Tinnitus Hub Meets Neuromod (Q&A)

(cheerful music) – So, here to do the Q & A for Neuromod Devices – and if you would like to
introduce yourself, Ross? – Yeah, so my name is Ross O'Neill; I'm the founding CEO of the company. We started it back in 2010 as a spin out of Maynooth University to commercialize some
research that we had worked on in that university.
– Yeah. First thing, looking at a little bit
of history on the device. You obviously came on the
market right about 2015, and then you backed away from the market.

So, what happened there, and why did you back away? – In 2015 we'd
completed the TAVSS study, which was a 60 patient trial to demonstrate the initial safety and efficacy of the device. That got us our CE mark, which allowed us to market
the device in Europe. Based on the results of the TAVSS study and the CE mark we opened a clinic here in Dublin. It was open for one day
a week for one quarter, and in that time we sold over 100 devices. But, at the same time we were raising a venture capital investment to pursue FDA approval; [and] part of that process involves conducting very
large scale clinical trials. We're a small organization, we've got limited resources, so, we decided at that time to focus those resources on completing those clinical trials, and we paused commercial
sales at that time. We paused commercial
activity here in Dublin, and we didn't open any other clinics across
Europe at the time. – What have you learned from
that time period up until now? – We've done two major trials.

We've done TENT-A1 <i>(Treatment
Evaluation of Neuromodulation
for Tinnitus – A1)</i> which is now completed – the patients completed treatment and also [a] 12 month follow-up. That was a 326 patient trial across two sites: here in Dublin and also Regensburg in Germany. Berthold Langguth, who
a lot of people know, he's the founder of the Tinnitus Research Initiative
(TRI). He was the principal investigator (PI)
[in Regensburg]; he is also on our science advisory board. And Mr. Brennan Conlon, who's a
leading ENT here in Ireland, he was the PI on the Dublin site. We completed that trial, and that was a parameter optimization and patient subtyping study. That was about looking at a number of different stimulation
settings on the device and looking at the
effects of those settings both in the wider tinnitus population, but equally in patient subtypes. So, this idea of patient subtyping is something that's emerging from the work of the TRI.

As you know, they have working groups on this. And, there are definite
groups starting to emerge: there's hyperacoustic tinnitus patients; there's somatic tinnitus patients. So, we wanted to see if any of these groups
differentially responded to any particular set of parameters. So it's very much in line with the most cutting edge research that's being published right now. – So effectively, originally
you started with tinnitus [in general], and then you've moved on [to] looking at the subtypes and just looking at how it affects diff-
erent people with… – Yeah, our approach
was this high frequency synchronous stimulation. – So, our approach is that we simultaneously stimulate the auditory [nerve] using sound, and the trigeminal nerve via the tongue. And our approach was to
use this high frequency synchronized stimulation. But, there's a lot of literature emerging that different parameters might drive different effects in different subgroups. So, what TENT-A1 has shown us is that high frequency
synchronous stimulation, which was always our approach, remains effective in the majority of the overall tinnitus population; but, [the trial] also has identified a number of highly
responsive subtypes, one of which are these
hyperacoustic patients – so these are patients that have both tinnitus and hyperacusis.

– The response rates that we're seeing in that group are much higher, [and] the levels of response
are much greater. What we've learned from this study is, we've learned to prescribe the device more effectively – so we target it. And we've also had some learnings around stimulation settings, [so] that we can derive further benefit than we did before. – Just sort of segueing a
little bit into hyperacusis: was that something you
were actually expecting, or is this something that
just kind of jumped out from the study? – No. In line with best clinical practices – you will see that the involvement of another member on our science advisory board, Professor Deborah Hall, who's been one of the most vociferous proponents of clinical rigor in clinical trials in tinnitus – one of the things you do is, you pre-publish your protocols – your clinical protocols – before you do the study.

So, we published the protocol of the TENT-A1 study in the British Medical Journal (BMJ), and that's freely available on our website, and [it] is also open access on the BMJ website. And one of the groups that we pre-specified that we would look at were
these hyperacoustic patients. So, we looked at those; [we] looked at a number of other groups; but [the hyperacoustic patients]
really emerged very strongly as being highly responsive to this high frequency synchronous bimodal stimulation. – So, did you
find equally it helped the hyperacusis and the tinnitus, or was there a bigger
effect on the hyperacusis? – No, and that is a very important point – is that these are tinnitus patients who have a concomitant hyperacusis, but what the data is saying to us is, it's not a treatment for the hyperacusis. So – we defined hyperacusis as sound sensitivity to loudness discomfort levels (LDL) of 60 decibels sound level (db SL)
or less; and when we looked at the [hyperacoustic patients']
LDL scores before and after, they hadn't statistically changed, but, their tinnitus scores
changed dramatically.

Now, we did another
piece of rigorous study – we looked at: did we just get lucky with that definition of hyperacusis? So, when we correlated all of the
patients in Arm 1 of the study – [when] we correlated their
level of sound sensitivity to the amount of [tinnitus]
improvement that they got – there was a very very strong
correlation between the two. So we know there's something special going on with these patients. – Did you distinguish
between pain hyperacusis and sound tolerance hyperacusis, or, potentially there's six
definitions of hyperacusis – [or] was it just hyperacusis as a complaint? – Our definition of it was patients who reported sensitivity to sounds of 60 dB SL or less. So, we didn't distinguish. But, now that [this subgroup
has] emerged, obviously we are going to
investigate that further and try to understand it a lot more. – [Regarding the] safety profile,
again for hyperacusis – of course, we are talking about patients who do not want noise. How do you manage that? Is it the device settings? Is it just [that] the volumes
are [at] quite a low level? Do you manage the tone, so that it doesn't
irritate hyperacusis? – The device is configured for your hearing levels to guarantee a minimum
level of stimulation in your lowest hearing boundary, or your least effective hearing amount.

So [the hyperacoustic patients]
got the same kind of configuration as everybody else. What we did see was that the compliance levels – compliance levels in the study generally
were very very high – they were about 83+ percent. Now, they were equally high
in that hyperacusis group. As you say, these patients are normally kind of averse to sound stimulation. So, the fact that they are so compliant to treatment is telling us that they are definitely
perceiving the benefit, because if they weren't, given that they are so averse to the sound component of the treatment, they wouldn't be so compliant. – Can you give us an explanation of exactly how the device works? Maybe start with, is it calibrated to the individual? – Yeah, so it's calibrated
to the individual in that it's tuned to their hearing profile; not their tinnitus. – We want to ensure that we get a minimum level of stimulation at their
lowest hearing level, in whatever frequency that is. So, it requires an audiogram, so they would have to see their audiologist to get that, and then that is used to personalize
the treatment for them.

How the device works – it pairs proprietary sound, which is a combination of both tones and some noise; but the tones are paired with trigeminal nerve stimulation via the tongue. How we do that is with this small electrode, this intra-oral electrode,
called the Tonguetip. It's a lot like a lollipop. So, the patient puts that on their tongue. It has 32 electrodes on it,
16 [on] each side, and basically, the tones that they get, that they hear through the headphones, are then paired with pulses on the tongue. It's very mild electrical stimulation. People ask what it feels like; I describe it a bit like those pop rocks, you know, pop rocking candy; but it's not as strong as that – that's going to be quite a vigorous kind of experience; this is much milder.

And basically, it pairs
those two stimuli together, and you undergo 30 to 60 minutes of that treatment every day for a minimum of 10 weeks. In the most recent study, patients underwent 12 weeks of treatment. So that's basically how the device works. – What about [re]calibration? Do you have to bring people in to recalibrate the device? I know we've looked at other audio treatments where there might need to
be some [re]calibration. – No, so unless your
hearing profile changes – [and it] tends to not change dramatically over the course of 12 weeks unless you've been exposed to loud noise or something – then it doesn't require any additional calibration, no. – So again, because you're not
matching to the tinnitus tone, [rather] you're matching a particular
sound, say a proprietary sound, it doesn't actually have that same issue with calibration. – Okay, I have heard of other therapies where you have to tinnitus match and then set notch filters or something like that, based on the tinnitus tone. [But] our device is personalized to the hearing profile, and not the actual tinnitus.

– In terms of using the device, there will be a fitting, there will be a calibration and then the person takes
it away and uses it at home? – Yep, so they take it and they use it in the comfort and privacy of their home for 30 to 60 minutes per day. Again, we have involved patients, doctors, ENT doctors, audiologists from the very start, while we were designing this technology, and we've listened to their input and we tried to satisfy
the needs of all – and one of the things the
patients said they wanted was something that they could use at home. They were resistant to things that they had to use in public, and they were particularly resistant to walking around with a Tonguetip in their mouth (laughs) in public, so they said: "Look, we are going to
have to use this at home." Now, as it turns out, our treatment regimen was being informed by a growing body of literature and research across a number of universities across the world.

It turns out that 30
to 60 minutes per day was what was emerging as the ideal treatment session time which was enough to drive therapeutic effects but
not be such a burden on the patient that their
compliance rates would fall off. So, in the TENT-A1 study for example, patients came in, they were fitted with the device, they went home, they
used it for six weeks, 30 to 60 minutes per day; they came back in after six weeks, we had an interim assessment with them. on the device, we assessed compliance. So, everything – all patient interactions with the device – are monitored. [We used] embedded logging on the device, so we know if they do – if they have any interaction with it – if they pick it up, press buttons – we even know if it's making
good contact with the tongue – there's contact sensing on
the Tonguetip electrode.

– We know the level of stimulation being supplied [by] the Tonguetip. We tracked compliance
very, very tightly. And what we saw was that
compliance was extremely high in this trial – it was 83+ percent. And, as I mentioned, Professor Berthold Langguth
is the PI on the German site – he has done multiple clinical trials in the field of tinnitus, and he said that the compliance rates that we're seeing in this study are very high compared to other trials.

That tells us a number of things: that the patients liked the device, but also, the patients who are experiencing benefits – it gives you almost a kind of sanity check – the patients are experiencing benefit, because if they weren't, they'd generally give up on the treatment and become noncompliant. – In terms of the way the device works, is it neuroplasticity based? – There's a lot of talk
about bimodal stimulation, about its preparing the brain and then delivering a
signal to the brain – is it [effectively] forcing
the neuroplasticity, in terms of your device? – I think the easiest way to explain it is to first explain the mechanisms that we believe are underlying tinnitus, and then talk about how the
device interacts with those. I often describe – we believe that tinnitus is, for the majority of cases, related
[to hearing loss]; and while there is a causal link yet to be proved, we believe that it is
related to hearing loss. I often use the analogy of an electric water pump. If you starve the supply of an electric water pump – practically bend the hose
of the water going in – the pump will oscillate
in a desperate attempt to try to suck in more water.

And we believe the same thing
is happening with tinnitus: when hearing loss occurs, the brain tries to fill
that gap with noise. And we see this in hyperactivity in auditory brain stem structures like the cochlear nucleus,
inferior colliculus, thalamus. So, you start to see that noise in the system following hearing loss. And we believe that that noise ripples up to the auditory cortex, where it's actually perceived as noise; and from there, actually what happens is that the condition becomes habituated by forming
a network with emotional and attentional centers that can feed off each other and habituate the problem.

So, we are using bimodal neuromodulation to try to disrupt and even reverse some of those neuropathologies. We know that bimodal neuromodulation – when you combine auditory stimulation with trigeminal nerve stimulation – that it has inhibitory effects in some of these lower order structures. We know this from the work
of Professor Hubert Lim, who recently joined us as our chief scientific officer; and other researchers
– Professor Susan Shore, in the University of Michigan. So, we know that this bimodal
stimulation has those effects, and we know this from animal studies, which were invasive, [where] we looked at these structures and [saw] the actual mechanistic effects. So, our idea then is to combine those two forms of stimulation. And we also know that, as you said, when you pair sound with electrical stimulation again and again and again, it drives these neuroplastic processes which lead to long-term effects.

So, we're trying to disrupt
these neuropathologies, and then, through repeated stimulation, make sure that that benefit is long-term, by driving this
process of neuroplasticity. – Is it designed to the actual individual's tinnitus,
the sound they listen to? – It's not. As I said, it's personalized to their hearing loss. We see tinnitus as a stimulation problem. When we approached this – when we were working
on it in the university – we looked at auditory stimulation alone, and we said, okay, there is – especially in cases where there is greater
levels of hearing loss – there is a fundamental limitation
to that therapy. Because – again, using
the water pump analogy – if the supply is restricted
due to hearing loss, there is only a certain amount of stimulation [that] you're going to get through to the ear,
due to hearing loss. So, we started looking at – okay, how else can we stimulate
the system? Now, there was a growing
body of literature – there were people like Bob Levine, Charlie Lieberman at Harvard – and they were all pointing towards this somatosensory side channel that innervated the auditory system and in fact was acting as a kind of inhibitory input into it.

So we said, okay let's try
to exploit that; let's pair sound stimulation in these damaged hearing bands with this inhibitory
trigeminal stimulation, and drive it again and again and again to disrupt these neuropathologies that are causing the tinnitus, and then drive long-term – if you'd like – hardwire that disruption into the brain through
repeated stimulation. – [A] question that people have asked is about tinnitus – so effectively the tone of the tinnitus – because a lot of people are reporting tinnitus tones that are above their actual
hearing capabilities. So effectively that tone is irrelevant, to what you are doing, because they can, where there are other audio treatments [that] say: "Well if your tone is above say 10 kilohertz
or eight kilohertz then we can not really
effectively treat it." But yours is kind of more of a universal thing if you like. – Exactly. So it's that the tonality, atonality, pitch of the
tinnitus is not relevant to the therapy.

– All right, so again with multiple tones, – Exactly. – Whether they've got one or whether they have got 10 [tones]
or what. And again with the fluctuation that wouldn't have an effect at all? If somebody had a fluctuating tone, whether they got
one tone one day, one tone another day, that wouldn't make a difference to actually tell the truth?
– No. – Neither tonality nor laterality, centrality,
they don't matter. As I said, we are approaching it from a stimulation perspective. It's about getting sufficient stimulation into these damaged bands, because the brain is making up the loss of sensory input, filling it with noise. So we are trying to get
more sensory input in there. The brain cannot live in
a sensory vacuum, it abhors. This is the reason, and I think it was Roland Schaette in London, [who] showed that if you use earbuds and kind of hearing protectors, and you deprive the sense of hearing for a period of time, I think it was weeks or months, that you can actually induce tinnitus. So that kind of shows that central gain phenomenon.

So we approached this initially from that kind of perspective. So we are independent,
or we don't really care what the actual perceptual manifest is, or the tone of it if you like. – How does it actually help the tinnitus? What were your primary outcomes? Were you looking at loudness? Were you looking at bothersomeness? What were you actually, what have you measured a reduction in? – So in the TENT-A1 study, the two primary outcomes were
THI <i>(Tinnitus Handicap Inventory)</i>
and TFI <i>(Tinnitus Functional Index)</i>. We also measured Minimum Masking Level. And basically the patients, as I said [when] they were enrolled at the start of the study, we took their baseline scores in those outcome measures. Then they took the device home. They used it for 30 to 60 minutes per day for 12 weeks. We also saw them at the interim point which was at the six week mark.

We measured THI, TFI, we measured MML and a number of other exploratory outcome measures as well. Essentially what we looked at were the 'within arm' changes. The patients when they came in, as I said, they were randomly allocated to one of three arms. Each arm got a different set of stimulation parameters. There was our preferred approach, which is this high frequency
synchronized stimulation. There was another one that was high frequency asynchronous
[stimulation], that was looking at the effects of delays in certain sub-types. And then there was another, a third arm, that was more orthogonal to our preferred approach, so it's low frequency
asynchronous stimulation. And patients, all patients and researchers were fully blinded, so the study was was completely blinded. So nobody knew what form of stimulation the patients were getting. At 12 weeks they came back in, they handed in the device, we did the final assessment, then we followed up [with]
a patient [at] six weeks, six months and 12 months later to see if they were retaining effects. So to determine the efficacy
of the intervention. We compared baseline to final, and then we compared – so that was 'within arm'
differences or changes.

Then we looked between arms, so we wanted to see how the
stimulation parameters performed relative to each other. And then thereafter, then in the follow-up phase
[at] six weeks, six months, 12 months, we wanted to see if those therapeutic benefits persisted in the longer run. So both THI and TFI were the two primary outcome measures. MML as [an] exploratory [outcome]
along with a number of others. So what we saw was that, within arm we saw statistically and clinically significant improvements in all outcome measures. And then, what we saw was,
then in the longer term, in the longer term follow-up
over the 12 months, that high frequency
synchronous stimulation outperforms low frequency
asynchronous stimulation. So we saw a strong divergence between those two arms over the 12 months. – Did they both have
an initial positive effect? – They both had an
initial positive effect, but then where they diverged
was in the longer run. – So at the minute, obviously [there's a]
limitation on time because of when you've done the trials, so 12 months' data is what
we've got at the minute.

And are you gonna be looking
at returning to those patients, over the course of time to measure them even
longer term in the future? – So we don't have plans to follow up with the
patients beyond 12 months. So the study, as I said, the protocol was designed, published in British Medical Journal, before the study [was conducted] and the plan was: measured
treatment over 12 weeks, and then follow-up over 12 months.
– Yeah – So that's what we've done. – Which is quite
a long follow-up time. – Yeah, I don't think, I'm not aware of any other clinical trial that has done such a kind of a long-term follow-up phase. – Say for example you get a patient, that will come to you;
they'll do three months, [with] the device
and say they have an event a couple of years after they've used it.

Are they able to come back
and use the device again? Do you anticipate that it
will have the same effect on the patient? Because we'll have
anecdotal reports from patients, who'll have an event,
who'll go to a concert, who'll go to something, and the tinnitus will jump back up again. Is it something you envisage would be useful there? Would you put them through
a three month trial, a three months process, again or it would be a shorter process? – I guess we can't answer that right now. We can only, all we can say is what we
have clinical evidence for.

But if they have… And what we know right now is that if patients undergo 12 weeks of 30 to 60 minutes stimulation per day, the majority of these patients experience a 12 month benefit from that treatment. Now what happens thereafter, we'll have to figure out later. If the patient has a flare up later, and has to undergo another treatment, we will probably follow the same treatment regime. And your other question was around whether it would be as effective again. Again, we can't say [but] there's no reason why we
believe it wouldn't be. – So in terms
of the measured benefit, can you give like sort of
percentage improvements? I'd appreciate it.

Have you published it yet or? Or you're still awaiting publication? – So what we are doing right now is we're disseminating the results. So Professor Hubert Lim, who's
our Chief Scientific Officer, Mr. Brennan Conlon ENT, who's our Chief Medical Officer, also Berthold Langguth, who's on our science advisory board, Sven Vanneste, who's on
our science advisory board.

They have been presenting the results, of the study at kind of high level, [at] very prominent scientific
and clinical meetings, and the publication is in preparation, and will be submitted for
peer review in early 2019. How long does that take? So the peer review process can take, you can never say exactly
how long that takes. It depends what feedback the reviewers come back with et cetera. It will be published, it will be open access. All of our papers are open access. They're available on our website, and on publisher's websites, under open access. So we always make sure that the patients and everybody can get access to both our results and our protocols. So right now we're just
disseminating the results. You asked about in terms of percentage improvement.
– Yeah – So percentages, I guess, they can be a bit misleading.
– Yeah – What I can say is that over 80% of patients, reported some level of
[improvement of] their tinnitus, after 12 weeks of treatment, more than two-thirds experienced
a clinically significant improvement in tinnitus.

So if you look at it
in terms of percentage, it's over 30% average improvement, but that includes responders and non responders.
– Yeah. – If you just look at patients who responded to the treatment, that percentage would be higher. So there's a couple of caveats there, when you talk about percentages. – Yeah. So in terms of responders, do you have anything mapped out? Because we do come across people who are non-responsive to audio. Is there a group who are
gonna be in your studies, that are being non-responsive
to the treatment? – So part of the treatment, as I said, was about kind of parameter optimization, or stimulus optimization, but also patient sub-typing. So we want to move towards more targeted, personalized treatment. We want to identify, be able to clinically identify, who is responsive to the [treatment]? Who's very responsive? Who's responsive? And equally who is non-responsive? Like we don't wanna waste patients' time, if they're not gonna, if they're not candidates for treatment.

So what we know at this time is that patients who have tinnitus, and concomitant hyperacusis, are highly responsive to the treatment. The responder rates are
over 90% in that group. The levels of response
that they are getting are twice what the rest
of the people are getting. And thereafter, we know,
so there's that group of kind of super
responders, then there is just the rest, the tinnitus population.
– Yeah – And we know that two-thirds
of those patients get clinically significant benefit, from using this high frequency
synchronous stimulation. – Does the degree of hyperacusis matter in this case? Does it matter if they have it really bad, or if they've got it mildly? – So it does, interestingly enough. So we defined hyperacusis as patients who are sensitive to
sounds 60dB SL or below.

And as I said, when we saw this group pop out who were very responsive, we wanted to be sure, that we just didn't get
lucky statistically. So what we did then, we included all the patients in arm one, so all the patients that got high frequency
synchronous stimulation, and we correlated their
level of hyperacusis, to the level of improvement, that they registered after treatment. And it turns out those, there's a very strong
correlation between the two. So the more hyperacoustic you are, the more responsive you
are to this treatment, the more benefit you will get from it. So that's very very exciting.

Because this group, they constituted about 20% of the overall tinnitus population, and equally they have been a group, that have been difficult to treat, because audiologists have, when these patients come in, the audiologists have
predominantly sound based therapy stuff for them, and these patients are averse to sound. They're sensitive to it. So it's very exciting that we found this, that they're responsive because as I said, they've been a difficult
group to manage clinically, so now there's a very
strong evidenced option for those patients. But equally if they're
not hyperacoustic patients, then their chances of
responding are still very high. Two-thirds of patients
achieve a clinically significant improvement after 12 weeks of treatment. And as I said, then the majority of
patients seem to enjoy that benefit for up to 12 months
after treatment is stopped.

– I guess there's more
work to do on the sub-typing. Is that something that you're gonna be
able to get from the data you've gathered in the trial, by delving a little bit deeper into it? So–
– Yeah. – Are you looking
at causation of tinnitus? I know we talked about the correlation between hearing loss and tinnitus as being the primary thing, but are you looking at other causes, where there could be multiple? For example, the somatic diagnosis, is that one of your key drivers as well, having the somatic diagnosis? – So our inclusion criteria for the TENT-A1 study was that, they were patients who had
essentially neurological or subjective tinnitus, so we ruled out things like what I call mechanical etiologies — – Pulsatile.
– Pulsatile. If they had whiplash injuries, TMJ, things like that, those patients, we didn't
include those patients, because they have some kind of mechanical somatic component that may
be driving the tinnitus and they tend to be candidates
for surgical treatments, or other forms of treatment.

So we wanted to look at these chronic tinnitus sufferers, patients that had tinnitus for
three months to five years. So we looked, that was time the time range
we looked at in TENT-A1. In TENT-A2, which is another
study we followed up with, I haven't mentioned, but we actually extended that. We're looking for three
months to 10 years now. – So, sorry.
– Yeah. – Just to interrupt there. So the actual duration of
tinnitus in your studies, was that a factor with people, less efficacy if you've
had tinnitus for long? Or did they–
– So we have, as you asked about kind of causes, and things like duration, and we have an absolute
ton of data right now, and we're working our way through that.

And we continue to conduct
exploratory analysis, so we will get more and
more answers over time. In our initial look at it, duration doesn't seem to be a factor. You mentioned also then
that we looked at, you asked about somatic tinnitus stuff. Again, we're still looking at that. But the sole group that
have emerged most strongly, are these hyperacoustic patients, but we continue to
explore this incredible, amount of data that, we have to see if anything comes out.

Now we're following TENT-A1
with a subsequent study, TENT-A2, which has 191 patients. So in total they will be
more than 500 patients, so there's 326 patients in TENT-A1, 191 in TENT-A2. So taken together, we will have this very
large amount of data. So we hope to get a lot
more information from that. – Is there a timeline on TENT-A2? – So TENT-A2 is underway. I won't discuss it today, because you and I have
discussed in the past about Tinnitus Talk is actually, can be problematic in that if patients are on a trial, and they're talking about their experience on Tinnitus Talk, they may undermine the blinding.

So that is underway. Patients are moving from the
final kind of treatment phase, into follow-up now. But again they're still blinded. They don't know which arm they're on. So we won't talk about
that study much now. – So when is it due for completion? – Patients have now moved into follow-up, so that will be completed. I would say we have to
follow patients for a year, so I don't actually have a
date off the top of my head, but it will be, I guess it'll be around
12 months from now.

– Have you had any instances of people, either becoming worse,
or people who've said, they're actually cured of
the tinnitus in the trials? – So we're obviously very
cautious of the word cure, it's a kind of a double edged sword, the word obviously, organizations like the
Tinnitus Research Initiative, their motto is, together towards a cure. We are all working towards that. But we have to be kind of careful, and responsible with terms like that.

So what we can say is that, we had some patients who've had a very very
significant improvement, anecdotally they might say to you that, their tinnitus is gone, or has stayed away. But again, we need to be
responsible in reporting, those kind of anecdotal outcomes. But yes, some patients have had fairly life changing experiences. Have patients gotten worse? There were a small number of
patients who have gotten worse. Not dramatically, their tinnitus
might have gotten elevated. These patients they were asked, whether they wanted just to discontinue the treatment or continue.

A lot of them continued, most of those cases then resolved. So we haven't had any serious
adverse events on the study. And so we haven't had any very… …yeah well the term serious adverse events, so there aren't any patients, that we were very concerned about. And the majority of patients did actually, in patients that, some patients experience
some change at the start, which is probably to be expected, if you're doing something, and you're disrupting these
kind of neural processes, there is gonna be change, you are gonna notice changes, but over the kind of
12 weeks of treatment, the majority of patients improved. As I said 80 plus percent of patients who got a high frequency synchronous stimulation reported some level of improvement, and two-thirds of patients then achieved clinically significant improvement. – So in terms of safety profile, effectively it's proved. So this is our, we have done multiple
clinical trials at this point. So we've proven again and again and again, that the therapy is
both safe and effective. So TAVSS study (2014)
was with 60 patients.

That proved the initial safety
and efficacy of the device. We've now repeated the safety and efficacy
outcomes of TAVSS (2014) in TENT-A1. We're now in TENT-A2, where we're seeing, okay, we have the initial
kind of data but we're seeing very
similar things from that too. So we've repeated it
again and again and again; the device is very very safe in terms of, and I'm particularly conscious, these hyperacusis patients, who are so sensitive to
sound and they will be, they probably have a lot of anxiety about, treatments that involve sound. So it's important to kind of say that, the device is, both the headphones and the actual device itself, have got inbuilt kind of safety measures to ensure that they can't go above safe levels of sound. In addition to that the device is calibrated
for their hearing level, so it's very safe. And there was some minor irritation of the tongue reported from the, from the stimulus, but again, that usually resolved
if the patient stopped for a short period.

It resolved. So there were no long term adverse effects of the treatment. – In terms of just thinking about the hearing profile
of the individual. So you do actually have
to have a certain level of hearing to qualify for the treatment? – Yes. So I mean if you are profoundly deaf, if you're a patient that's
a cochlear implant candidate then our device in its current format, well, you're not a candidate for it. Because you have to have
a certain level of hearing still available to stimulate
the auditory system. The device could be used with cochlear implants in the future. We know that cochlear implant patients do suffer from tinnitus. We know that cochlear implants are very good at suppressing tinnitus when they are turned on, but unfortunately patients have to turn them off and take off the cochlear implant at night to go to sleep.

And what we have heard anecdotally from a lot of cochlear implant patients is the tinnitus spikes at night, which is not great because it's the time they are trying to get to sleep. So we in the future we
would like to look at cochlear implant patients and instead of having headphones as we have now, we will pair the device
with cochlear implants. – Thinking about
the headphones again, so we have covered the safety side of it, but because there are a lot of tinnitus patients who will say, well actually I don't want
to be wearing headphones, I don't want to be wearing
that because there is a number of people who feel that is possibly one of the things that's caused the tinnitus in the first place.

So again on the safety profile. You haven't had any
issues with the patients? – No. Again, there are very
strong safety directives from the European Union
about the maximum level of sound stimulation these
devices can administer. In addition to that, I know that the British Tinnitus Association have pointed to that longer
exposure periods of even safe levels can potentially lead to hearing loss and tinnitus.

But our treatment is 30 to 60
minutes per day in the trial. We fairly strictly control that. So patients could only
do one treatment per day. The device is very safe, can't deliver dangerous levels of sound. The maximum they could
set have been regulated by the European Union. It's a very safe device. In terms of the headphones, right now our device has Bluetooth over ear headphones, we will
see what happens in the future. Patients often say to us: "Well, could I use it with my own ear buds?" Or patients have asked us can they use it with their hearing aids because their hearing aids
are Bluetooth enabled. We are looking at that, but when you are doing a clinical trial, you have to do it in very controlled, you have to control for all
these different variables.

So the technology definitely
has to remain the same throughout the trial. You can not have that variability. So that is the current product format. – So would you end up having
to actually run another trial on hearing aids or another trial on earbuds to get the efficacy
for a different device? – Possibly. There are ways that if you have demonstrated efficacy initially using one technology, if you can prove another technology's technically equivalent
– so that, for example, that hearing aids can deliver the same types of auditory stimulation that we used in the trial – then there are regulatory pathways open that you can get those devices approved, but they have to be
technically equivalent.

The pain of tinnitus
is in different places for different patients. For some patients they say,
I cannot at sleep at night, so I am trying to get to sleep at night I'm distracted
during the day by noises, by talking to people. At night it's quiet and I can focus on my tinnitus and I cannot get to sleep. For other patients it's
about concentration, or it might be that it's intrusive in that they can't interact with their loved ones or whatever. So it impacts, while
the primary symptom is the same for all patients, it impacts in different
aspects of their life. And that's one of the beauties about the
THI <i>(Tinnitus Handicap Inventory)</i>
and TFI <i>(Tinnitus Functional Index)</i>. It looks at all of those. It's kind of almost independent of where it's having an effect. It averages them all. So, some of the patients report dramatic improvements in sleep.

And we talked about,
one of the questions was about comorbidities. So sleep is one of the ones that's included in the THI and TFI. And some of these
patients they talk about: "Oh, I was down to two
hours' sleep at night." "I was just just passing out
from pure exhaustion and now I am up to eight." They talk about having 12 hours' sleep, I cannot remember what that was like. (laughing) – Been a while since
I have been a student.

– Yeah, exactly. But some of them are talking about, pretty dramatic, but it's in different parts of their life. Other people talk about being "I'm less irate with the children", "I can concentrate better at work." So that's again as I said, what is so good about the THI and TFI, and that is why they are. And we looked at all the outcome measures
that you could possibly use in every clinical trial. We basically did a systematic review of outcome measures and
we found that the THI was the most widely used,
followed by the TFI. And then MML <i>(Minimum Masking Level)</i>. But a lot of people report
difficulties with MML in that, as I said, it's difficult if you've got two types of tinnitus which they then try and mask, the laterality of it, all that.

So it's difficult and if one form starts to come down then what
do you measure then? And you measured the other
part of it, it's challenging. – In the trials,
again because we often talk about this severe group. The one to two percenters
you would call them. In the trials did you have representation from that group? – No. So one of the inclusion criteria, one of the exclusion criteria was we removed or we excluded people that were at the floor and the ceiling if you would like. So the people at the floor,
they have nowhere to go they cannot improve, right? If you have got less than
10 points on the THI…

We do have people turning up to the clinical trial with very very low scores of THI. But as I said so, they have
no capacity to improve. So we want to look at the patients who have room to move
one way or the other. We also, for the same kind of reason, we look at, we don't include the top percentile of the patients, because we want to, as you asked about some patients get worse and better. We want to see as a group do they get worse or get better. And if they do not have
the capacity to get worse or get better then it's a problem. So you take out both of those ends. Also the really top patients, the patients who were scoring really really high on the THI and TFI tend to have a lot of
complex comorbidities.

And they tend to be kind of intertwined. So they can suffer from depression, anxiety, a lot of issues. A lot of them tend to be medicated or are using some levels of medication. So how do you tell that it's your intervention having the effect,
and not making some change in their medication? So that is the reason you exclude both of those groups. So what we can say is that again, we can only say what we have proven and what we have proven is in the TENT-A studies. The patients, from the moderate up to below severe, I would say below catastrophic. Those patients, if they undergo 12 weeks of 30 to 60
minutes per day treatment, they have an average improvement that's kind of double the published minimal clinically important difference. And that that seems to persist
12 months after treatment. – Are you able to
actually see how it works? Have you have got any brain imaging data or anything like that? – So it's difficult to see how
these things work in humans.

What we know is there's lots of animal data that shows that bi-modal neuromodulation
has demonstrated effects in the brain of animals. So both Professor Hubert
Lim, when he was working in the University of Minnesota
before he joined us, Professor Susan Shore, who is working in the University of Michigan. So they have lots of studies, and other researchers as
well, have lots of studies that show the effects of bi-modal neuromodulation in the brain. But those studies are
invasive, so we cannot conduct those studies on humans, but they allow us to see in great detail what is going on mechanistically. Now we infer that the same thing is happening in the human brain as what's happening in the animal brain. So then when we move over to humans, then as you alluded to, we've got brain imaging technologies, we've got MRI,
we've got EEG et cetera, ABRs, but they are not definitive either.

We have to look at changes
in brain signals, and again, infer what might be happening underneath from those
changes in brain signals. So they don't give
us a definitive picture and there is yet
this is kind of, well, kind of golden egg that we
all want, this objective biomarker of tinnitus. An electrophysiological
signal that we can say yes, that is tinnitus, that
has eluded us so far. We've got — people have different theories about different signals that
might represent tinnitus or changes in the brain related
to tinnitus et cetera, but again, we do not have it. So we cannot see exactly
what is happening; what we have is, we can see what is happening in
the brains of animals. We can infer what is happening in the brains of humans. Now we've got some brain imaging data that we can loosely probe, we can infer insights from that. But for us, our view on it is to do large-scale clinical trials with hundreds of patients and
measure the clinical outcomes of the treatment.

It's like a person who worked in the pain field said to me:
It's about how many people you get back to work. So we want to help patients
to improve their sleep, their concentration, their irritability around their family members, wherever tinnitus is impacting their life, we want to improve that. So we have done large-scale clinical trials with lots and lots of patients, over 500, including these latest two trials. And we are looking at the
psychometric outcome measures that I guess include all of
those impact areas of tinnitus. – What is the science
behind using the tongue? Why the tongue? Why not the temples? Why not the earlobe? But why the tongue? – So you can stimulate
the trigeminal nerve kind of anywhere in the face or neck. The reason we chose the tongue initially was that it is one of the most densely
innervated parts of the body. The fingertip is the only other part, as densely innervated.

It also doesn't have the epidermal layer. So in terms of stimulating it, it's very easy, you can stimulate with very low levels of energy. It's very safe.
It also has, luckily enough, has its own electrically conducting electrolyte which is saliva, and it's replenishing all the time. So it's just an ideal site to stimulate. But Hubert Lim, and this is when he was
working independently of our company, there were
three groups as I said, kind of working on similar technologies. There was us, there was Hubert Lim and there was Professor Susan Shore. And Hubert published a paper
in Nature Scientific Reports where he looked at
different stimulation sites and he identified that the tongue was actually the best place to stimulate.

So we had chosen it for, I
guess for engineering reasons, and also for neurological reasons, but then he confirmed in
these animal studies, where as I said, you can see in very fine detail exactly what's happening in the brain. – With using the tongue… We have touched on the safety profile. But is there any risk of damage to the tongue, to receptors on the tongue, through the treatment? – So again we have done
multiple clinical trials now and we have looked at
safety in all those trials. So we have got pushing on
6-700 patients now that we have safety data from. So all of these patients have used the device 30 to 60 minutes
per day for 12 weeks. What we are seeing is that
in a small number of cases there can be minor
irritation to the tongue, but if the patient discontinues treatment for a short period of time,
that usually resolves. We have not seen any long-term deleterious effects of tongue stimulation. – Why did you use
audio rather than another form of stimulation in particular? – So again, we approached it
from that tinnitus was arising from hearing loss and it was
a stimulation of the auditory system problem, if you like.

So again, loss of input through the ear, leads to hyperactivity
in the auditory brainstem that ripples up to the auditory cortex where it's perceived as sound. So we want to stimulate
the auditory system, so we are looking at supplementing
the auditory stimulation with somatosensory stimulation. There are papers, again Hubert
Lim, other people have shown that if you stimulate the
somatosensory system alone, the trigeminal system, you can stimulate the auditory system.

But it actually has adverse
effects on the auditory system. So somatosensory stimulation alone is probably not advisable, or at least that is what some
of the science is showing us. – Have you gathered
any data around children at all or was it all adult population? – Our clinical trials only
included patients over 18, so we have no data for children. So the device is not currently
indicated for children. – In terms of release of the treatment, I appreciate certain things we
can and we can't cover on this, but I'll ask the questions anyway: When is it scheduled to release? Where, you're looking at Ireland first? – Yes, so we have, as I
said, we have CE marking which allows us to market
the product in Europe. We've had that since 2014. So we're looking at initially,
making the product available in 2019 in Ireland. Thereafter, we're looking at a number of other European countries and sites. And then in parallel, we are
going to pursue FDA approval. So we have appointed leading FDA experts and now we're working
towards getting FDA approval so we can launch it in the US.

So it will be available in
a limited capacity in 2019 in certain European sites. Ireland first and then from there then we'll make it more widely available both in Europe and in the US. – Are you able at the minute to say anything about
the price point or not? – So the price point is to be determined, as I said we literally,
since 2015 we have focused… Again, we're a small company, we have focused the limited resources of the organization exclusively on this pretty extensive
clinical research program. It's one of the largest
clinical research programs that have been conducted in tinnitus, by patient numbers, by
investment, by all standards. And we have, so we've been
really focusing on that, being very sure that
the device is effective, finding out who are suitable candidates; we are trying to identify who are also not suitable candidates. Unfortunately that's not emerging as a clear picture right now, but we'll continue to work on
that in the exploratory data. So up to now we've been focusing on that kind of clinical activity and now we're starting to move
on to commercial activity. So things like pricing, availability, we don't have that much information on that at this point.

– For somebody to use the device, it would be fitted by an audiologist? – Yes. So the device as I said,
requires an audiogram. So generally an audiologist,
or as in some cases an audiometrist, can carry out a pure tone audiometry test. We envisage that the device
will be personalized or tuned and fitted by a clinical audiologist. And in the longer term
we'll see what happens but that's the plan right now. – So are you training audiologists or is the process of
actually fitting the device going to come via
training from the company? – Again, we, as I said, we involved, we had audiologists on staff
and ENT doctors on staff from the very start of the company, from the very start of when we started to develop the technology. And as I said we took their
input to ensure that the device… Because one of the common complaints we heard from the clinical people who managed tinnitus was,
about different technologies [that have] come to market,
was the burden that they had on these already very busy healthcare providers.

So if you go to an audiology
clinic or an ENT clinic in any public hospital in Ireland, certainly it's probably same in the UK, but they're extremely busy. It's about just getting the patients through, through, through. So if you have some device that's going to make
that consultation longer or more involved, that's a burden on the healthcare system. And therefore the doctors are not going to be as motivated to, to utilize that treatment. So our device, it only requires,
as I said, we're coming at it from a stimulation perspective, so it actually only requires
a pure tone audiometry test and then setting the actual
levels of stimulation on the device is very, very easy.

So it doesn't, it doesn't
pose a significant burden on the healthcare provider
or on the patient. So we tried to make sure
that it was kind of suitable or attractive to all
kinds of stakeholders. – One thing that people
from different countries are quite interested in is could they access it from their country? Potentially if they were to get the audiology tests, get their audiogram, [they] could then potentially
purchase the device, say from Ireland or say from the UK, wherever it launches next? – So patients will have to physically see their audiologists to get the device. We're not going to, well
we don't have approval to sell into the US.

We have European approval. They have to physically
see their audiologist to get the hearing test,
and really patients need to be under the care of a healthcare clinician, right. So they have to see the patient to get [it]. But also then in the longer term, the need to be able to talk to, if they have any concerns or if there are any issues, if their tinnitus fluctuates or if they get irritation of the tongue, they need to be under
the care of a doctor.

So, and ideally, I mean if they're in another country, it's
not the ideal scenario. But I guess that's, we
have regulatory approval for all of Europe [and] patients
do travel for treatments, but what we would say, the responsible kind of
thing is that they have to be under the care of an audiologist. We will work to get the
device in patients' hands as quickly as possible. Like we have worked long and hard to develop this technology to prove the clinical
efficacy of [it], the safety, all this kind of stuff. So we have spent a lot of time on this, and we haven't dedicated
a huge portion of our lives so that this can't get into the hands of patients; we're
motivated by the problem. We want to solve this problem. And so we're going to work to get it into the hands of patients in every market we can, in
the shortest time possible. – Touching on FDA approval,
do you have a timeline? Because obviously it's a large market. It's around about 50% of the people that visit our site are from the US.

So do you have any sort of timeline on FDA approval yet? – So our target, again, it's a bit like the peer review process, you don't know, there's a certain amount of variability, and it depends how much
information they want. Bimodal neuromodulation for tinnitus is completely unique. There is no other treatment
on the market for [it]. We're the first bi-modal neuromodulation treatment on the market for tinnitus. So it's when you have a technology that is a step change from
anything that's come before, the regulators tend to be cautious.

They're going to go: "Okay, we haven't dealt with this kind of technology." "We're very comfortable
with sound therapies." There are lots of those [therapies]. But this is something completely new. So, we can't say exactly how long it is, but we would aim to have
FDA approval in 2019, within the calendar year of 2019. – Are you looking at availability on healthcare and insurance? – Yeah. So we want our technology to be accessible to patients. We haven't worked this hard to make the thing available for it not to be accessible to patients.

So we are looking at reimbursement. That varies from market to market. So we'll have to look at it in each case. But we believe there's
a very strong argument for our product to be reimbursed. If you look at the experience of most tinnitus patients, they'll have seen their
ENT doctor at least twice. The British Tinnitus Association did an excellent piece
of research recently that showed that many patients have seen their ENT or a
second ENT twice in one year. And that's because these patients are not being adequately
treated or managed. So they're obviously frustrated enough to go back to their family doctor, get a second referral, go to an ENT to see if there are any other options that are available.

So it's a very, very frustrating
experience for patients. But it's also I guess a
frustrating experience for the doctors. And there's a cost to the
healthcare system as well. The doctors … I heard an
anecdote, a patient saying that, his ENT saying: "I'm not sure why you're here again, because I can't offer
you anything different or give you any different information." So that's very, very frustrating to both doctors and patients. And as I said, there's a cost to the healthcare system of them having been in the hospital twice. So we believe that our
TENT-A1 data, which is very positive both in terms of the level of improvement, but also the long term effects – that if patients use our treatment, they may get that kind
of long-term benefit.

That means they don't have to go back to the doctor a second time. They don't have to go to the ENT. And that's better for the patient. It's better for the doctor, the doctor can then move on to seeing new tinnitus patients. And it's also, there's cost saving to the healthcare system. Now all of that taken together, there has to be a very strong case for reimbursement there. So these patients, we're arguing that from the patient perspective, from the doctor perspective,
and also from the wider health care system perspective, there's kind of a very strong argument that the product should be reimbursed. – Looking at the actual device, and outside of the tongue stimulation, could it potentially be
delivered on a smartphone? – So the intervention
or the treatment requires auditory stimulation
and tongue stimulation. So in terms of, it can't, it would have to have those components, so the smartphone could potentially replace the controller device.
Right now, both the tones that the patient hears and the stimuli that the patient feels on their tongue, they're generated and controlled using this controller.

That could potentially become a smartphone in the longer term. Right now the product
format is what it is. It has a controller, wireless headphones and then a wired Tonguetip. But in the longer term,
who knows what will happen. – We've got a few people asking questions on the financials as well. Firstly, are you accepting investors? I don't know how much money
they've got by the way, whoever asked this. (laughs) – Well, the company was
initially funded by, by the founders ourselves, the friends and family that we roped into giving us some money to help us bring the technology along, from a number of successful businessmen who suffered from tinnitus and were frustrated that there weren't more treatment options available for them.

And they heard about our
work in the university and they wanted us to bring this technology to market. But that was kind of early in our story. Since 2015 we have, we have been funded through institutional investors. So they're the kind of investors that you need to talk to, to fund these large scale
clinical research programs, the kind of program that we're running with TENT-A1 and TENT-A2, which is hundreds of patients. That kind of research does not come cheap. So unfortunately you need to talk to the kind of investors that have the firepower
to fund that kind of work. – Somebody did ask this, which I will say: Any financial relation to Tinnitus Talk? I can answer that, but I'll let you. – I'm not aware of any
financial relationship right now between Neuromod
and Tinnitus Talk. – We'll talk about it
afterwards off camera. – What about the
marketplace at the minute? How competitive do you
view the market place? We know there's not very much for tinnitus around currently.

– Yeah. So we see the market as fragmented. So, and what we wanted to do was come to the market from a position of strength and credibility in terms of belief in the efficacy of our intervention. So we did that venture capital deal to invest in large scale
rigorous clinical data. We're working with all the
top scientists in this space, professors Berthold
Langguth, Deborah Hall, Sven Vanneste, Rich Tyler
from Iowa more recently, and Hubert Lim.

So we’re pulling together
all the top people. We’re putting together a really rigorous clinical research program to really try to move the field forward, move not only the understanding of our intervention and how it works, but also how tinnitus
more generally works. So we're seeing some
very interesting things that are synergistic with
what the TRI are finding. So the TRI <i>(Tinnitus Research
Initiative)</i> is an organization, again backed by philanthropic investment. So they have conducted large, very large scale research
that's moving towards this subtyping personalized treatments.

And so we're seeing a lot
of, some of our research is probably in the same order of magnitude of what they're doing. So we're seeing a lot of,
we're finding a lot of things to compliment each other's research. But we believe that's what it's going to take to move the field of tinnitus forward is a lot of investment, a lot of great researchers
working together; and to quote the TRI, working together towards, if not a cure, definitely very well evidenced and very effective treatments. – So MBCT is your
competition at the moment in the marketplace? – So right now the only actually clinically recommended treatment is CBT
<i>(Cognitive Behavioral Therapy)</i>. A lot of clinicians will
use auditory stimulation using hearing aids or hearing aids that
have tinnitus components. So again there's some fragmented kind of early stage technologies, but I don't think anyone has invested in the level of clinical
evidence that we have. We've invested significant
amount of money. We've done very large
scale clinical trials.

We've done very long follow-up so that we can stand over our claims with great confidence and
hopefully credibility. (upbeat music) – So it's quite interesting. There's kind of a combination
of different audio things and it's quite, after using
it for a little bit there, I could feel the sort of
tinnitus blending down with it where to start off with it,
it was actually above it. Which is quite unusual because when I'm listening
to other things it often kind of jumps above it. So very strange, it kind of is like having popping
candy on the tongue. It's a really interesting sensation on the end of the tongue there. But very interesting. So I'd just like to say thank you very much for doing the Q&A. I think we've managed to cover everything that was asked on the forum.

– Great. And we'd like to say thank you to you guys as well for the opportunity. We think you've done an
amazing job with Tinnitus Talk. It's great to have a forum where patients can share their experiences, and so there's a huge, I think there's a huge problem around tinnitus in general –
it's just about awareness, knowledge, education. So I think you guys are
doing a fantastic job and kind of helping raise awareness understanding, but also mutual support between the patients for each other. So we welcome the opportunity
to engage with you guys and to help educate
patients I guess about our, what we're doing. So we're very excited about that. – Excellent, thank you. (upbeat music).

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