that, what we refer to as precision gene therapy, is really leveraging our genomics platform to understand how genes are controlled in situ in the selective cells of the ear that we're trying to target and to take those promoters, enhancers, molecular control units out of their natural situation, put them into a gene therapy.
LAURENCE REID: So we can really bring a precision of expression of the transgenes of, hopefully, the right corrected gene in the right cells of the inner ear. And we think that's where the field is. That's where modern gene therapy should be. And we have data that suggests that we see better ultimate power of delivery when we deliver the gene more selectively to the cells where nature intended it to function.
KEVIN DAVIES: Right. Do you envision this as being a once and done therapeutic approach?
LAURENCE REID: That is, of course, the million dollar question. And yes, we do. And I think the combination of the durability of the molecular control and the precise location of expression and the fact that the cells don't turn over gives us a very good belief that that should be a durable and achievable goal. Obviously, it will be proven. But durability, and as I say, a lot of the work we've done at Decibel linking the benefits of precision that then play out, apparently, in animals in terms of durability, we think is really important.
LAURENCE REID: And so yeah, that is absolutely the vision of the approach.
KEVIN DAVIES: Would it matter what age the patient was in terms of when you gave the therapy?
LAURENCE REID: Yeah, it's a great question. So we believe very much. You're a parent, right? You think about when your child learned to talk, the interactions you were having with them. Eight, nine, twelve months, you begin to have those interactions. So the cochlear implant, which is the sort of competitive device that we're really trying to improve upon, is given to a child today, ideally in their first year of life, maybe in their first one to two years of life.
LAURENCE REID: I think for hereditary reasons, we're going to start in infants who are a little bit older than that in terms of our trials. But given the importance of hearing in those formative years, at some level, the earlier we can intervene, the better ultimate prognosis we think we're going to have on the ability of a child to develop their hearing and to develop their linguistic and social and cognitive skills and abilities.
LAURENCE REID: So yeah, it's definitely something where we ultimately will be aiming to intervene probably during the first year of life.
KEVIN DAVIES: Great. Let's talk about the business, state of the business, for a minute or two. So you took Decibel public about six months ago--
LAURENCE REID: We did.
KEVIN DAVIES: --through an IPO that raised almost $125 million. And that--
LAURENCE REID: That's right.
KEVIN DAVIES: --came not just a few months after you'd had a successful Series D, oversubscribed I've read, raising another $80 million or so. So why go public so quickly after you had just sort of restocked the coffers, so to speak?
LAURENCE REID: Well, I think it was a fairly classic crossover type of situation where our colleagues at [? Albemed ?] really looked at the company, really fundamentally, I think, believed in the power of gene therapy for the ear. And I think when you're building a company, you're building a pipeline, one is trying to think about how do you finance the company to get to outcomes that really demonstrate that you're having a value, ideally an impact, ideally, in somebody's life, a child's hearing and their life.
LAURENCE REID: And so for us, it was trying to think about a financing strategy that took us from where we were last year out through the first clinical readout. And we had some sense of what that would cost. And it was clear that, given the enthusiasm for the new field, the interest of investors in new companies coming into this field, and the real, as I said, open water in terms of pharmaceutical development, that there was a lot of interest, that the notion of gene therapy-- and these technologies, they go a little bit in and out of favor, right?
LAURENCE REID: But nonetheless, that gene therapy has been something that's been incredibly interesting to the investment community broadly. The notion of the ear really is one of the new vanguards of gene therapy for the reasons that hopefully I convinced you of a few minutes ago--
KEVIN DAVIES: Yeah, yeah.
LAURENCE REID: Was very generally exciting. And so we were able to grab the opportunity to link from the so-called crossover financing that [? Albemed ?] led to our IPO a few months later and put the company in a position where we have money on hand now to take our first gene therapy for otoferlin mediated hearing loss into the clinic next year, get to clinical readouts over the subsequent months, and really, I think, demonstrate-- well, hopefully, therefore begin to demonstrate to the world the power of the approaches we're taking.
LAURENCE REID: So it was the overall financing strategy and ability to tie those two events together that really took us down that path.
KEVIN DAVIES: Yeah. How has your role changed now running a newly public company compared to the halcyon days of being private?
LAURENCE REID: Yeah. Yeah. Well, it's different. It gives you a much more diverse set of people to whom one is ethically accountable. It also gives you a daily readout of how good a job they think you might be doing with their money, which is certainly humbling. One tries not to look at it too often. But it's important.
LAURENCE REID: And it's a reminder. But I think the real thing is that the investors who drove the crossover to the public really believe that there's is a really important opportunity here. And so it's like, OK. You put the money together. You have a great team.
LAURENCE REID: We have an outstanding vision and a fantastic platform, and you guys need to execute. And so that's the support and advice that we get from our investors and our board. And that's very much the mindset. We have the capital at hand. We have a fantastic team. And really, we're now-- we're focusing on driving the products into the clinic.
LAURENCE REID: And when we do that, and when we succeed at doing that, and if the results then follow, the value will come, will come in the company. It's been a slightly torturous few months in terms of the share price. But if we can execute, then we'll get to where we need to go as a company. And we'll put ourselves in a position to achieve that.
KEVIN DAVIES: Let me just ask one question about that. I don't want to prolong this. But as you mentioned now a couple of times, the price has come down maybe roughly two thirds from its high roughly at the beginning of this year. Has that been an overreaction to any particular news or updates that the company has released over the last six months? And I'm guessing I know the answer to this question. But do you think the stock is currently undervalued?
LAURENCE REID: So largely, the reaction is almost nothing to do with the work that we're doing. I think that, as a young public company holding the attention in today's market of investors is quite a challenge, as a young public company. And I knew this going into the IPO, that we get into next year, we have really important things happening around our non-gene therapy program. We have really important things around otoferlin going into the clinic.
LAURENCE REID: And suddenly, we're going to be out there with really material statements about our progress that I think will be very clear to people. The intervening few months, our news flow is a little limited. And so it's hard to keep top of mind for investors. We have a very tiny volume of shares change hands on a daily basis. And so the ability to drive momentum into that, a combination of those things, is pretty limited.
LAURENCE REID: So that's how I think about it. We announced a delay in our non-gene therapy program, which was a COVID impact. And so we got some reaction to that from some of the people who follow the company. It's a secondary value driver in the company behind the gene therapy platform and got quite badly held up by COVID during the course of last year, 2020, excuse me, of course.
LAURENCE REID: And we got that back on track now. But it got delayed by probably six to nine months overall. So we had to deal with that back in our Q1 earnings release. And so that was information that was out there. And we're working our way through that. But in terms of executing on the gene therapy, the otoferlin program, the team is doing a fantastic job executing on that. And on track for an IND or a CTA in Europe next year exactly as advertised.
LAURENCE REID: So touch wood. We're working hard on that. We've got a fantastic team. And they've really been pulling the platform and the technology together on a confidence that they're going to get that.
KEVIN DAVIES: You mentioned COVID, Laurence. How has COVID impacted the progress of some of these products in the pipeline?
LAURENCE REID: So the preclinical programs have really not been impacted. Our clinical program, which is rather different-- it's for the prevention of the ototoxicity caused by cisplatin-based chemotherapy. And it requires a collaboration between an audiologist and an oncologist. And during COVID, a lot of non-essential interventional care really was not top of priority. And in addition, in some of our clinical centers, literally the logistics of an audiologist walking across the parking lot or up and down to go to the oncology suite was verboten for a while.
LAURENCE REID: And so it just completely gummed up the logistics of that trial. Our preclinical programs with, I think, a lot of creativity and drive from our teams, we've kept very much on track. And a lot of juggling of resources, distant working, which, of course, we've all adjusted to these challenges. I've been really proud of the Decibel team. The resilience and the determination that we were going to keep going, I thought, was really was fantastic.
LAURENCE REID: And there are other challenges, which I suspect you've heard about, things like the animals that one uses in the preclinical experiments, a lot of these animals are in very short supply right now. They're being shipped from other parts of the world. And then a lot of them are being, probably appropriately, grabbed for COVID pharmaceutical and vaccine development. And so there's a combination of supply and demand that's gone out of whack.
LAURENCE REID: We've managed our way through that, we believe, and dealing with third party suppliers and collaborators who all have their own working challenges and operational constraints that COVID's imposed. I think we're-- Well, the world changes every day, as we all know, right? But my team has done a fantastic job of maneuvering many of those, which is why we think we're on track for dosing patients next year, which would be incredibly important for the company.
LAURENCE REID: And the [INAUDIBLE] more importantly.
KEVIN DAVIES: Yeah, some viewers may be interested in your-- you've struck a relationship-- Well, you mentioned Regeneron as one partner and also on the manufacturing side, with Catalent for one of your gene therapy programs. Where does Catalent come in? And do you think that's a long-term partnership? Or would eventually you want to assume control over all of your manufacturing needs?
LAURENCE REID: Yeah, it's a great question. And it is true that many gene therapy and related genomics companies have asserted control of and invested in their own bricks and mortar to do that. We are investing in a lot of the pre-work prior to real GMP manufacturing, the process development, GLP processes, and building the capability to do that.
LAURENCE REID: Our friends at Catalent, they've delivered on their part of the deal. They are one of the leading gene therapy manufacturers today. In biologics early on-- I'm not sure we're there yet in gene therapy-- in biologics, early on, manufacturing was a very strategic role. Then, of course, eventually, it went down the path of more of a CMO type of approach. But probably in the period of transitioning to more of that.
LAURENCE REID: So we've been really impressed with Catalent. And they have different types of flexible relationships that they're willing to strike with their partners. And they've been a very strong partner despite COVID. So it's been going really well. Our relationship with them covers otoferlin. And that's what we're working on with them for now. And I think we evaluate the topic on an ongoing basis. But I think ultimately, if we don't have to build that infrastructure, and we can take advantage of great relationships with people of their type of caliber and quality, then we're very happy doing that and having a strong interface with them where we're working with the product early to understand its initial characteristics and then helping them transition it to more of a bulletproof post-GLB GMP process.
LAURENCE REID: I like that strategy. And then Regeneron, just perhaps quickly.
KEVIN DAVIES: Yeah, please.
LAURENCE REID: We put together a relationship with Regeneron at the end of 2017. Big pharmaceutical companies, as we glossed over a little bit, have been absent from the field. Regeneron believe that they had a lot of technological capabilities, both around biologics and gene therapy, that they could bring to bear in this field. They weren't strategically committed to entering the field. So we put together, long before my time, a really interesting deal in which we have an R&D collaboration.
LAURENCE REID: Decibel then retains the commercial rights and compensates Regeneron with a royalty stream to represent the value that they've created in our products. They're an unbelievable R&D powerhouse, both the quality of advice and help we get from them. They collaborate on some of the projects. They've helped us with and done some of the preclinical early manufacturing work.
LAURENCE REID: And it's a fantastic company. And it's been a lot of fun to work with them. And we've learned a lot from an incredibly mature, experienced organization while we're still building up our team and our infrastructure.
KEVIN DAVIES: Right, right. Just a few questions to close, Laurence, as we move into injury time here on Close to the Edge. Will you stick to gene therapy? As we mentioned, David Lew, earlier in the show in our interview, and our previous guest on Close to the Edge was John Evans the CEO of Beam Therapeutics, which is spearheading the commercialization of base editing. One could certainly imagine from my naive perspective that base editing might in principle provide a brilliantly sophisticated precision therapy for some of the disorders that you may or may soon become interested in.
KEVIN DAVIES: So is that off the table or would you consider that if you felt that that was the approach most likely to succeed?
LAURENCE REID: I think that as those technologies mature, and also you and John talked about the most famous human mutation of all time, right? I think if your gene lends itself to gene editing, then-- and of course, that happens sometimes and not others. Otoferlin, there are many, many different mutations that can cause the hearing loss. So the beauty of putting back a new wild type copy of the gene is a universality. And we're talking about an orphan disease and how much it gets fragmented by the genetics that nature handed over.
LAURENCE REID: So of course, as these technologies get better, as they get more robust, and as they're applicable to the right genes for us in the hearing field, yeah, of course we'll contemplate those technologies. And we've explored other routes of administration, other technologies of administration, other oligonucleotide approaches including RNAi and ASOs as well in the ear.
LAURENCE REID: We think there's a lot of opportunity with AV-driven precision delivery of genes that are either complementing a genetic mutation or driving a biological pathway in a gain of function type of way that we think we can use to regenerate hair cells. So we're pretty bullish on the technology platform. We continue to invest in it. How do you make it better, how can you control it, either from the exterior or temporally, will be future versions of that.
LAURENCE REID: And yes, will we get to these other molecular technologies in years to come? I'm sure we will. But right now, I think AV-driven gene therapy, providing a wild type copy of the gene under precise molecular control, that's the way we're going to change people's lives, I think, in the next few years.
KEVIN DAVIES: Yeah, obviously you're focusing on somatic gene therapy. But a couple of years ago, and just before you joined Decibel, hereditary deafness was in the news in the wake of the CRISPR babies He Jiankui debacle when a Russian geneticist named Denis Rebrikov announced that he was going to use embryo gene editing in Moscow to help some Russian couples with an inherited form of deafness-- I think the gene was GJB2, if I recall-- to try to have a hearing enabled child.
KEVIN DAVIES: And a Science Magazine reported he successfully recruited couples and seemed like he was on the verge of trying at least to try to begin those experiments before the Russian authorities, backed by the World Health Organization, said, not so fast, Denis. Put a hold on that. And I don't think any official report that has come out since would have condoned or considered hereditary deafness to be sufficiently serious a disease to tackle that.
KEVIN DAVIES: But I'm just curious on your thoughts because you've obviously got to know people in the hearing loss community. Do you feel there would be, if it was proven safe and effective, would there be some interest in potentially considering germline gene editing to tackle some of these severe hearing loss issues? Or do you think that should be completely off the table?
LAURENCE REID: I think it's just off the table for many years out in the future. We work on GJB2. GJB2 is the most common form of genetic deafness. Over a quarter million patients in the Western world suffer, I believe, do suffer from defects in that. That's our second most advanced program. Other companies also work on that target. And based on what I've tried to convince you of the power of gene therapy in the ear, I think there's a good chance that for some or many of those patients, we're going to be able to rescue that postnatally in a local fashion.
LAURENCE REID: And so I think we're a long way away from needing or it being appropriate to talk about--
KEVIN DAVIES: OK.
LAURENCE REID: --about preconception.
KEVIN DAVIES: Fair enough. Have you started to think about pricing? I guess you can't just wait until the thing's approved and then sort of convene a meeting to say, well, guys, what are we going to-- I mean, how do those sorts of conversations take place?
LAURENCE REID: Yeah, so it's a good question. So yes, we've thought about it. But our molecules are just going into the clinic. We've just had the beginnings of an early commercial team at Decibel. And so I think part of it is also there's a whole new road to layout now in terms of the value that one brings to a patient and their family. If one is able to instate normal hearing into a child born completely bereft of hearing, how does that play out in terms of their social, cognitive, overall emotional health?
LAURENCE REID: And we think that's going to be very profound. So we'll be building the arguments to really begin to go and lay that path down with people who make pricing decisions. But we're very early in that [INAUDIBLE]..
KEVIN DAVIES: Understood. So final question. It's been a really interesting conversation. What are the next pivotal events for Decibel Therapeutics that we should be looking out for over the next year or two?
LAURENCE REID: Yeah, no, thank you. So the leading indicator is very much going to be our own otoferlin program. So as we've talked about, we expect, during 2022, to file an IND in the US or a CTA in Europe and dose our first patients. And we'll be building a patient base over the coming months. So hopefully, months to small numbers of years after that, we'll start to see the impact of that.
LAURENCE REID: So that's really a driver. And it's going to be a validation of some of the things that I've been researching about the potential power of gene therapy in the ear. And it's our first program. And so we have others behind that. We will be announcing the development candidates next year, we hope, for the GJB2 program that we talked about. And then we've talked less, but I've mentioned, our small molecule program for cisplatin for the prevention of cisplatin mediated ototoxicity, which has a very significant negative impact on people often middle aged or going through cancer therapy.
LAURENCE REID: We will have proof of concept data from an interim analysis of our study in cancer patients that we'll be, hopefully, announcing in the first half of next year. So a different part of our overall strategy, but nonetheless, in terms of impacts on patients and innovation that came out of Decibel, we're also pretty excited to be sharing those data in the early part of next year. So it's a lot going on in the company.
LAURENCE REID: To me, it's an incredibly exciting adventure to be part of and a big year to 18 months coming up.
KEVIN DAVIES: Very good. Well, Laurence Reid, CEO of Decibel Therapeutics. Thanks so much for sharing your insights and progress at a really interesting company for a really important large group of disorders. And we look forward to hearing big things from Decibel over the next few years. Also, we'll be keeping tabs on your soccer team because the US women needs some new blood, clearly, from the Olympics performance.
LAURENCE REID: With Carli hanging up her boots. Yes, no, there's plenty more where they came on. Women's soccer in this country is in fantastic shape.
KEVIN DAVIES: Despite your best efforts. Yes.
LAURENCE REID: There you go.
KEVIN DAVIES: All right.
LAURENCE REID: Absolutely.
KEVIN DAVIES: Thanks, everyone, for watching. We'll be back soon with another great guest on Close to the Edge. I'm Kevin Davies. We appreciate your company. Thanks for watching, and goodbye for now. [MUSIC PLAYING]

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