Hello and welcome back for another episode of the Future Ear Radio podcast!
This week, I’m joined by Ross O’Neill Ph.D. & Hubert Lim, Ph.D. from Neuromod to discuss their game-changing tinnitus treatment product, Lenire. Ross is the founding CEO and Hubert is the Chief Scientific Officer of Neuromod.
During our discussion, we discuss:
– The backstory of how Ross & Hubert met and ultimately partnered together on Lenire
– Hubert’s research and papers he wrote about paired stimulation & Pavlovian conditioning, which included data that identified tongue stimulation combined with sound as a promising direction to pursue
– An overview of what exactly tinnitus is and why Lenire presents such a novel approach to treating tinnitus
– Other types of synchronous-stimuli approaches that have emerged in other healthcare verticals (i.e. mirror therapy for phantom limb pain)
– The challenging process of gaining FDA approval and the clinical trials that were conducted throughout the process
– Being featured as the cover story on Nature Communications
– The initial roll-out of Lenire, the current state of the provider network, and the real-world data that’s being collected and published
This is truly one of the most exciting products to enter into this whole industry since I can remember. A game-changing new way to treat tinnitus.
-Thanks for Reading-
Dave
EPISODE TRANSCRIPT
Dave Kemp 00:08
Okay, everybody, and welcome to another episode here of the Future Ear Radio podcast. I am stoked today to be joined by two great gentlemen I have Ross O’Neill and Professor Hubert Lim with the company Neuromod and their product Lenire. So guys, how we doing today? Thanks for coming on.
Ross O’Neill Ph.D. 00:29
Good, good. Thank you. Yeah.
Hubert Lim Ph.D. 00:30
Thanks for having us. David, appreciate it
Dave Kemp 00:33
Absolutely. Well, as mentioned, you know, wanted to bring you two on. I would say that Lenire was absolutely one of the stars of the show at this year’s ADA conference, and has been, I think, kind of up at the top of the list of most talked about developments within this industry. I, for one, have been no have not avoided, you know, expressing my excitement and enthusiasm about this. I think this is a really, really exciting development for the industry, for the profession, and obviously for the patients. So I wanted to have these two guys on today to just sort of share the story of how Neuromod started, how Lenire came to be, how you two met. So with that, I will kick it over. Why don’t I kick it over to you, Ross, and let you kind of set the stage however you want. And go back to the start when this was all just an idea.
Ross O’Neill Ph.D. 01:30
Yeah. So thanks, David. So I guess it started back in in university, back in Ireland, as part of a research group, and we were looking at these collection of disorders that we called illusory perceptual disorders. So they would include phantom limb pain, tinnitus, you know, Charles Bonay, which is a illusory perceptual disorder of the visual system. There’s kind of one for almost every system. And we were looking at, how could we develop neuromodulation interventions for these and I guess I always had entrepreneurial ambitions. Always wanted to start a company in the medical devices space. And you know, anytime we advertised, even for a small study in the university for tinnitus patients, we’d, we’d have people queuing around the block. So it was very, you know, unsophisticated, palpable, first hand, you know, evidence of a major unmet hearing healthcare needs. So it was pretty obvious. And so whenever I talked to Ents or Audiologists, they said, Wow, so many tinnitus patients. You know, if you ever develop anything for these guys, it’ll be a game changer. So that was this, you know, I didn’t really need much more evidence to say that this is the opportunity. And so I started to look at it. So at the time, the interventions were mostly sound based interventions, like hearing aids, sound therapies. You know, there was stuff on the cognitive behavioral side as well and but you know, what the literature was saying at the time was that these sound based therapies don’t provide a lasting relief in the brain. They don’t hardwire the effect into the brain. They provide relief while the patient is using the hearing aids, but if they take them off at night to go to sleep, then the tinnitus spikes, and, you know, they find it hard to get the get to sleep, and that that’s one of the major quality of life things that you hear patients talking about. So we started looking us at ways. Then how could be, you know, made that effect more long lasting, or hardwires into the brain. So we started looking at this idea of bimodal so, you know, there were, there were approaches called paired, associative stimulation, which Hubert can talk to in detail, but they date right back to Pavlov and his dogs and, and, you know, it’s where you pair one stimulus with another and, and that’s so that’s where we came up with the idea. And I think, you know, as we started working on, on the technology and the literature was growing, I became aware of of Hubert, who was working in in Minnesota, and he, you know, I remember 2015 he wrote a paper where they looked at different stimulation sites of, you know, where you paired sound of different stimulation sites on the body. And one of the sites that really stood out was the was the tongue. It was like one day optimal sites. And you know, we joked that if we we didn’t know Hubert at the time, but we joked that if we paid him, he couldn’t have written a better paper for us, because his, his his study found that one of the best places to stimulate was the tongue, which was where we had kind of identified as a as an optimal target as well. So it was kind. Of a happened, chance that we kind of both kind of, you know, ended up on that, that target site and and then, you know, as we kind of really started to gain momentum in the company, we had formed a Science Advisory Board, which included Professor Sven Nest, and he jokingly told me that there were, if there were two guys that were ever meant to work together, it was me and Hubert Lim so, so I found out what he meant by that later, after I got introduced to Hubert, but, yeah, it’s been a very, very exciting time working together with Hubert on this. That’s
Dave Kemp 05:36
so cool. Okay, kind of continuing on this. Hubert. How about you know, you fill us in on what was going on in your world leading up to even being introduced and approached by Ross about joining the Scientific Advisory Board, clearly, you were doing some research in the bimodal neuromodulation type studies. So I’d be really curious to hear what even kind of got you interested in that, and how these two paths also mainly were positioned to even meet.
Hubert Lim Ph.D. 06:08
It’s kind of interesting because I, you know, I actually knew of Ross and Neuromod since 2011 12 time, because they had some, you know, media out about their approach. I actually wasn’t a tinnitus researcher. You know, initially 2000 I did my PhD at University of Michigan, and I was focusing on central auditory implants. So like cochlear implants, where you stimulate the nerve portion of the cochlea to activate those pathways to the brain to restore hearing in deaf individuals, but I was trying to approach it from a deep brain simulation approach, directly stimulate the brainstem, the midbrain. So I focused that on my PhD, and then in 2006 I moved to Germany, because I was able to run a clinical trial for deep brain stimulation for hearing in the auditory midbrain initially, but also worked with a lot of patients who are implanted at the Cochlear Nucleus. So that’s like the brainstem, you know, the auditory portion of the brainstem. What was interesting, though, was, you know, because tinnitus is linked to hearing loss, right? A lot of these individuals who are getting these hearing implants have tinnitus and the challenge with these implants, and, you know, I guess it was a disadvantage for the research I was doing at the time, but it was very intriguing from a tinnitus perspective, is the electrodes were not always placed in the proper regions. They were placed in some of the non auditory pathways of, you know, of the brain, and so we would end up stimulating those to see if we could get an auditory sensation. And a good number, honestly, a lot of them, we were actually able to modulate the tinnitus in these patients. And so that, that was actually my first entry, that was around 2007 ish time. And I thought to myself, geez, you know, if we could stimulate these non auditory pathways and modulate the tinnitus. That would be potentially a game changer for the tinnitus field, thinking of implants, right? And then I started to research more, and I and, you know, I was already interested in paired stimulation for my PhD, looking at sounds paired with body stim or or invasive stem but it wasn’t an issue for tinnitus. It was trying to cause learning of plasticity in the brain. So this all started to converge together. And when I went to University of Minnesota, actually, my job talk in 2008 was about using paired stimulation for treating tinnitus, but it was actually to do invasive implants, stimulate the somatosensory pathways, stimulate the cortex and pair it with sounds to drive or Ross was talking about this paired plasticity, right? And induce these changes. So then I came to Minnesota in 2009 and realized, geez, trying to push implantable technologies and get it, you know, to patients, is going to be a long journey. And so I split my lab, 5050, 50% implantables. But then 50% was, can we try to access some of these? Well, non auditory, but reinforcement signals, non invasively, by stimulating the body. And that’s the paper that Ross was talking about. I just looked at lots of different body locations in animal studies, and then it just happened. And I’ll be honest, Ross, you know this, I didn’t want to publish it, because at the time, Ross was my competitor. I viewed him as a competitor. But the data showed that electrical stimulation of the ear was a pretty strong driver of this paired plasticity, and electrical stimulation of the tongue was also and so in that paper, in the discussion we you know, the data is the data. So we wrote a paragraph to say, tongue stimulation combined with sound is really a promising direction to pursue, and that’s how Ross found that paper. And then we connected at the time, just for your audience, I mean, just to understand paraplasticity, it’s not that complicated, pretty straightforward. Where you know it’s basically, we already know that you play sounds, the brains are going to be attending to it. But if you pair a reinforcer, right, you know could be body stim, could be food, it’s going to cause your brain to attend to that even more aggressively. And pavilion conditioning is the key example, where a bell means nothing to the dog. You pair it with food, and then, now, when you just play the bell, the dog will salivate, you know, to the bell sound. And people have done experiments to show that that’s coded in the brain, right? And it’s, it’s enhanced the sensitivity of the brain to that sound. And so we’re just using that concept. It’s not, you know, it’s not that complicated. But the the way we use it is actually kind of the inverse. If you have tinnitus, sound ultimately, you know, if we can ideally create this is to figure out what sounds are, not your tinnitus, and then you pair it to those sounds, and it shifts the brain away from the tinnitus so that that’s for your audience. That’s the general idea of
Ross O’Neill Ph.D. 10:57
it. Yeah. Well, I’d add to that is that, you know that tinnitus is really the combination of three kind of nodes in a network in the brain that feed off each other. One is audiological, right? It’s the it’s the illusory audiological percept. You wake up one morning and you hear a sound that wasn’t there before, right? So what happens next is you pay attention to it, right? So that’s the second node. Is attentional. And, you know, you go, what the hell it was that like, it’s, it’s like, I turned my head and it’s everywhere. It’s, you know, shouldn’t be there. And so then the next thing is, it kind of frightens you. So that’s the emotional node. And those three nodes kind of feed off each of each other. And I guess what? Um, historically, some of the treatment approaches have been to attack either the audiological node or the emotional node. So cognitive behavioral therapy would seek to attack the emotional node, and you know, hearing aids and sound therapy would try to attack the audiological but nobody has ever really gone off to the attentional note. And you know this paired, associative stimulation approach is just so incredibly powerful in the brain, and attention can be directed either to something or away from something, using this approach of combining two synchronous stimuli. And it’s just the way the brain, you know, kind of assesses the world and measures the world that uses these Bayesian models. And if two things start arriving in on two different inputs at the same time, the brain goes, Okay, this has to be really important. Let’s start paying attention to it. So that’s really the basis of the approach of by modeling our modulation. I
Hubert Lim Ph.D. 12:44
think Ross should be the chief scientific officer. Though, that was actually really good. Ross, I’m a believer.
Dave Kemp 12:52
Well, what I find really interesting about this is I and I want to ask you, like, what was that landscape like when you were kind of, you know, Huber, you were coming at this from a research standpoint, Ross sounds like, you know, you were already sort of envisioning what this product might look like. But from a broader healthcare standpoint, outside of audiology, outside of tinnitus, what other kinds of it seems like, this whole novel approach of really going and doing this paired stimuli activity, these brain based activities. Were there other examples that you were sort of taking your cues from, whether it’s like in the vision space, or, you know, some of these different disorders that you mentioned at the top? I mean, were where was the science at from that standpoint? Because it seems to me like what is so exciting is we’re getting our first introduction as an industry of what these sort of synchronous stimuli approaches look like and what can be done. And maybe this introduces whole new ways of treating things and providing therapies. But a lot of it seems nascent. A lot of it’s like, this is a totally new frontier of science in general, and I would be really curious of what’s come before, that sort of Lenire-esque, but for a different segment, different vertical for a different kind
Ross O’Neill Ph.D. 14:13
of disorder. Well, the one that really, I thought was pretty cool, that was Mirror therapy for phantom limb pain, so where you’d lose maybe the lower half of your arm, and you you’d, you know, experience this excruciating pain in this limb that was no longer there. And so they used mirror therapy. So they would hold a mirror in front of of the missing portion of the limb, and then they with the other arm, they would maybe get you to do an exercise like dumbbell curls or something like that, and it would look like you were doing it in both arms and and they’d tell the patient to imagine it in both arms. So that was one of the early things that I saw that I thought that is pretty cool, because the brain is is now going to sense check the pain signals that it’s getting on the mid. Single limb, right? It’s going to say, because if it’s getting really strong pain signals, it’s not going to question it, right? But if you were sending in a contradictory input from another another sense, which is vision, it’s going to say, Okay, we need to sense check this pain and, you know, and then when that feeds into those Bayesian models, then what it does is it weakens the pain signal, so that that was one of the, the kind of the, the early things that I saw that really made me think, you know this, this could work for tinnitus. Because the problem is with, with tinnitus, as Hubert said, your brain is paying too much attention to this one sound, and it’s because it’s kind of gripped in a kind of a, you know, a fear state, and it keeps paying attention to it, and you’re kind of stuck in this loop. So if you get something to to break that loop, loop up, right? If you start to, like, use this approach to direct your attention to other sounds, which is what our product does it, you know, cycles through all the other sounds that are outside the de tinnitus kind of sound, and drives your attention to them. And so it just kind of dilutes the the amount of attention that is given to this one percept and spreads it more evenly across your your frequency, spawn response, response, I guess so. Yeah. So that was on the early things for me that really, that I really thought now, to be honest, I thought that the and you pointed out that we’re kind of still at the at the early stages of of this approach. I thought there would be more bimodal approaches by now, and but, you know, we’re actually the first ever and only FDA approved by modal device. So we had to, unfortunately, because nobody else had gone before us, we had to engage, you know, in a very in depth way, with the with the FDA, we had to design clinical trials together, and, you know, blaze the trail together and and we have to created an entire new device category as a result. So we created us regular regulatory history and doing that. And so we were the first, and to date, there hasn’t been anyone else that has followed us. But, you know, who knows what? What that will hold in the future? Maybe there will be more bimodal approaches,
Hubert Lim Ph.D. 17:20
yeah, yeah. And then the hearing space, yeah, we basically kind of set, set the stage for bimodal to come through. And there are other researchers in the space that have been trying to get some developments going outside of the auditory field. Like Ross mentioned, mirror therapy is pretty impressive. You know, it’s trying to, it is like multimodal stim too, because you’ve got, like, your hand, and then you’ve got a mirror that’s looking at that, you know, reflecting that hand. And behind the mirror, you know, you’re missing your hand, your limb, and so your brain is using all those signals, and it’s kind of reinforcing, and then it residually sticks around during that time too. There were groups, you know, doing transcranial direct current stimulation, some vagus nerve implants and and auricular and other kinds. And they were trying to reinforce for other kinds of, you know, conditions. At the time, Ross knows, you know, I was supposed to go to DARPA for four years. And DARPA was really pushing paired stimulation for all sorts of health conditions and skills. So they were looking at training, you know, military operations and combat, even like sniper shooting and pairing electrical stem of the vagus nerve pathways with that. You know, other on the rehabilitation side, you know, stroke recovery, things where it’s related. People were doing it originally with transcranial magnetic stimulation, where they would try to stimulate, you know, in a motor region and reinforce some movements and try to cause paired stance. So, you know, there were groups that were all kind of dabbling in this space. More recently, there was FDA approval for, like, a stroke recovery using vagus nerve, implantable microtransponder. I think that’s the name now they go by, right, Ross, and, you know, they’re reinforcing. So I think it’s still all kind of early. There are a lot of research early on. I would say we brought it to a stage where it’s much more widespread now for auditory field. But I think combined with what we’ve done and then those early stage research and people kind of dabbling, you’re going to see many more. I’ve had people approach me in other fields and say, oh, you know, I’ve thought about this for a, b and c, and we’re trying to move it forward. So I think you’re gonna see in the next five years, maybe more bimodal, trimodal, I don’t know how to say for quadrimoto, but quad modal, quad modal, they’re gonna start to come out, right? Because it’s all about, how do you reinforce your brain? Like, this is important, you know? Like, that’s how our body works. We, we’re, we’re constantly taking multiple inputs, and the more things that come in, you know, the more important it is to us, right?
Ross O’Neill Ph.D. 19:55
Yeah. And I think that a lot of people, as as Huber pointed out, also, we got the FDA approval, and. That, you know, is, is it became kind of, you know, reasonably big news, and a lot of people started coming to us with ideas, and it’s any condition where brain pays too much attention to something, and, you know, this could potentially be used as a as a therapy for that. So we, the neurotech conferences are always the most. That’s where we have guys coming up to us, left, right and center. You should use this for this, yeah, so about 20 conditions now that people want to try this for, but they On the plus side, I suppose, now that we have regulatory approval, there is a pathway. And you know, so we’ve, we’ve done the hard work and and, you know, but that was part of of a wider strategy and building credibility around this technology. So when we started to look at the the tinnitus space, it was an area that was, I would say, you know, beleaguered by, by credibility issues. There had been a lot of things, you know, that had, you know, making over, over inflated claims, you know, without the evidence base to back it up, you know, without the clinical trials and and, you know, a lot of people trying to cut corners. And I think, you know, so it so we came, you know, when we looked at the opportunity, we said, Okay, we essentially want to be the category creator for for this condition. So a lot like what copier became for the the profound deafness market, we wanted to do that for the tinnitus market. So we decided that we would work with all the top scientists. We do the biggest clinical trials ever conducted in the space. We’d publish, pre publish our protocols, and then we’d post, publish our results in top tier, peer reviewed journals. To date, now we’ve three major publications in three top tier journals. Got the cover story in Science Translational Medicine for our 10 day one study, scientific nature, scientific reports for our 10 day two study, and we’re currently the cover story in Nature Communications for our 10 day three FDA study. So, you know, I think we’ve gone above and beyond through the credibility of the of the the technology, of the clinical efficacy. And now what we’re starting to do is publish the real world evidence so and we’re seeing that, you know, that the real world evidence is actually highly consistent with the clinical trial data, and so we’ll just keep publishing all of that data and just continuing to build the credibility of this technology for this indication, until we deliver on that mission to become the category creator for Fort Genesis.
Dave Kemp 22:45
I mean, I am just want to, like, pull up and just say congrats. And how does it feel? I mean, it sounds like it’s been a very arduous journey getting to where you all are. And I’m sure there might be some people out there that might appreciate just a little bit of color around what those days were like in terms of, did you did you think that you’d get this far? Were there times where, you know, it felt like you wouldn’t ever get through that FDA approval process? You know, I just feel like that as we were talking about at the top of the conversation, or before we started recording, is you see these exciting new technologies that sort of come to light, and they promise the sky, and there’s all these, you know, grandiose ambitions and all that. And then reality hits and, you know, actually bringing and materializing an idea in bringing it to fruition. And then, you know, to make it even that much more challenging, doing it in a regulatory environment that’s extremely rigorous, you had to define the category. You guys have achieved a lot, and it’s probably pretty gratifying. And, you know, we, like, we were kind of joking about, it’s like you get, you kind of surpass these hurdles, and you get to it, and it’s just Okay, good job. It’s like, you don’t ever really get a chance to you’re always moving on to the next target, the next goal. But I think it’s worth at least, maybe, you know, having a little introspection and saying, Wow. Like, what an accomplishment it is to even get to this far, so that you can get to the point to where you can do these real world clinical trials. And like I said, you know, at this year’s Ada, I mean, I think that was kind of the talk of the conference, was that you’re putting your money where your mouth is, more or less. There’s all kinds of evidence now that supports what once was hypothesis. And again, like kudos to you guys for persevering through what I perceive to be just an incredibly challenging sort of process that’s rife with, you know, arbitrary red tape, or just things that don’t seem to to make any sense, and you just have to battle through it.
Hubert Lim Ph.D. 24:59
Yeah. On. Maybe I’ll just give Joe. Oh,
Ross O’Neill Ph.D. 25:01
go ahead. Said mess up. Huber started out looking like young men when we started this journey. Unfortunately, Huber still looks like, no, that’s just telling hair more.
Hubert Lim Ph.D. 25:13
You just gotta smile more, Ross,
Ross O’Neill Ph.D. 25:17
but yeah, I’ll let Hubert, yeah,
Hubert Lim Ph.D. 25:19
yeah. The one thing I’ll say, I mean, thank you, David, because it was a long journey. And, you know, it’s challenging because, like, there’s a lot of steps you have to do to bring something to FDA approval. And you know, I didn’t take it lightly joining Neuromod, because, you know, two things. One is, you know, I was going to start my own company and this space, and I am a professor at the University of Minnesota, so you know, as an academic, it’s critical to maintain rigor and and transparency in the process. When I was considering to come over to Neuromod to serve as the chief scientific officer, it was very important that I understood and knew for sure, as sure as you can be that they would support large scale clinical trials and figure it out, because at the time, you know, when we talked, we said, look like there’s something here, but we have to convince folks. We have to convince ourselves. We need to figure out, like, what are effective parameters, what’s working, what’s not right. And so in academia, it’s hard to run large scale studies. You know, you could go for grants, there’s lag time. It would take even longer. And so when I met Ross and he, you know, the board members and and the investors and so forth, they came from the pharma industry, so it was, it was really refreshing, because from the device field, it’s like, we could do 15 patients. We could do 20 patients here. I was like, Yeah, we could do hundreds. And I was like, wait, what can we really do hundreds of patients? And it was like, Yeah, let’s do this, right? Let’s, you know, run a series of studies. I said, look, it’s going to take a few, you know, series, a few few clinical trials, and we’ll converge in what words now to share that with the community was challenging, because every study we’re going to do, it would be under high scrutiny, and it was like, is that study properly designed? And we tried multiple times to explain that we’re doing a progression. You know, this even in the title of the protocol paper, we said parameter optimization study. And then for the longest time, people kept saying, Why didn’t you run that? Was a terrible, controlled clinical trial. And we’re like, you know, we called it a parameter optimization. So, you know, it was, it was just this kind of messaging and trying to get it across, you know, why we’re doing what we’re doing. And, you know, it was also a lot of pressure from individuals like, why are you taking so long? Or, you know, why didn’t you do it this way or that way? So we tried our best, you know, we put protocol papers published, even the papers that we did, finish the clinical trials, if you look on there, and kudos to Dr rich Tyler for suggesting this, that that was a great idea. You know, we have these scatter plots where it’s like all, you know, each individual participant, the data that we have, we put that on there, right? So people might criticize the way we analyze the data, or how might be presented. I mean, that’s all fine. Everyone has, you know, their opinions, and we totally accept that. But they could go to the papers and they could look at the data, and they can make their own assessments, which many people did, and they look at, you know, and see what happens. And so we’ve kept that rigor, we’ve kept that transparency, and each stage of the way we present the paper. We, you know, do podcasts. We do our best at conferences. I was presenting the results. I won’t lie, you know, I felt like I got punched a couple times in the stomach, in the in the face, you know, for people that didn’t like the design. But, you know, totally understand, this is the science field. We need to take that and then do better, right? That’s the idea. And FDA, I have to say, I mean, they were very collaborative. I think a lot of times, people may have bad experience with FDA, you know, but that’s because they’re not engaging them earlier. You know, they have a tough job, they have a lot of information they have to process, you know, they got tight timelines, and they’re doing the best they can, and they care. That’s why they do the job. And we’re all just trying to get to the same place. So that was where we engaged FDA early. And it was just very refreshing and supportive to see them so collaborative. And they’ll say, Look, that’s not enough for us. Okay, this is exciting. That’s meaningful. You know, you need to design it this way. Now, I will say the clinical trial, which you get to later, was a high, bar, and I’ll explain to you later why. So we were like, oh, you know, that’s going to be a very tough study, because we’re not showing relative to Sham, we’re showing relative to like treatment, you know, already, but we managed to get through that, and they were very supportive. So I will say, Yeah, I mean, it was a tough journey. It took some, you know, we could have probably explained it better to the community and found ways to do that. It’s a learning process for us too, because we’re just moving so, you know, quickly and trying to get what we could out there. But in the end, you know, I’m happy, really proud, Ross, of what we’ve been able to do, not perfect, but hopefully, you know, your your audience and the community understand that. You know, we’re doing the best we could within the constraints we had. And you know, we. We know it’s not still the perfect study or the perfect situation, and we’re going to keep, you know, striving to improve the treatment, and we’re always happy for feedback, right? And collaborative discussion, which we do, we bring all the people that criticize or support us, and we bring them together, and we always have discussions about it, right? To move it to the next stage, yeah,
Ross O’Neill Ph.D. 30:18
I think as Hubert’s, you know, as we look back, you know, having kind of sophisticated and very supportive investors was was so important. And so there’s a venture capital firm based out of Dublin called healthcare partners, and they got behind us. And as Hubert said, they come from the kind of pharma, kind of biotech space. So they took that lens and brought it over to to this kind of device space. And I think they could see that the size of the opportunity. And I think they they could see what we were trying to achieve. And, you know, I think we engaged the the top scientists, you know, our science advisory board, Berthold Langguth, you know, who’s one that I’ve been most published scientists in the tentative space, Sven Vaness, Deborah Hall, rich Tyler, all these guys, you know that we brought together, and they helped us inform our designs, our clinical trial designs, and and then I think we just went for it. You know? You know, with the kind of philosophy, No guts, no glory, you have to, you know, you have to go for us and and I think that Huber’s right. I don’t think everybody fully understood what we were trying to do, that we were kind of refining, refining, refining, working through a couple of phases of exploratory trials, where we worked through parameter settings, where we worked through patient subtyping, getting to that ultimate point where we knew who, what was the most effective form of the treatment, and who was it most effective for, which is what we got to with the pivotal trial when we took that to the FDA, and then kind of very collaborative, I would totally agree with Hubert. They were incredibly collaborative and great partners to work with. We worked through and came up with a design that gave them what they needed and got us, you know, the approval. So, yeah. So it’s been a very challenging but incredibly rewarding journey over the last, you know, 10 plus years, you know, since, since, I guess, we’ve, we’ve been working on this. Yeah.
Dave Kemp 32:20
Yeah. I mean, okay, so let’s talk about some of those clinical trials. I’m curious, you know, without going too far down into the weeds, you know, understanding what made it so challenging, as you alluded to, there Hubert some of these rigorous parameters, and then also, what were you sort of learning and throughout that process, as you said the whole point was to iterate on the parameters itself. So I’d be very curious of kind of just in broad strokes, understanding, sort of the clinical trial piece, and then ultimately how you were able to progress it along to the point to where you got to where you are now, where you’ve got now you’re at the point where you’re collecting real world data, because I think that ultimately sheds some more light on, like you said at the top, Ross, you know, it’s like, you’re, you have to obviously do this in a way that is very, very rigorous. Maybe that’s why this hasn’t been well defined in the past. And so it would just be, it’d be, I’d be really curious to hear more about that portion of of your guy’s story. I
Hubert Lim Ph.D. 33:26
could probably start here. Um, there are a few things, right? Like one, you know, I think probably David you’ve heard before is, you know, the control condition and the sham, right? This has always been coming up. And, you know, what people may or may not know is that the bimodal stem approach. And we started in Europe, and in Dublin, Ireland, particularly people already aware. I was aware of the technology. I googled it. I knew mute button at the time. That was the name of it. And so, you know, and it’s super threshold, the tongue, you can feel it, the sound, you can hear it, and you might be able to trick some individuals into saying, Hey, you’re getting stimulated, you know, but you don’t feel it. But there’s a lot of risk there to try to design a study based on deceit, to have a sham control, because that if it is a good design, but if it fails, that it’s it’s kind of the worst design you could do if you have that bias, right? So we there’s no way we could have, I know people say we could have, but we thought about this early, and even FDA through the discussions, you know, we couldn’t come up with a solution. There was not a blinded, Sham control way to do the study. So the alternative, which is actually, my opinion, a more rigorous design, is to do an active control that’s harder, because you’re actually trying to find differences in effects that are you’re expecting, but one is going to be more effective than another one, right? And to me, that’s actually the true gold standard, because that can be fully blinded, you know, there’s no questioning, were they really, you know, thinking that they got the treatment or not? You know, even though they got the sham, and also you can actually look at parameters and so forth. So all of our studies, 10 a one and 10 to a two were designed that way, with active controls, right? So that that that’s how we designed it. We explained that. But somehow, I don’t know, Ross, we probably maybe could have made some more visuals or something to help people understand that. But that was something that we did hear a lot about, and when I explained it to people just sitting down and chatting, people got, got that point, right? So I would say that that’s one. The other is parameter optimization, right? Where do you start? Because you have so many settings that you have to look into. You know? It was the tongue parameters, the sound features, the timing, the different kinds of background sounds. And so, you know, you could either do like 10 settings and do 10 patients each or participants. But then we’re back to the challenge we discussed before with the small numbers with medtech, right? So what we did was we actually bundled, we bundled a lot of settings together in, for example, 10 a one was three arms, and there were three bundled settings that had many things or multiple things that were different across settings. And, you know, there’s criticisms there that, well, how are you going to know which it is if you’re changing so many settings, you know, across, across the arms? But this is the strategy we took, you know, pros and cons. People may have their view if that was, you know, the best way or not. But we we took that strategy and we did that through 10 a one and 10 a two. And what ended up happening then is that we start to narrow in and so from 10 a one to 10 a two, and finally, when we started approach 10 a three, we realized the critical things ultimately are tones and tongue stimulation, and, you know, pairing in a precise timing and, and I’m not too shocked by this is that it doesn’t have to be on the millisecond level. And when you think about Pavlov’s dog, actually the salivate. You know, the dog salivating also happened to the footsteps of the person bringing the food when they heard the footsteps out. So, you know, there is some, some window there. But the key thing was paired Association, to certain extent, with tongue stem and sound right tones, tongue stem and tones, and then 10, a three, then led where FDA said, Okay, now you need to show that. Yes, it looks like both are critical. But you need to show that with the tones. And then you add the tongue on top of it, that the tongue stimulation provides additional critical benefit above the tones alone. And that was what FDA wanted us to prove in 10 a three, right? So that’s the progression that happened. We narrowed it down, and FDA said, this is the last piece you got to show that that’s effective. And that’s what we achieved in 10 a three,
Ross O’Neill Ph.D. 37:38
yeah. And what I’d add to it is, I think, you know, it’s important for people to realize how challenging or how high a bar that is. So the patient’s got six weeks of sound alone. So they’ll, they’ll, you know, sound therapy was already a kind of one of the standard of care, standards of care. So, you know, they will have gotten benefit in that first six weeks. And then when we introduced the bimodal that the tongue stimulation, they wanted to see, you know, additional and synergistic benefit that outperformed what they saw in the sound therapy alone. So that’s like, you know, if you go to the doctor and, you know, you get a an antibiotic or something, you know, it will do, you know, a lot of the of the the handling the infection or whatever. Then if you get any additional medicines after that, they’ll they should have marginal benefits, right? Still, because the first one has, has done the bulk of the, the heavy lifting. Now we have to show that the second intervention outperformed the first one, you know. So it was, it’s an incredibly high bar, yeah, so it’s, it’s so I think a lot of the subtlety of that is missed on a lot of people. You know that, because usually you know, when you give a second medicine or a third medicine, the additional benefit is only, you know, minorly incremental, whereas this, we had to say, show it outperformed the first one.
Hubert Lim Ph.D. 39:02
Yeah, but it’s actually even more intense than that, David, because it’s, you know, it’s like, let’s say you get 40, like, 30% benefit in the first phase, or 40% that means that you can’t just get 40% after. You have to get like, 60% right? That means you have to have a increasing slope of benefit. So it’s, it’s like, I mean, that’s after they already got benefit. Then you’ve got to show what happened in the first stage of sound and actually beat that. So you’re, you’re getting an increasing slope of benefit, which, you know, of course, when we heard that, we’re like, oh, geez, that’s like, that’s not even compared to Sham. I would have taken a sham control any day, because that’s just showing benefit to, you know, placebo, we’re talking about placebo and sound effect, and then surpassing that after we’ve already had benefit in the first stage. So that that was, that was a bit, you know, I mean, if it didn’t work out, we wouldn’t know if it was actually beneficial or not, because if we had done it to Sham, it could have been better than Sham, right? And placebo, yeah, that was. That was a risk, you know, yeah,
Ross O’Neill Ph.D. 40:01
Sham study would have been easier, you know, yeah, yeah, and so. And I think that, I think people who are particularly people who’ve worked in active land, implantable devices, or they get that right, they get how, how, what a high bar this is to overcome. And, and I think people are starting to get at it and starting to appreciate it, and, and, you know, if people read the paper, as I said, it’s the currently, the the cover story on nature comms. So if they go into Nature Communications web page, you’ll see it there. And, you know, read the paper, it’s, it’s, it was a high bar to overcome. So it’s, we’re very proud of it as an achievement. If
Hubert Lim Ph.D. 40:38
you allow me to be a little bit geeky here, David, so Nature Communications is a very top journal. They don’t, they don’t accept a lot of papers, and then they publish, because it’s an open, open journal, they publish, you know, few 100 papers a month, right for all different categories, and they pick one paper, one paper, to put on their website for multiple weeks. And that’s our paper up there. So I was really proud. That’s really that, yeah, I mean, that’s and it’s up there. You go to the website, the main page, and you see our featured paper. And so it was a it was nice to know. And by the way, we put up, like I said, transparency, the reviews up there, our comments are up there. Our data is up there. I mean, I don’t know what else more to showcase, unless they show the inside of my body, you know, then put it up there too. You know, it’s, it’s like, Great, yeah.
Dave Kemp 41:30
Well, I’m really glad though that, like, I know that we kind of got into the weeds a bit there, but I think it’s actually really important to illustrate just what a high bar that you guys had to clear was, which I think really does validate the legitimacy of this. I mean, to your point, I didn’t know that about the the FDA and that, you know, you had to basically show that it outperformed, and, you know, something that has already existed, which are the sound therapies. And so you had to prove that there was an incremental benefit that that was even greater than the whatever that ceiling is, I guess. But I think that that really helps to illustrate, like, we’ve been operating at a ceiling, you know, you can basically provide this much marginal benefit for somebody, and you’ve shattered that, and you guys are proving that there’s actually a lot more room of benefit that you can provide people, which I think that it was probably a pretty challenging study to go through, but by being on the other side of it, in the way that you are, it’s kind of undeniable that you’ve gone through a really rigorous methodology here that really illustrates the efficacy of this versus The kind of the status quo. Yeah,
Ross O’Neill Ph.D. 42:41
I think, and like, I don’t want to denigrate the hearing industry, you know, I think it’s an amazing industry. And, you know, my own daughter, it’s as as hearing loss issues and benefits from the technologies that the the industry develops some you know, listen, I work in the industry. I’m wholly committed to it and but I think that notable regulatory approvals are probably rare enough, because, you know, it’s probably FDA clearances. So when you see products are more more likely to be FDA cleared, which means that they’ve, they’ve gone via the 510, K so they didn’t really, they didn’t have to go through the rigors that we had to go. We’re FDA approved, and that’s a big difference. It’s another thing that I’ve, I’ve found people and don’t quite get the subtlety of the difference between the two. We had to actually put clinical data in front of the the the FDA, you know, their statisticians, their Ents, their audiologists, their, you know, all of their experts had to, you know, go through a rigorous review of that data and and approve this product on that basis. So it’s, it’s quite unique in that regard. And you know, that’s why, you know, listen, anyone who, who you know is unfortunate enough to follow me on LinkedIn knows that one of my favorite hashtags is first and only, you know, I’m just incredibly proud that we, we put everything on the line for that, for that approval, and we are the first and only FDA approved by mobile device for the treatment status. So very proud of that piece of work. That’s
Dave Kemp 44:20
awesome. Okay, so I know we’re getting tight on time here to kind of wrap up, I wanted to, you know, kind of bring this whole thing, you know, to its conclusion, talking about where you are now, like I said, it was at all over the place, at at Ada, and it’s just kind of been the talk of so many different conversations that I’ve had. I think people are genuinely, really, really excited about this. I think people are trying to temper expectations even a little bit and try not to get too carried away. You know, I know that at the booth Ross, we were talking, I was talking with, with Emily, you know, up in Alaska, and it sounds like you have an efficacy rate. Rate of about 92% so the question is, you know, well, what’s going on with those 8% of people? And so I guess it’s kind of this, like never ending pursuit of, how do you make sure that this is as universally applicable as possible? But I wanted to give you guys a chance to just kind of close this out here, talking about, you know, where what that real world data is showing, sort of these earlier, early results from the from the clinicians that are linear certified, I think you know, even maybe talking about this network and and how you know you can join it as a clinician, what, what the plans kind of look like, from that standpoint, I think in 2025 I think a lot of clinicians are going to be looking at this as something that they are very intrigued by and would like to get involved. And so I think here’s a good opportunity to kind of share with them what the vision is in terms of building out this network, and kind of what you’re seeing from these early adopters. Ross,
Hubert Lim Ph.D. 45:59
maybe I’ll just talk briefly on the clinical side, and then you could close it up, you know, in the closure here. But this is the thing, like, I’m a scientist when it comes down to it, and I’m never going to be happy or satisfied with where things are unless it’s 100% and that will never happen. So in other words, my whole life, I’ll never be satisfied. That’s certainly what it got. But like that in our studies, with our current version, it’s about two thirds that we’re seeing in the clinical trials. And I was already, you know, our team was already quite happy with that in the US, at least. You know, it was quite astonishing to see when you add in a lot of these other factors, because in the clinical trial, we try to keep it treatment and move it along, move it along, but systematically. And you know, you always wonder, when it goes to real world, how it’s going to behave, because it’s not so systematic. And we thought, okay, might be a little bit lower, you know, maybe 50 to percent to two thirds right now we’re hitting 80 to 90% in these clinics. And I think, you know, honestly, it’s a lot of other factors that are contributing to that level of success, right? That are 90% you know, Emily’s just amazing, you know, caring person who’s treating these tinnitus patients. And you add in some of the other things that she’s observing and helping with them, combined with Lenire, and we’re hitting that level. I will say that for me personally, and Ross, you know, we talked about in the company side, we want to make the treatment also better, in addition to, you know, these other factors that will contribute, and so we are looking at ways to make the treatment more customized for each individual. Because it’s not, it’s a one size fits all, right? Well, it’s not one size fits all I mean, we calibrate to the audiograms, and we do some other things, but in terms of the tinnitus itself, we do want to make sure that the stimuli are presented that are going to be optimized for each individual. And I do think if we move that direction, you know, on a general scale, we can get that higher to, like, 70 to 80% and then you mix that in with a lot of these other factors, you know, we will start to approach 90 to, you know, not 100, but 90, 95% across multiple clinics, right? So that that’s my, my, my hope, from a scientific, clinical perspective. And we are moving in that direction because we don’t want to stop, or we want to keep get better and better, and so that that from our clinical science program, that that’s, that’s our goal there. And I’ll let Ross talk about, you know, the other business and more access site too, right?
Ross O’Neill Ph.D. 48:18
Yeah, well, let’s say is, you know, Hubert said, you know, we, we saw a certain efficacy rate in in the clinical trials, and we’ve, we’ve started talking about it in terms of the three P’s. And so in the clinical trial, we evaluated the product as a standalone, you know, that intervention, but layered on top of that. Now, in the real world, you know, we, work with the best providers, and we make sure that they, you know, are trained and and work as per the best processes. So it’s it’s product, provider and process, and, you know, as we roll out across the US, and we have our provider network now, and what we’re seeing is that the the addition of those of the provider and process laid on top of the the product, you were seeing efficacy rates, as you said, in the 1880 90% where, and in addition to that, responder rates, we see mean improvements that are in the 30 points, 40 points, 50 points. So. And I would say that we’re, as Hubert says, we’re like, we’re wholly committed to to improving on all fronts, and so that’s what we’re really trying to do. Our mission is to advance tinnitus education and care for providers and patients. You know, so, and I think we’re building a movement now around this, I think there’s a lot of excitement. People are hearing about the real world results, and we’re getting a lot of enthusiasm at the at the provider level, it’s always been there. At the patient level, patients have always been looking for a solution for tinnitus, and I think we’re at the start of a very exciting journey. And it’s only going to get better from here. And, you know, I think it’s a it’s a great time. You know, we’ve just heard that Apple are moving into the hearing space with over the counter. So I think, you know, the industry is there’s going to be a lot of changes and a lot of exciting dynamics. And what I would say, it’s a really good time for audiologists to think about clinically specializing. And tinnitus is just a hugely it can be hugely challenging, but it’s a hugely rewarding field, because, literally, some of these patients are so incredibly impacted, and if you can turn things around for them, the the improvement in quality of life and how appreciative those patients are, it’s quite dramatic.
Dave Kemp 50:52
Couldn’t agree more, I’m I’m really excited from that standpoint, I think that it couldn’t have come at a better time to have a company that’s really offering tinnitus therapy and treatment, and I think that it ties into a lot of what’s been discussed on this podcast about the the sort of existential need to specialize, particularly as An audiologist. And I think that this presents a really interesting avenue for people that can offer this that we know there’s so much crossover between the patient demographic and, you know, for the longest time we’ve had, we’ve had treatment for hearing loss, but we haven’t for tinnitus, and so the thought of that becoming resolved, we’re talking about, I think, a total addressable market that could quite literally be bigger than the hearing loss market. So anyway, really, really exciting stuff could not thank you guys enough for coming on and sharing all this information. I’m really excited to see what 2025 holds. I know that there’s, there’s a long line of providers and clinicians that are very eager to learn more about this and potentially become a provider. And I hope that in 2025 we see this really expand in a big way. And you know that that all the different people out in the country that are dealing with debilitating tinnitus. Hopefully it becomes as easy as them just finding where their closest linear provider is. And people really starting to see this, I have to imagine that, you know, as things really start to get going, that the sort of compounding effect of the word of mouth the power of that, when physicians and other medical professionals start to get wind of this becoming an option and that it’s dispensed through an audiologist, you can kind of see how this could really actually be a game changer, and not say that, you know, just sort of as like a cliche.
Ross O’Neill Ph.D. 52:59
Yep, couldn’t agree more, awesome. Thank
Hubert Lim Ph.D. 53:02
you. Thank you David for all saying all that, absolutely
Dave Kemp 53:06
awesome. Guys. Well, it’s a real pleasure to have you on today. Thanks so much for everybody who tuned in here to the end and we will chat with you next time. Cheers. You.