Hearing Therapeutics in 2025: Where Are We, and What’s Next?

Hello everybody.

Welcome to the ‘State of Hearing

Therapeutics, Opportunities

and Challenges’

Today we have assembled a panel

of experts on the topic of

hearing therapeutics in 2025,

where we are and what’s next.

I’m your host, Brian Taylor,

and with me today I have a panel

of experts on the field of

hearing therapeutics.

And we’re just going to go ahead

and dive right in and I’m going

to have each of our panelists go

around and introduce themselves,

talk about their company and

what they’re involved in.

So I’m going to start with

Douglas Hartley.

Thank you. I’m Doug Hartley.

I’m a professor of otology.

I’m a cochlear implant surgeon

in Nottingham.

I’m also I lead the objective

measures group in the University

of Nottingham.

And I’m also the chief medical

officer of Rinri Therapeutics

who are pioneering a cell

therapeutic for hearing loss.

Excellent.

Hugo could you introduce

yourself please?

Yes.

Thank you and thanks for

having me today.

I think my most relevant

credential,

especially compared to

all the experts here,

is that I’ve been working on

Spiral Therapeutics for the

last eight years or so.

I have a background in otology,

but on the commercial side my

background is in business. And.

Yeah,

so at Spiral Therapeutics we’re

developing therapeutics

for the treatment of the inner

ear especially balance disorders

and hearing loss.

On the balance side,

we are working on a treatment

for Meniere’s disease.

And we’re actually just out of

phase two where we collected

successful data.

So we’re continuing to advance

this program and we’re also

advancing a pipeline of

different small molecules and

small peptides for other

inner ear disorders.

Excellent.

Jonas

My name is Jonas Dyhrfjeld-Johnsen.

I’m the chief development

officer and managing director of

Acousia Therapeutics in Tübingen,

Germany.

Down in the south, we are small

biotech focused strictly

on hearing, we

are developing Kv7.4 potassium

channel activators broadly to

treat either by enhancing outer

hair cell function or preserving

outer hair cell function.

We currently have our lead

program in ACOU085 in phase two

development as a candidate for

preventing ototoxicity

induced by cisplatin.

A long time ago my background

was in biophysics and

neuroscience,

but I’ve spent the last 15 years

in drug development and hoping

to continue doing that

for a while.

Excellent. Jian. Hi,

my name is Jian Zuo.

I’m currently the co founder and

CEO of Ting Therapeutics,

a small startup company focusing

on developing small molecules

for cisplatin induced

hearing loss.

And we have developed multiple

pre clinical drug candidates

that would be suitable for

preventing the cisplatin

induced hearing loss.

And before that I have been

a Professor for 25 years

developing you know,

studying the mechanism as well

as the therapeutics

for hearing loss.

Excellent.

And finally we have Tony.

Hi, I’m Tony Ricci

I’m a professor at Stanford

University.

I’m part of a team that’s

studying hearing loss called the

Stanford Initiative to

Cure Hearing Loss.

My background is cell physiology

and neuroscience, biophysics.

I also work on drug delivery

and surgical approaches and

ototoxicity, things like that.

Excellent.

I think since many of our

viewers may be unfamiliar with

the term hearing therapeutics

and since I introduced you last,

Tony,

if you could take a crack at

defining for our viewers who

are mainly hearing care

professionals how would you

define a hearing therapeutic?

Well,

I think the idea is that hearing

loss can be treated in

a variety of ways.

So there’s

traditional

hearing aids and cochlear

implants. So kind of hardware,

device design.

Theres also small molecules

or chemical therapeutics,

so drugs then there’s also we’re

moving into, you know,

targeted gene therapy

approaches.

So

I think it would be really

pretty broad.

I personally would also add

diagnostic tools for early

detection of hearing loss.

And finally,

I guess what I’ve said so far

really focuses on the periphery.

But there’s a lot of central.

Processing.

Issues that happen with

peripheral hearing loss.

And so I would extend

therapeutics to deal with

cognitive function that’s

impacted with hearing

loss as well.

Okay,

thank you and thanks to all of

you for taking time out of your

busy schedule with us.

We really appreciate it.

And I think to make this kind of

flow smoothly we have some

talking points and some topics

that we want to address.

And rather than just wait for

all of you to chime in,

I think to get the ball rolling,

if you don’t mind,

I’ll just kind of introduce the

topic and then I’ll call on a

couple of you to expound on

what that topic might be.

So the first one is the current

landscape around hearing

therapeutics.

What are some of the promising

developments in gene therapy

cell therapy,

drug delivery can you talk a

little bit about that and

I’ll start with Doug.

Yeah, thanks. So look,

I mean there’s a lot of

development in this field.

I mean gene therapies you know,

have made huge advances in sort

of targeted approaches like gene

replacement or editing and you

know really opening up

opportunities for specific forms

of genetic hearing loss.

Obviously demonstrated recently

by the Otoferlin trials.

And a number of companies have

been aiming towards that as a

sort of first in human target

and certainly have gained some

very promising results there.

But obviously these offer

curative potential at least in

an early stage of the disease in

relatively small groups of

well defined individuals.

In terms of cell therapies,

companies like Rinri

Therapeutics are definitely

pioneering that field by

exploring you know,

regeneration of both neural

pathways but also the

sensory hair cells.

And you know that has the

potential to you know,

leap us forward in biological

restoration of hearing.

The first in human trial for

Rinri Therapeutics is due to

commence later on this year.

And you know I think such

therapies could really restore

function where current devices

like cochlear implants really

fall short including addressing

that neural hearing loss

condition that doesn’t currently

have any treatment whatsoever.

And unlike other approaches,

I think cell therapies can be

effective regardless of the

underlying pathology and

potentially at a later stage

of the pathology.

In terms of metabolic approaches

you know there have been many

trials conducted and current

trials you know,

are looking towards protecting

or restoring cochlear function

through biochemical pathways.

Key examples include Otonomy’s

trial for OTO 413

targeting synaptic repair

and other drugs

like Pipeline Therapeutics for

example with synaptopathy

repairs. So look,

these treatments can rely on

enhancing connections you know,

but rather than necessarily

directly addressing the genetic

or defects or the regenerative

regeneration of cells,

but you know,

with promising effects you know,

targeting conditions like noise

induced hearing loss and

age related decline.

There are kind of challenges

with any of these approaches

including you know,

targeting the specific pathways

and demonstrating sustained

benefit and also you know,

delivering those drugs to

the right location.

But you know there’s a huge

amount of promising work

in this field.

Hugo do you have anything

that you’d like to add?

Yeah,

I think what Doug share

is obviously accurate.

I think important aspect from my

perspective is that we have no

treatments available maybe with

the exception of Pedmark which

is the drug that Fennec brought

to market for systemic treatment

of chemotherapy in the US

Hearing loss in pediatric

patients. Other than that,

there’s been little success in

clinical translation

in our field.

That contrasts with the very

promising preclinical data that

I believe the field has been

able to collect over the

last few decades.

Part of it is work that Harvard

and even Stanford,

led by Tony and some

of his colleagues,

have done over the years.

But this lack of clinical

translation is something that

we’ve looked at very hard and

where we came to the conclusion

that drug delivery might be an

aspect that will help address

that challenge.

We think that getting drugs into

the inner ear for the right

duration and at the right place,

right that’s going to be really

important and that’s really

going to help us bring drugs to

market for a range of diseases

that are just going to

be very important.

And when I look at the field of

ophthalmology, for example,

where pathophysiology and

mechanisms and everything is

very similar with, with a ear,

with the exception that location

and access are much different

and much more complicated on the

ear side I think there’s a lot

of inspiration for us to

take from that field.

And even when we think about

those drugs or mechanisms that

have been successful in

ophthalmology the idea of being

able to identify right patient

population right duration of

delivery and making sure that

the drug gets there that should

really help us address

underlying disease and some of

the conditions that these

patients are suffering that they

have no treatment for.

So from that perspective and

especially at spiral,

we’re extremely committed to

that aspect of drug delivery.

I think the field is starting

to recognize that largely

the gene therapies obviously

helped because those are

therapies that require

placement.

So that was a first step.

I think it’s really nice to see

what Rinri’s is doing also for

their gene cell therapy

delivery.

But I think also there also.

Other players with small

molecules and intra-tympanic

injections are also starting to

recognize that that’s going to

be a significant aspect of

future success for the field.

And I think to Tony’s point

about diagnostic, I think,

you know,

in a field with no drugs

approved everything is

held back. Right?

So as we keep thinking about,

you know,

maybe having treatments that

will start showing prominence in

late stage trials eventually

commercially that’s really going

to accelerate the way that

we understand disease,

the way that we have an

incentive to bring patients in

diagnose them and make

sure that, you know,

it’s not only just that we know

what’s happening with them,

it’s also that we have a

solution to what’s happening.

And today, hearing aids,

cochlear implants,

obviously remarkable progress

that has been made.

And when we think about being

able to implement machine

learning and some of

those aspects,

that’s really going to help

improve audiology and maybe

understand better and different

subsets of patient population

especially across hearing loss.

But yeah,

I mean in the end we might not,

you know,

we might not be in a position

where we have to look for,

you know,

rocket science to really

change the field.

We just need to be smart in the

ways that we get drugs there and

in the ways that we select those

patients that are going to

respond to those treatments.

So that’s the way I see the

future of the field and

where we are today.

Thank you for that Hugo.

Lets expand on this current

topic and talk a little bit

about some of the recent

successes a little bit about

some clinical trials and

other areas around

some of these successes.

So Jian,

could you kind of share with

us some of your insights,

findings around clinical trials.

I may not be the best person to

outline some of the

recent successes.

I think the recent gathering

of all this

industry leaders in the JPM

meeting in the past week,

right led by Hugo and Jonas may

have better outlines of all

those recent successes.

But according to my knowledge

there are quite a few successful

examples not only in the

otoferlin gene therapy field

like outlined by both

Doug and others.

There are also very exciting

studies of outcomes of Spiral,

Hugo’s group and also from

Jonathan Kil at Sound

Pharmaceuticals company

clinical trials.

I know that Jonathan Kil’s the

ebselin has very good success in

treatment of Meniere’s disease

in the phase 3 clinical trials

as well as some of the

the sudden hearing loss as well

as noise induced hearing

loss clinical trials.

I think this is really a very

exciting development and I think

Hugo can go a little bit more

about their success in the phase

2 clinical trials

for deliveries.

I think that’s the two very

exciting developments and I

think Jonas has also had some

ongoing phase 2 clinical trials

and we are looking forward to

those successes in the future.

I think there are also a few

other recent developments

that are very exciting.

For example they outlined the

otoferlin clinical trials and

they have been awarded to the

ARO clinical trial recipients

this year.

I think it was very exciting.

Also publish a few papers

in the, you know,

about the restoration of hearing

for those genetic diseases

with otoferlin.

I think it’s very exciting.

I think that those are the few

items that I had in mind.

Maybe some other panelists

can ask.

Well you mentioned Jonas and

Hugo, so let’s go to Jonas.

We haven’t heard from you yet.

So how could you expound

on this topic?

Well,

maybe just to be slightly

provocative to begin with.

I’m not sure

that we necessarily

have a massive,

massively different challenge to

getting drugs to the

inner ear than in.

In so many other fields.

I think to a large extent it

depends on your candidate.

I mean

Pedmark is systemically

delivered,

reaches the inner ear.

JZ just mentioned Jonathan

Kil’s work with ebselin

systemically delivered reaches

the inner ear.

Other drug candidates are not

adapted or appropriate for

systemic delivery.

Be that gene therapies or

molecules that don’t necessarily

diffuse well across the broad

labyrinth barrier.

But certainly the

ophthalmologists have

an advantage.

The eye is readily accessible.

You can fairly easily do an

injection directly or even

topical eye drops,

something like that.

On the other hand,

CNS drugs we typically deliver

systemically as tablets,

as pills.

They are also behind the blood

brain barrier inside a decently

strong bone like the

temporal bone.

So I think it comes down to

maybe

getting a little bit away from

trying to go too fast

with repositioning of existing

candidates and trying

to survive the pressure

of delivering fast,

which we’re all sort of

suffering under to some extent.

As long as long as there’s

very few successes or candidates

that have made it all the way to

market in the field there’s

always going to be a

lot of uncertainty.

There’s going to be a lot of

assumed risk in this field.

So everybody has to deliver as

fast as possible, right?

But classically speaking,

if you’re,

if you’re doing CNS

drug development,

one of the first steps you’ll

take all the way back to

medicinal chemistry and

selecting your,

not even your lead candidate but

your potential leads. Right?

What’s starting to narrow down

your hits is distribution study

ADME work to see if there’s

a likelihood of your,

of your candidate getting

to the ear.

So if you have a target and

multiple potential candidates

hitting that target,

well you better,

you better pick the right one to

begin with instead of putting

all your eggs in one basket and

hoping you can find a way to

deliver something that maybe has

other advantages such as an

existing talks package or a

phase one study that has been,

that has been passed

successfully.

So I think on one hand

we’re special.

On the other hand there’s a lot

of learnings to be taken from

many other fields and simply say

we have to apply best practices

and not necessarily simply try

to go as fast or as low cost as

possible because it’s hard to

get funding because there’s a

pressure to deliver

because investors

are looking to see fast results

because they don’t have a lot of

reference saying that this

can be done. Right.

On the other hand I think

there are other things we can

also still do better and

starting to happen for example,

doing extended high frequency

audiometry.

It reveals a lot of things that

are considered hidden.

I tend to get in interesting

discussions with people about

hidden hearing loss who’ve done

PTA up to 8 kilohertz and then

considers that the patient has

a communication issue on

understanding speech

and noise problems.

So it must be hidden

hearing loss.

Couldn’t it just be extended

high frequency audiometry?

We have recent very interesting

data both from previous

clinical trials.

We see it ourselves in our

ongoing phase two trial that

once you go up to 16,

18 kilohertz,

all of a sudden things like

cisplatin ototoxicity in adults

becomes a problem for

80% of the patients,

not for 30% as it was assumed in

the literature some

10 years ago.

And we’re not talking sort

of mild impact, right?

We’re talking 40dB

and up so again,

do we need to develop new

measures or do we simply need to

apply state of the art of the

current measures it’s probably

not one of the.

But probably more a little

bit of both.

I’m personally very encouraged

by at least one drug having

made it to market.

One drug that’s systemically

delivered.

One drug

that at least answers a

number of questions.

It shows it’s possible.

Of course it’s a smaller

indication that comes with a lot

of caveats in terms of potential

drug-drug interaction,

impact on chemotherapy,

survival, et cetera.

But it sets,

it sort of sets a stake in the

ground saying this is doable.

Right.

And for some candidates we’re

going to need special delivery

from techniques or approaches

or formulations.

For others doesn’t seem

to be such a big deal.

So

we, we need to do the,

the hard work,

the systematic work to,

to really enable as many of

these promising therapies

to make it all the way.

Right.

Okay, well,

let me let’s hear from

let’s take another minute or so.

JZ mentioned Hugo that he

would maybe have some insights

onto this around clinical

trials. So Hugo, very briefly,

if you could chime in about

this before I go.

well since I already spoke,

I saw Tony maybe wanted to raise

his hand and add some thoughts

to what Jonas was discussing,

which I thought Jonas for sure

really appreciate your

counterpoint about like drug

delivery is a problem,

but maybe not so big since

they’re all drugs that have

worked. But Tony,

I think it’d be great

to hear from you.

Okay, let’s hear from Tony then.

Oh, thank you.

Yeah,

so I guess in terms

of drug delivery,

I think that

both answers are correct.

I think there are places where

systemic approaches are going to

be useful and we just need to

take the time to figure it out.

But I also think that if we want

to move into gene therapy or

regenerative approaches and

things like that that’s going to

have to be a local delivery.

And understanding

the blood labyrinth barrier,

the connection between the ear

and the brain, fluid wise,

I think is

where,

where we need to be if we really

want to get into biological

solutions.

I also thought the comments

around diagnostics and measuring

high frequency hearing loss

is really critical because I

think standard of care right

now is not what it,

what it should be.

And it’s not a matter of needing

new technology. We do,

we do better testing on mice

than is typically done

in the clinic.

And that’s nothing to do with

audiologists or anything

like that.

It just has to do with the

healthcare system and what’s

considered the appropriate

testing right now. I mean,

with aminoglycosides we know

that there’s a much higher loss

hearing loss than is.

Than has been published.

As has already been mentioned.

The same is true with cisplatin.

What hidden hearing loss is may

in fact simply be how the

diagnostic tools are done and

not the underlying biological

question.

I mean people are not studying

in mice where hidden hearing

loss was kind of described.

Doing high frequency hearing

testing in mice hasn’t really

been done very well either.

Even, even though it can,

it’s just a little trickier.

So

I do think that you know making

that the technologies are here

for us to apply in a

more clever way.

The tools are here which is why

it’s such an exciting time

to be in the field.

It’s just working around the

specific questions that we need

to get at and catching up with

other fields and applying

technologies and the knowledge

that’s there.

Into the clinic.

Thank you for that.

Tony. Does anyone else want to

talk about other barriers

to progress?

I know that there must be some

regulatory hurdles that all of

you face given the complexities

of the research and the

interventions here.

Doug or JZ.

Do you want to go ahead and.

Expand on that before I get on

to any sort of regulator?

I mean I think drug delivery,

a lot of very pertinent points

have been brought up around

the challenges there.

I think you know direct delivery

is you know definitely the key

for gene and cell based

approaches.

I mean you know there is a,

as a cochlear implant surgeon I

regularly approach the inner

ear and there is a,

there is a role for adjunctive

therapies and certainly Rinri’s

first in human trial is an

adjunct to cochlear implantation

for example.

So whilst we have to not only

approach the inner ear but also

approach the internal

auditory meatus.

So really going you know

entering a CSF containing

space to deliver

the otic neuroprogenitor

cells in Rincell-1

You know there is a lot that we

can do in order to piggyback

on existing surgical

approaches and

in order to deliver those cells

and therapies safely

and effectively.

Diagnostics are absolutely a key

area that you know we’re failing

I think to pinpoint specific

pathologies you know,

amongst them auditory neuropathy

spectrum disorder for example

and you know really leaving some

patient groups underrepresented

or untreated. And you know,

whilst a lot of the outcome

measures we’ve got for early

phase trials definitely can

focus on safety and peripheral

efficacy,

you know for later phase trials

we don’t really have the right

real world outcome

Measures that are appropriate

and often not fit for service.

So if purpose fits,

you know patient reported

outcome measures and a lot of

the speech comprehension and

quality of life measures are not

really appropriate

for our field.

You know conducting trials in

our field are challenging

you know,

not only for the specific

unique challenges of

you know,

hearing

associated with hearing

patients.

You know there are the

extremes of ages.

They have obviously

communication issues,

comorbidities but also the field

is not as familiar with clinical

trials as some other fields are.

And indeed the professionals,

whilst audiologists,

ENT specialists are well versed

in hearing devices,

hearing aids,

they’re not necessarily so

versed in drug based or

advanced therapy.

So lots of gaps there for

adoption and likewise the

regulators aren’t quite

so unfamiliar as well.

So coming on to your you know,

your question, you know,

we have to

meet with regulators at very

early stages of our trial

designs to ensure that they

are kind of on board with

our whole trajectory.

And you know there are kind of

very specific challenges

in certain territories.

For example,

combining novel you know,

treatments and drug

delivery devices you know,

might be okay in one,

one territory but certainly not

in another. And you know in,

in our own,

in in the UK for example,

that that combination has led to

some cell based therapy trials

being conducted.

You know,

although they’re being you know

run and funded in the UK they’ve

been conducted in other

territories. So lots, lots of,

lots of challenges and

hurdles. But you know,

I think with the successes

of some

you know, recent trials,

a lot of those hurdles,

particularly with the regulators

lacking you know,

clear understanding of the

field and you know,

the unique challenges

distinguishing between you know,

device based solutions and

emerging biological therapies.

I think you know we are you know

in the foothills of overcoming

some of those, those challenges.

Before we leave this topics of

this topic of barriers

to progress,

I was wondering if maybe Jonas

I’ll call on you if you could

talk about some funding gaps

with respect to securing

resources to conduct

these studies.

Sure, sure.

Maybe just to go back to the

delivery for a brief minute.

I’m,

I’m neither pro or con either.

I think it’s the right tool for

the right job and for the right

patient population.

And in fact we do deliver

therapeutics for different

populations and the same target

but different molecules with

both systemic and local

administration so no,

no religion on my side,

but pick the right one for what

you are trying to do.

Funding gaps is certainly I mean

I think all of us in the field

have seen that the last couple

of years have been challenging

in terms of funding in general.

That’s not specific to

hearing therapeutics.

That’s a general struggle for

all biotech companies.

But certainly it doesn’t make it

easier when you’re in a field

with a lot of unknowns.

And it has helped a little

bit to as I said to,

to get the first drug approved

and marketed both in the

US now also in Europe.

And a positive opinion from the

UK’s Nice Commission on Pedmarqsi

as it’s being called in Europe

as opposed to Pedmark

in the US that helps,

but it’s one is one example.

Right. And I think the, the.

The challenge for,

for all of us is to keep

generating good data,

generate

successful

step by step

clinical trial outcomes.

You will probably be expecting

that almost everybody will say

well come back when you have

proof of concept in clinic

phase two data.

At least the phase 2A study

of course living up to all the

other standards that’s expected

in the field.

But the challenge is still

it’s a young field.

People are not familiar with the

challenges. Like Doug mentioned,

regulatory is not necessarily

educated on the challenges too.

But what. Neither are VCs.

And the typical reaction from

VCs to all these unknowns is to

say well we’ll let somebody else

take that risk and come back and

see us when you have some proof.

Right.

So the more success we can

collectively generate,

the more de-risking the

whole field will take.

And of course people are still

looking at what still remains

fairly recent phase three or

late phase 2B trial failures.

Right.

So we have to generate the

evidence to the opposite that

this is actually feasible.

That we can do it in

a rigorous fashion,

that we can overcome

not lack of enthusiasm on the

clinical trial sites but the

lack of experience and make sure

we build everything so robustly

that what we deliver will be

considered good evidence will

be considered solid.

And generate that rising tide

to, to lift all the boats.

JZ,

I see that you want to

weigh in on this.

Yeah. So maybe in addition,

this is in the topic of

barriers to progress.

I want to point out a few more

points that had not been

mentioned yet.

In terms of a Gene therapy.

I despite the software,

you know,

great progress in the recent

years and I still feel there’s a

strong biological limitation for

gene therapy for congenital

deafness in particular at the

time of the gene therapy and

the mutation induced

biological damage.

I think this is the key problem

for gene therapy that we’ll

be facing in the future.

The perfect two examples are

VGLUT3 and otoferlin,

which are both involving the

similar biological events.

However VGLUT3 cannot be really

gene corrected by later

stages of life,

especially when the

baby were born.

Those are key representative

problems for our gene therapy

field and I hope that this

can be resolved.

Not technical problem,

but more about biological

limitations.

And then I also want to mention

that in the noise induced

hearing loss for example during

the clinical trials there are a

lot of successes or not success.

A lot of trials,

about 30 or so registered

however none of them are

approved and not successful.

There are a large number of

problems that are facing this,

you know,

noise induced hearing

loss field.

One of them is that has not

been mentioned yet is that it’s

illegal to have noise induced

hearing loss as a profession in

any developing or developed

countries.

In the United States

for example,

you cannot have

you know,

noise induced hearing loss occur

during your during work

hours and so on.

So the military sightings

as well as you know,

construction workers in

the airport and so on,

you’re not supposed to have

hearing loss induced

hearing loss.

So these represent a significant

legal challenge for any of these

clinical trials to move forward.

And then the second is

that thanks to the

mention about the diagnostic

things and diagnostic not only

can provide some of the

populations that can be know

enhanced for the clinical trials

but also it has a significant

drawback.

The more you diagnose

those people who.

Are susceptible for hearing loss

the less clinical population

you’re going to get

in the future.

So this represents another

significant challenge I think.

And then finally I would like to

mention about the regulatory

challenges as everybody’s

mentioned.

It’s very challenging.

For example in terms of VCs

as Jonah just mentioned they

need to be educated for many of

those things that we

just mentioned.

There are

intrinsic risks that we

don’t have control on.

But this is the nature

for example many of the you know

many of the VCs that they

just don’t like to invest

in the hearing field.

Not only because of the many

recent failures in clinical

trials but also there’s

significant

I don’t know it’s a bias or

a risk associated with it.

Just for the fact that

the recent their

ophthalmology represent

investment in this VC field

represent pretty high ranking

you know investment in

their portfolios.

While the audiology is not even

on the list on all the

percentage besides all of the

you know the cancer immunology

and all the stuff and

cardiovascular.

But you know otology in the old

VC field is almost minimal.

It did not even list,

make the list on top 20 or 30

in the investment field.

That’s really difficult

if I may.

I think that’s also driven by

the fact that with the very few

or just Fennec’s Pedmark being

approved and that being in the

early days of commercial stages

it’s very difficult to establish

the size of the market.

And I think we can be

convinced that you know there’s

large numbers of patients

suffering from hearing loss.

We also know that you know just

you know obviously hearing aids

are a solution for them but we

don’t know exactly how

they’re going.

The market is going to react to

there being treatments

for hearing loss.

You know there are other

indications within the inner ear

with more acute symptoms that

where the expectation for market

size might be better,

you know easier to approach.

But when you think about broader

hearing loss and men needs it’s

hard to really estimate

willingness to pay size

of the market.

And I think that also drives a

little bit of the hesitation

from the venture capitalists

where they have to make

decisions based on return

on investment,

not just their passion for

science which is obviously what

we’re all here for but all these

other commercial considerations.

Right,

well let me ask the panelists

that haven’t waited on this

how do you see what’s,

how do you look at this?

What’s the market size?

What’s the prospects for

commercialization of the

therapeutics that you’re trying

to bring to market?

I’d like to hear from each of

you on that if you

could briefly.

I think for those of us you

know, doing the, the work,

we’re going to tell you

that this is huge.

This is a huge amount need

and then there’s so many,

so much opportunity just even

beyond the current programs that

we have, that we have ongoing.

Theres you know,

the way I see it,

two main aspects that happen in

the eye that again looking

at ophthalmology as well,

which is a multibillion dollar

market you know inflammation and

neurodegeneration are probably

the two largest aspects for

peripheral and needs then so

obviously the CNS aspect that we

might also want to get

to at some point.

This also you know,

being something that,

that could be represent a

huge market. You know,

sometimes we joke that you know,

if you had a treatment that,

that could reduce or,

or slow down hearing

loss by 50%.

And you know that was a

once a year treatment.

If you think about, you know,

what anti-VEGFs have done in,

in the eye you know those could

be like multibillion dollar

markets even to the point of

reaching size of you know,

the current GLP-1s.

But but then again there’s

a willingness to pay.

There’s the how hearing loss

is perceived also from

a societal standpoint where I

think people are more willing to

just walk around with poor

hearing than they are to walk

around with poor sight. Right?

So those are also part of the

education and again availability

of treatment.

If you have nothing

that is practical to use,

that is

patient friendly.

Its just going to be really hard

to establish how big that

that could become. But,

but I think you know we,

we can be confident that we,

if we can address inflammation

of the ear,

if we can address

neurodegeneration of the year

that’s going to lead to a

very significant opportunity.

Also on the commercial side.

I think it’s an interesting

point from, from you Hugo,

that the

I think we can all agree that

it’s a massive market.

I think we just have to look at

the patient numbers. Right?

I usually joke with people to

say that if they missed out on,

on GLP1 there’s twice as many people

with hearing loss.

So inherently it’s potentially

a massive market.

So that should interest the VCs.

But conversely I think

we also have a,

a similar challenge as

to another young and,

and growing field in terms of

longevity therapeutics that

you also have to come up with

something segmented, concrete,

realistic.

Because if you’re just going to

say well we’re going to treat

everybody with age related

hearing loss and you’re going to

make more money than Elon Musk

that’s a that’s a sort of pie in

the sky dream that’s not very

concrete for the VCs as well.

So how can you segment,

segment things down to something

that is attractive but

still palatable and,

and doesn’t seem

too unrealistic.

And we’ve looked at Cisplatin

alone as a standalone market

that easily gets into

the billion,

billion dollar peak sales.

Looking at something like

age related hearing loss. You,

you have to come up with,

with maybe a little bit more

realistic approach and say we’re

not just going to put this in

the drinking water and,

and treat everybody and,

and of course speaking from a

small molecule perspective

wouldn’t work with

the gene therapy.

But how can you sort of come up

with something that is

fairly realistic?

Patients that are addressable,

that already have contact with

an ENT physician where a

potential big pharma doesn’t

have to go out and build a sales

channel, find the patients,

run a lot of marketing

campaigns.

How can you sort of come up with

a well defined subset of

patients that you can start

with? In the same way as,

as I think longevity

therapeutics are often

struggling with coming up with

something realistic and say

we’re going to make Everybody

live forever versus we’re going

to give people another 10,

20 good years where they don’t

suffer a lot of the morbidities

of aging.

So I think that that’s really

where the commercial modeling

strategy pitch

has to be really worked on.

Well to say how,

how do you make this feasible

while still keeping

it attractive?

Okay, thank you for that.

Thats in the interest of time,

let’s move to

your take on visions

for the future.

I’m curious to know

from each of you

how do you see the field

progressing over the

next decade?

What are some things that are

needed to accelerate progress?

And if we could start with Tony

and then move to Doug

that would be great.

I guess optimistically I think

the big thing that hopefully

will happen in the,

over the next 5 to 10 years

is the recognition by the

general public how hearing

loss impacts their life.

And in fact I would say their

brain function. And so,

you know,

do you want to live to 90

if you can’t communicate with

the people around you and if

your cognitive function is

declined to the point where you

don’t know that you’re

living to be 90,

and that’s going to take early

intervention and attention

to hearing.

And I think identifying

therapeutic windows is really

going to be key for

a lot of this.

I think it was kind of alluded

to with the gene therapy side of

this that are we going to be

doing in utero gene therapy to

deal with some early, you know,

genetic losses or what are the

targets that we can actually get

at later. So I think that,

and I think those are solvable

if people just kind of take

them on head first.

Well you know, from,

to me as a basic scientist,

I mean what we need is a

workforce that’s larger.

We need people thinking,

who think differently that see

solving the problems of hearing

loss as actually doable.

I think that’s why people

don’t go to doctors.

I mean because there is.

No, there’s not.

They know there’s not

much treatment.

They look at their grandparents

and they don’t wear their

hearing aids and so why

should they? And,

and it just kind of trickles

down and so getting people

to really look at,

see it from the population side

and getting, you know,

young scientists more

excited about

the potential of the field.

Right. So for me, you know,

if you wanted most of the

techniques that I use,

you could, you know,

electrophysiology and imaging

and things like that you can do,

you know,

in the brain and it’s

way easier to do.

And so if you’re interested

in the techniques,

that’s where you’re going to go.

And, and you know,

it’s sexy to think about working

dementia and Alzheimer’s disease

and things like that,

where you know,

taking those tools

and doing it in,

in the cochlea or in the

vestibular system

is just a lot harder.

Right.

And so why would you do it?

Because what are you going to

do next in life? Right?

There are there, you know,

now at least you guys are

at least, you know,

pushing where there are some

companies available,

there’s some interest in trying

to do translational work,

but it’s really hard

to get scientists,

especially the junior

scientists to see,

kind of have a long view that

this is a place to work.

They see me as the old guy doing

research in the ear.

There’s not a lot of funding

available at the basic

science level,

at the translational level.

And there’s not been a lot of

success with it easy either.

Like a simple example, right?

So you can do semicircular canal

drug delivery in a mouse.

And it’s definitely better than

round window or other

approaches.

So if you’re studying something

like gene, you know,

gene therapy,

say you use semicircular canal,

and then, well,

now what do you do?

So, you know,

who’s going to pay for

you to develop the.

Drug delivery method,

not in a mouse as a

basic scientist,

because the university is not

going to give you animal space

for whatever the model animal is

and then NIH isn’t going to

really want to fund that

kind of narrow band question.

Even though it is a roadblock.

So I think it’s going to take

more partnerships between

academics and,

and companies and whatnot

to really. I mean we,

I feel like we’ve been doing a

lot of griping but I mean

the field is really,

it’s just waiting. Right?

I mean I think everything is

there and it’s just having

enough people with the resolve

to get the work done and the

recognition that it’s work

that needs to be done.

Okay.

Sorry

Thank you, Tony.

Now let’s move to Doug.

We haven’t heard from

Doug in a while.

I would take everything that

Tony says, I would say,

you know, look,

my vision is that we will be

seeing a very significant

increase,

I hope in both early and late

phase trials within the field

and the first market authorized

therapies emerging within that,

you know, decade hopefully.

Were going to need not only Tony

mentioned that collaboration

between academics and industry,

but also with clinicians

involved as well. You know,

obviously patients and public

need to be brought on board

here too and you know,

helping direct

those treatments.

I think we definitely need

improved diagnostics and

outcome measures

that are really better aligned

with real world needs.

And the field desperately

needs you know,

funding and regulatory bodies

that are more familiar with and

supportive of advanced therapy.

But I think with that

enhancement in knowledge

and trial methodology,

I think you know,

a cultural change could,

could occur to address a lot of

the fears and misconceptions

amongst professionals,

patients and investors about

advanced therapies in our,

in our field. And you know,

ultimately what we need is

success stories. We need,

we need success stories in early

and late phase trials to really

boost confidence in the field.

Excellent.

JZ. Yeah,

I just want to echo

one sentence.

We need some successes

in the field.

Okay, thank you Hugo.

I think that’s right and I think

it all comes together to.

Once we have one success,

everything else is going

to accelerate.

So the better diagnostics,

the better understanding

of the VCs,

of the opportunities so

everything gets funded better.

Researchers also get excited

because they see that there are

things that actually are getting

to patients instead of just

being stuck in that, you know,

animal study phase.

I think all of that is right.

And you Know,

the perspective that we’ve,

you know,

I’ve personally taken

at Spiral,

and the team obviously

follows this.

You know,

and back to what I

said early on,

maybe this is not a matter of.

And of course,

different disease requires

different treatments and novel

mechanisms and new chemical

entities are going to be very

important and also recognized by

the investors as an opportunity

for

For to focus and you know,

because of that, IP protection.

But, but in the end you know,

just simple solutions that can

get us to success and very,

you know,

clear improvement of how we

manage those patients are

already going to be very

important. And you know,

particularly at Spiral,

our lead candidate is,

is a steroid. It’s,

it’s dexamethasone.

And you know,

while that doesn’t

sound very sexy,

we think that that’s

very important.

Every field of medicine has a

steroid that is approved and

that is necessary not only for

primary treatment of

different disease,

but also as an adjuvant

for different things.

And having the ability to

deliver a steroid durably,

conveniently to a patient

to affect the disease.

We think that that’s going to be

a significant change

for the market.

Hopefully that will be a part of

us contributing to that field

getting more exciting and the

understanding of, okay,

there are things that can work.

So now let’s keep investing in

novel mechanisms and more

differentiated things which we

also have in the pipeline.

And we recognize, you know,

Acousia has.

And Rinri and you know,

just and JZ

also working on those things.

Of course the field is,

is it’s very exciting right now,

but we didn’t need to get there.

We need to get to that

breakthrough so that people,

you know, everything, the,

the whole community starts

understanding that.

Even the clinicians,

like Tony said,

understand that there are

other solutions that,

that we can recommend to the

patients that we can say, okay,

it’s not just a surgery.

It’s not just, you know,

you know,

here’s a hearing aid that might

patch the problem but not

really resolve it.

Here we’re really working on

addressing the underlying issue.

And it might start with very

basic things that help build the

foundation for the field to then

start getting excited about

other more innovative solutions.

Thank you, Hugo and Jonas,

we don’t want to forget you.

I think anything that

works is sexy.

So I don’t think you have to

worry about dexamethasone if you

can show the good results.

Hugo.

I think it’s an overall

ecosystem that needs the success

I think if of course the onus

right now on more success

stories that will bring

investments is on the level

of the industry.

But success on the industry

level will bring interesting

therapeutic options

to the clinicians.

It’ll also hopefully help retain

some of the young smart people

that Tony is mentioning in,

in the hearing research.

Because there could

be collaborations,

there could be funding,

there could be increased

awareness around the field.

Right. So to bring it forward,

it’s not just one part

of the ecosystem but,

but every part of the ecosystem

has the possibility to

positively affect each other

as well. So the more,

the more collaboration and the

more focus we can bring on

hearing as a disease,

as a therapeutic area,

the better it’ll be for

everybody not just in the

ecosystem but eventually also

the biggest, most important,

perhaps part of the ecosystem,

namely the patients that can get

better treatment opportunities.

Well,

I know we’re over our time but

if you’re able to stay on,

I would love for each

of you to chime in,

weigh in on what is one thing

that you would want

clinicians,

hearing care professionals

people with hearing loss.

What’s one thing that we maybe

haven’t talked about yet or one

thing that you want to elaborate

on. If you could each be,

you know,

keep your response to a minute

or two, that’d be great.

I’ll let you weigh

in as you’d like.

Maybe to go back to what we

talked about earlier on and what

Tony emphasized as well,

that

do the maximum possible with

what you already have.

Don’t wait necessarily for new

things to be invented

or developed.

I think we can do a lot

if we simply would,

generally speaking

do the extended high frequency

audiometry to really understand

what’s happening on

each patient.

That could help a segment that

could help the patients perhaps

get a validation of what

they’re experiencing,

but that doesn’t seem to

correlate with their current

audiograms and it could help us

understand where to go

with candidates.

So use the existing technology

to the fullest while we work

on additional solutions.

Excellent.

Others maybe I can jump in.

I think the one thing I would

like the clinicians and patients

to do is to stand up to

influence the policymakers and

VCs and many others that this

hearing loss is important and

has a huge market and it’s

profitable and is going

to get return,

is going to affect a significant

number of people.

So I think that is the attitude

that I think we all

should work on,

and particularly

the doctors as well as patients.

Thank you,

Tony. Hugo,

Doug.

Yeah,

I’ll put my chime in for let’s

move beyond the audiogram in

order to diagnose hearing loss.

You know,

degree of hearing loss is,

you know, a factor.

But let’s become specific about

what the cause of the hearing

loss is in order to direct

some of these

patients to appropriate and

emerging therapies.

You know,

is it move beyond the hearing

aid and the cochlear implant can

really restore hearing and

natural hearing for

these individuals.

Tony, Hugo,

do you have anything?

I’ll echo a little bit

of what’s been said.

I think one,

I do think diagnostics

has to be applied

better word,

word recognition types of tests,

things like that,

not simply audiograms.

I think assessing high frequency

is similar to assessing,

you know speech in noise.

Types of tests need to be used

for early identification

of hearing loss.

And I think

you know, to me,

clinicians are really in the

most powerful position

to change culture to

impact patients and to impact

funding agencies around the need

for further diagnostics.

But also how hearing loss

impacts so many aspects of life

that we really need to hit that

and get awareness that,

you know, that there, you know,

if there aren’t exactly

tools ready now,

that tools will be there.

But that only happens with first

recognizing that there’s

a problem.

Thank you.

And finally I don’t think, Hugo,

we’ve heard from you

on this last.

On this last one.

I think I really don’t want

to be too redundant.

I think everything has

been addressed.

I think ultimately it’s our

obligation to also or our

mission to just give the

clinicians the tools to keep

innovating and helping us think

about what are the solutions

going to be in the future.

So I think we can ask

a lot from them.

But in the end we also need to

guide where things are going and

we need to just be

proactive there.

Well,

I can’t thank all of you enough

for the engaging discussion,

the shared insights.

Its not often that you get such

an esteemed group of experts

together to talk about an

important topic like

therapeutics.

Thank you all very much for your

time and your expertise.

Thank you.

Thank you.