- [Voice Over] The Dementia

Researcher Podcast,

talking careers, research,

conference highlights,

and so much more.

- Hello and welcome to another episode

of the Dementia Researcher Podcast.

I'm your host, Dr. Anna Volkmer,

an NIHR funded senior

research fellow at UCL

and a speech and language therapist.

And I am absolutely thrilled

to have you join us for today's session,

which we've titled lecanemab,

donanemab and amyloid.

Although this is such a fast moving area,

I am sure there will be two more emabs

by the time we finish.

Now, this topic was identified

by our very own listeners

as something they wanted to hear about.

And it isn't just our

listeners, aducanumab,

lecanemab, amyloid or

donanemab, lecanemab,

they're such a mouthful and amyloid

have made it to the mainstream media.

And the current trials are a

popular topic of discussion

amongst patients and family members

whom I work with in my clinical role.

Well, today's guests are

here to tell us all about it.

They are three extremely

experienced researchers

who have made massive

contributions to this field,

two of whom I have the absolute pleasure

and privilege of working with clinically.

They are going to explain the facts

and dispel some of the myths.

So by the end of today's podcast,

we will have a much clearer understanding

of the amazing work going

on in this area of research

and the future challenges

in this field future.

So let's meet our guests.

(logo chiming)

Now it's my pleasure to

introduce Dr. Cath Mummery.

Professor Sir John Hardy

and Professor Nick Fox.

Hello everybody.

- Hi Anna.

- Hi.

- Hi, Anna.

- Hi, Nick.

Why don't you tell us all a

little bit about yourselves.

So, Dr. Mummery, can you go first?

- Sure. And that was a really

kind introduction, Anna.

Thank you. Far too kind.

So I'm Cath Mummery.

I'm a neurologist

and I work at the Dementia

Research Centre alongside Nick.

He's literally next

door in the next office.

I am clinical lead for the service.

So planning what we are gonna be doing

with these therapies in

the future, hopefully,

but also have been doing clinical trials,

looking at what these and other treatments

can do within the brain, how

to treat Alzheimer's disease.

- Exciting. Thank you.

I can't wait to hear all

about it. Professor Fox,

do you want to introduce yourself?

- Yeah, thanks Anna.

So as Cath said, I work at

the Dementia Research Centre,

which is here at Queen Square in London.

And we're a clinical centre

and a research centre.

And the clinical service and the research

are really intertwined,

and that's always been

ethos and our purpose.

And my research has been focused

on biomarkers and imaging.

But also about how we can

bring forward the search

for effective therapies

and then deliver them.

And it finally finds,

it feels like all those

bits are coming together.

- It really does. It really does.

Thank you.

And finally, professor Hardy,

would you like to introduce yourself?

- Hi. Yeah.

Nice to be on this call.

I'm just across the square.

I am looking out of the window

at the building with Nick and Cath in it.

I work very closely with them. (laughs)

I work very closely with

them. I'm a basic scientist.

I'm a geneticist and I work

on the genetics of the,

actually I work on the

genetics of the patients

who come into the Dementia Research Centre

and that's really how this story started.

- Well, thank you so much, John.

(logo chiming)

Well, this is such a big topic,

but perhaps first and foremost,

we need to understand

what this thing amyloid is

and what role it plays in Dementia

and perhaps Professor Hardy,

you could start us off.

- Yes.

So when you look at the brain

of somebody with Alzheimer's disease,

what you see is you see two

types of histopathology,

two types of microscopic pathology.

You see amyloid plaques,

they are rather cotton wool

like lesions in the brain.

They're about a 10th

of a millimetre across,

and they're made up largely of a peptide

called the amyloid peptide.

You also see inside nerve

cells, you see tangles,

which are made up of the tau protein,

gumming up, if you like, the neurons.

Besides those two elements

of the microscopic pathology,

you see neuronal loss, the

ventricles that are enlarged.

The hippocampus in particular is shrunken,

but the shrinkage all over the brain.

So you see, that's the pathology.

And if you like, the thing that turned out

to be very important in

this is that we had a family

who came into the precursor of

the Dementia Research Centre

where many people were

affected by disease.

And in that family,

actually the family still comes

to the Dementia Research Centre.

In that family, we found

mutations in amyloid.

And that allowed us to say,

really for the first time,

the pathology is complicated,

but we know in that family

it starts with amyloid.

And the simplest, if you

like, generalisation,

is perhaps it starts with

amyloid in everybody.

So that was the breakthrough

that started this really.

- And I still have in my office, Anna,

the letter which starts saying,

and I do this as it's a

lovely historical artefact.

A really important one.

But it's also a reminder of

what we do and why we do it,

because the letter starts Dear Dr. Hardy,

who was a mere doctor then I think John,

two or three lines down

in the letter it says,

"I think my family could

be of use to the research."

And she was absolutely

right, wasn't she, John?

- Absolutely really

and a remarkable woman.

- Yeah. Why is that in

your office, Professor Fox?

And not in.

(all laughs)

- Because we have in the room next door,

a whole series of,

we still got the paper

beautifully labelled files,

and there's a family file which

has all the correspondence

for each and every one of the

families who've contacted us.

And they started at number one.

And we're I think we're

600 or something now.

And this was family 23,

and it was called Family 23

because it was the 23rd folder,

literally the 23rd folder,

which had all the details

of the family in there.

- Gosh.

- We have all the high tech here.

(all laughing)

- Actually, it's even the

tech is even lower than that

because they were piled on my desk.

And in fact, this family were

the first to write to me.

But I'm so inefficient

that by the time I replied,

there were 22 other folders on top of it.

So actually it should

have been family one,

because the family wrote to

us absolutely immediately

they got the advert.

- Wow, that's amazing.

But they weren't family one

in terms of the world

of discovering amyloids.

So tell me, maybe Professor Hardy,

you could also fill in our listeners.

How exactly was amyloid discovered

in the very first place?

- Well actually, amyloid, the protein

was first characterised

by protein chemists.

Somebody called George

Glenner, who did it in 1984.

He got the sequence of amyloid

Colin Masters in Australia

got the sequence very soon afterwards.

So we knew the sequenced,

the gene was cloned in 1987.

So the gene was there and known

to be on chromosome 21 in 1987.

We did genetic linkage analysis.

What you're doing in

genetic linkage analysis

is you're getting DNA samples

from all the members of a

family and you're saying,

"Which bit of the DNA do all

the effective share in common?"

And we found that the bit of the DNA

that they all shared in common

included the amyloid gene.

So we sequenced the amyloid gene,

and that's when we found mutations.

- So that is a short history of that work

just to continue the importance

of that particular family.

So that first lady was the

first person to go into a trial

of a treatment against amyloid

in people with genetic Alzheimer's disease

and she did that here.

And her son is now involved in

a prevention treatment trial

to try and prevent the onset

of disease in the first place.

So they're an incredibly important family.

They've done so much to help us.

- And along the way, Carol,

this is in the public domain,

helped us set up our, some of

our first support groups on,

which again, I think speaks

to the importance of both of the families,

but also that research

can't go ahead in isolation.

And that research should

be much more holistic.

It should be around supporting families

and very much a sort of

co-creating of that research.

- Yeah, I'm glad you've said

that, that makes total sense.

But it also illustrates how

young this area of science is

in actual fact.

I think people presume it's this science

has been around for a lot longer

and even maybe presume that

we've been exploring treatments

for a lot longer.

So we know there are these new treatments.

I mentioned that in the introduction.

But Professor Fox,

could you tell us what

the treatments actually do

and how they work to

address the amyloid issue?

- Well, the treatments

you've just described,

which you refer to as the MABs,

which mean monoclonal antibody.

So what what is that that's antibody

much as we're aware of from

immunizations against COVID

and other things,

we generate antibodies

in response to that.

And actually this story

started with an idea that,

as John had said,

recognised that that

amyloid was a real culprit.

And but initially wasn't

quite sure whether

it was a driver or a consequence.

But the genetic element says,

"Oh, with this, it must

be driving the disease,

at least in the families."

But we weren't quite sure

in the rest of the population then,

or the Alzheimer population then.

And so there was the

strategy of immunising people

against amyloid.

This protein that John talks

about builds up in the brain.

The brain has great

trouble disposing of it,

and it just simplistically clogs things up

and causes toxicity to the

neurons directly or indirectly.

And then you get that,

that destruction that

John was talking about.

And so, it started with

can we immunise people?

And that was a remarkable experiment.

And it showed that in mice a

model of the human disease,

it cleared amyloid.

And the same thing went into humans

and they got tremendous

inflammatory response.

So it was getting into the brain,

it was doing what it was meant to do,

but doing it in an uncontrolled way.

And that set the field back,

the trial had to be stopped.

It was dramatic. It was

very worrying for the field.

And then everything

went quiet for a while.

And then it was restarted

with using antibody.

So you can control how much

immune response if you like,

you get because you're

doing that artificially,

you are not doing an

uncontrolled immunise,

see how much response people generate.

And that has been,

while vaccination

continues to be a strategy,

the dominant MABs have been

giving people antibodies

and what they have shown

using amyloid imaging

that this really did

clear it cleared amyloid,

which we know builds up over 20 years.

It cleared it over about 18 months,

which I still find quite remarkable.

I mean, it feels like, it's

an amazing achievement.

And those first monoclonal

antibodies that were seeming

and the immunizations, what wasn't clear

is whether or not that would

deliver clinical benefit.

And that's been the most recent change.

So they've been refined

and they've been generation

after generation of monoclonal antibodies,

generation of MABs.

There will be some more

coming along I'm sure,

but now these ones both remove amyloid

and have shown for this to first time

there is a slowing of clinical decline.

- These MABs can distinguish

between harmful amyloid plaques

and any, I gather there are

non-harmful forms of amyloid

that also exist.

Can they actually differentiate?

- So, I can make a start on answering that

and others can chip in.

So one of the things that

was done when in response

to the vaccination trial

was to try and engineer

the monoclonal antibodies

to go after particular types of amyloid,

but also not to generate a

certain type of immune response.

So you could get the clearance

without getting uncontrolled inflammation.

And the different antibodies

have different selectivity

for different types of amyloid.

And in fact, there's a

lovely twist to the story,

which goes back to, to that first,

almost the first letter

that I'm very disappointed

to know that it was

piling up on John's desk.

But one of these treatments, lecanemab

came from a finding in a family

with one of these mutations

that people looked in the brains

and in the cerebral

spinal fluid and looked

and a particular type, one

of the forms of amyloid

along the cascade from the gene

down to the amyloid plaques

was thought to be a good target.

And that eventually led to

lecanemab a great story.

- It is, it's really

circular. It's fantastic.

And that's why UCL

are so much at the centre of

this whole story of the MABs.

Is that right?

- Well, I think that's partly right.

Yes. I think it's a-

- It's a worldwide, it's a

huge effort for everybody.

I mean, the John contributed

phenomenally to the genetics.

We've contributed in some

small way towards imaging

and the biomarkers.

And we have contributed

particularly through Cath

to some of the trials.

But this is a massive effort.

I mean the number of

scientists in industry

and outside who probably have

spent chunks of their careers

moving these things forward.

- Yeah there are millions and

millions of pounds and hours

that have gone into

getting to where we are now

and 20 years of a number

of lack of success

and perhaps ongoing debate about amyloid.

So I don't think UCL could

ever claim the entire success,

but we've been a very

important part of that process,

I think you'd say.

- But Dr. Mummery, you highlighted,

we've really just been

focusing on amyloid.

Do these treatments have any

impact on the tau tangles

that Professor Hardy was

talking about earlier on?

- Well, there are some

interesting findings

from some of the more recent trials.

And a number of these

drugs have shown that,

as Nick was saying,

they massively reduce amyloid in the brain

and then some of them

associated with that,

there is a modest cognitive change.

So they slow decline but modestly.

If you look at other biomarkers,

so whether you are looking at

tau levels in the spinal fluid

or in some cases towel levels on pet,

you can see small changes.

And with some of those drugs,

those changes have been significant enough

to make us think we really need

to continue looking at them.

So yes, they have downstream effects,

which is what we think means

that there is disease modification

that comes from the amyloid lowering.

But there are of course other ways

to target those pathologies,

which I'm sure we'll talk about later.

- That sounds good.

But I want to know about the trials.

So Dr. Mummery, can

you tell us what trials

are happening in the

field right this moment

what happens to these participants

when they're actually

involved in the trials?

- Okay, would you like to

know just about amyloid

or about the whole sphere?

Because there's a lot going on.

- [Anna] Let's start with the MABs.

- The MABs specifically, okay.

So the ones that are shown

positive results in phase three,

will then go through a

process of assessment

as lecanemab has done in the

states in different countries.

And those countries will approve

or not approve the drug to be used.

Alongside that,

there are other ongoing trials

in perhaps earlier stage individuals.

So for example, those people

that don't yet have symptoms

but have got amyloid

rebuilding up in the brain.

You've also got studies

using monoclonal antibodies

in people back to the story about genetics

in people with genetic

Alzheimer's disease.

And in them, what we

are doing is two things.

Firstly, as I mentioned, trying

to prevent onset of symptoms

in some and disease

even earlier in others.

And just to come back to Nick's point,

you have amyloid building up

for 20 years in your brain

before you even get symptoms.

So if you know you have a genetic risk,

then you know and you know,

roughly when that family

tend to have disease, starting

with onset of symptoms,

you have a window of opportunity

to treat before they ever get symptoms.

And that's one of the things

we've been doing for about 10 years.

Now, we are doing that even earlier.

So people that are 15, 20

years before symptom onset,

we're going to start giving

them an anti-amyloid therapy

to try and prevent the accumulation

occurring in the first place

and actually prevent the

disease, which is extraordinary.

That's never been done before.

So very exciting.

These people are in their early 20s.

This is not a group of people

that are in their 70s, 80s,

these are young people.

And so they have huge

motivation and ambition for us

to help us to find treatments that work.

So that I think is a very

important area with the MABs.

Would you agree Nick?

- Absolutely. And it's challenging

stuff to go really early.

The question that really

faces the field now,

which is so relevant to

what Cath was saying,

is these trials were for

typically around 18 months,

the ones that have shown benefit.

Now, if we slow disease for 18 months

and that's it,

that's better than nothing.

But that's not what we want to do,

really want to do is stop

it before it even starts

or show and that that will be

another step of the trials.

Will this slowing be progressive?

Will it be cumulative?

Will you continue to

get benefit at two years

if you continue treat,

would you actually get more slowing

or is it just a temporary phenomena

and then the disease carries on the way

it has done inexorably?

And to put that in constant context,

it is remarkable to think

that this is a disease

described 120 years ago,

but obviously been around

for longer than that.

It has always inexorably gone

down through these families

and affected people at all ages

with nothing that can slow it.

So what the benefit from

these particular MABs

will be earlier in disease

or later in disease

or longer duration, we don't know.

But those are really important questions.

- One of the things that

we have to do, Anna,

as we start to give these treatments

is follow people that are on treatment.

'Cause as Nick said, these

trials are limited in time.

We have some people that

have been on extension

on these monoclonal

antibodies for up to 10 years.

So there is some information

starting to come out

about what it might look like

for somebody to be on

these for a long time.

But to get the real answer about

what a treatment does in the real world,

we have to have registries of those people

that start treatment and follow them

and see how they get

on, not over 18 months,

but over three years,

four years, five years,

and work out as Nick said,

does this continue to

build in benefit or not?

- I think you said earlier

you are trialling these with people

who also already have

symptoms or as well, right?

- That's right.

- So have you been, and

you mentioned cognitive,

the downstream effects.

So have you, I guess I'm quite interested

as well in what have been

the cognitive impacts?

What do we see in those clients?

- So in in the studies

that we've had so far,

there's been a convergence

over several trials now

in terms of the levels of amyloid removal,

but also the levels of cognitive benefit

we see in that period of time.

And so if you take the 18 months

and you look at the trials

that have shown benefit so far,

it's around 25 to 30% cognitive slowing.

So as Nick said, it's not stopping it.

It continue to decline on average,

but at around 25 to 30% slower.

And what that means in the real

world, if you are a patient,

is if you are over 18 months,

you are on the treatment,

you've got maybe around five months extra

at a higher level than if

you are not on the treatment.

- [Anna] Yeah.

- Does that make sense?

- Yeah does make sense.

I guess it sounds,

I think Professor Fox

kind of emphasised that,

it doesn't sound like heaps

at the minute, but it's huge.

I mean, I'm wondering

what the scale of the,

I guess what the most

significant findings are so far.

What do you think is like,

and how is that gonna develop,

do you think?

- The fact that we can change

the course of the disease

at all is that means

that this is a proper

turning point, right?

That okay, it's a modest

effect, but it's an effect.

And we've had nothing for decades.

So that will reinvigorate

the research world.

It provides hope.

It increases people's

interest and commitment

in this sort of research.

And it's our foundation,

this is the foundation

on which we build better

MABs, other drugs,

different targets,

and we can now put those

stepping stones in.

So I think that's the biggest thing

is that we've shown a change.

- Yeah, I completely agree.

The analogy I like to use is,

who would've believed if they

watched the Wright Brothers

on that North Carolina beach,

that when they got that

sort of modified bicycle,

that this was gonna be

the start of the time

when we could fly.

But what they showed is

you could get heavier

than contraption off the ground.

And that led other people

to do better later.

And we had flights from London

to Paris, 15 years later.

And I think it, as Cath is indicating,

this is where we are, we

know what we need to do,

and the drug companies

know what they need to do.

And the argument about whether

this is a good target or not,

that argument is over.

So it that unifies the field.

So all of these things are

gonna make things better.

No doubt.

- Although you do still

get jet lag when you fly.

So I'm just curious,

let's say jet lags the side

effect of the Wright brothers

at work.

What might be the side effects?

Or are there any other

unexpected outcomes that you-

- That was a contrived link there.

- That's nice segue.

- Well, there are, and

Nick's the Wright person

to talk about this because the side effect

is called amyloid related

imaging abnormality.

And Nick is the imager part excellence.

And what happens is the first

thing the antibodies hit

is amyloid in the blood vessels

and they cause inflammation

in the blood vessels.

And that's a problem.

I'll let Nick do this

because he knows what he's

talking about on this topic.

- And I'm making it up as I go along.

- As John said, these

antibodies are removing amyloid

from the brain and from the blood vessels.

And as they do that,

it's not a some sort of

very simple dissolving

of these proteins miraculously,

that involves recruiting

our body's immune system.

It involves inflammation.

You are removing amyloid,

which has been incorporated,

as we said, over 10, 20 years.

And that amyloid is within blood vessels.

And as it gets removed,

particularly if it gets

removed very quickly,

those blood vessels can become leaky.

There can be areas of poorly

controlled inflammation.

So there are two types of ARIA,

nothing to do with jet lag,

amyloid related imaging

abnormalities. ARIA E, misspelling,

it should actually be O which is edoema

in the American spelling,

or H which is haemorrhage.

And haemorrhage is a bit

frightening actually.

The haemorrhages that we usually

see are tiny, tiny, tiny,

very small amounts they're

called micro haemorrhages.

The inflammation or the

edoema bit is a swelling,

both of which that are

important side effects

of the therapy and

predictable to some extent

that we know that it's a class effect.

If you stop the treatments,

the edoema will go better.

And in these therapies, again,

this has been a long period of learning

and of engineering the antibodies

and engineering the dosing

and engineering how you

need to adjust things.

But 80% of people who get

these things are asymptomatic.

So it sounds very frightening

and clearly in the worst case it is.

But I think it's fair to

say that it isn't something

that the majority of people experience.

It's a minority and we've learned

a lot about how to manage it.

- Absolutely.

I think that's absolutely right.

We, so we know, as Nick

said, 80% asymptomatic,

you stop the drug, they go

away, you restart the drug,

they're fine.

That's the majority of people

that have that it's happened to me with

when I've been doing the trials.

That's the vast majority.

- And only a proportion will

get these in the first place.

- Exactly.

- And that varies by antibody.

- Exactly.

And it's, if we're talking

about these antibodies,

then lecanemab,

the one that's been

approved in this states

has a 12% risk of this happening.

So while that's a significant risk

and some of them are

higher, it's not everybody.

The other thing is we can

predict that the vast majority

will happen in the

first six months, right?

At least 80% happen in

the first six months.

So, you know, to monitor

really carefully with imaging

when you're first giving the treatment

for the first six months, and

then it's much less likely.

And the other thing is,

and we're working really hard

to continue the learning,

one of the things we know

well is that some people

have a genetic risk factor

that makes this more likely to happen.

And so we can help

discuss risks with people

in a more nuanced way

if we know the different risk factors

that each individual has.

So I think we know a lot more than we did

about 10 years ago.

We need to continue learning

and we need to ensure that

when we give these treatments,

we have the appropriate

monitor and safety in place

to pick them up and deal

with them the right way.

- All those genes again, isn't it John?

- It's the genes again yeah.

- Yeah. We have to, this is a problem.

We are really working hard to

understand better of course.

And if we could understand it better,

I'm sure we could find

other ways around it.

- Yeah, yeah, that makes total sense.

So I confess, I mean I get

frequent questions from patients

and people I meet in my

research about these trials.

And I guess the most common question

is they ask me about how

they can get involved.

So they're even asking speech therapists

about how they can get involved.

So can you tell us and the listeners

who might be eligible

and whether or how people

get involved with these studies?

- Yeah, sure.

I think maybe I'll start

and the others can chime in.

So in terms of, firstly, in

terms of how to get involved,

because everybody can

get involved in some ways

in Dementia research and everybody

is welcome to get involved,

just to put that out there.

Trials are a more specific

and more demanding thing,

which I'll come to in a second.

In terms of generally

wanting to get involved.

Then there's joint Dementia research,

which is one way

nationally it's a matching,

it's like a dating match.

- [Nick] For the UK.

- For the UK the whole of the UK.

So if you're interested

in research in Dementia,

you join up with joint Dementia research

and they'll match you up

with different studies

and potentially trials.

That's one way.

Then there's another portal

where it's NIHR portal

where you can go on and

it says, find my research.

And again, that's a relatively new way

of working out what's happening,

but I think what you are making the point

that they're coming to you

and asking about trials.

I do think it's still difficult

for people to access

that sort of information.

And we're working really hard

on trying to make that access much easier

for our site particularly,

basically if anybody

wants to know anything

about what we do, they

just should get in contact

and we are very happy to

talk to absolutely anyone,

but it needs to be easier.

I completely agree with you.

And we need to work harder on

making it easier for patients.

In terms of who can get into trials,

typically trials for

disease modifying therapies

tend to be done in people that

have relatively mild disease.

Now, a lot of that is because

these treatment trials,

they require a lot of commitment.

You need to understand what's going on.

You need to be able to be comfortable

with the sorts of investigations

and assessments you are having.

And that isn't for everybody,

but some people find it a

really positive experience

and we support them through that.

So I think if people have a diagnosis

and they're interested, the

first thing they should do

is ask the question about who to talk to.

And we would then go

through a process with them

of making sure that it was

the right thing for them,

that they understood what it needed

and also that they would be eligible

or likely to be eligible for the trial.

Once you're interested in a trial

and if you have signed up

to be involved in that trial

and you've gone through all

the information and questions,

then what happens is there's a process

of different tests that you go through

that make sure that it

would be safe for you,

that you have the

disease we think you have

and that the treatment

will potentially help you.

So that's what we do.

- Well thank you Professor

Hardy, Professor Fox.

Do you wanna add anything to that?

- Well, I just to say that the only

we've talked about all the huge work

that scientists have done,

whether it's in design therapies

or understanding the disease process,

the ultimate is does it work in people?

And none of these studies will be possible

without the generosity of people

who take part in research.

So people saying to a speech therapist,

how can I get involved

is exactly what we would like to happen

and we should make it that

every clinical contact

should be able to say,

"Yes, I work in the centre

or this is my local centre,

this is the local trial.

Please do get involved.

And we've seen the progress

that's been made in other disease areas.

You know the percentage

of people historically

that went into trials

for Alzheimer's disease

is a tiny, tiny fraction

of the total huge burden

in the population.

In other areas, some of

the childhood cancers,

they expect 50% of all people

with that condition to go into a trial

and that transforms things.

- I was just going to say,

I think that's an absolutely

fundamental point,

but you should have access to research

at the point you enter a clinical system

and everybody you meet

should be able to tell

you what's available.

Everyone, whether it's the porter,

the speech and language

therapist, whoever.

So if we can get to that stage,

that would be nirvana, brilliant.

- It links back to the,

I did a podcast a couple of weeks ago

where we talked about

justice, about recruitment.

So many of our listeners might

go and revisit that podcast.

But that's the point we made that research

isn't currently routinely

offered in clinical settings.

Whereas in other disease groups

it's often something

people expect to talk about

in all their healthcare encounters.

So yeah, that would be

I an ideal situation.

So the other question I get to ask,

and we haven't really

talked about this yet,

is when do you think we

can expect these treatments

to be in use in the NHS?

I dunno who to start with.

I think that's the

million dollar question.

- I was on a meeting this

morning where this came up,

so I might start with that and then see

then the others can challenge me.

How's that?

So I was talking to NHS

England this morning

and their estimation

in terms of the processes

that happen in the UK.

So obviously this has to go

through a regulatory process

and the first part of that

is the medicines Health

Regulatory Authority

approving the drug for the UK.

Once that's happened, if that happens

and I think it's likely that will happen,

then it goes through the nice process.

So this is this assessment

of not just effectiveness,

but also cost effectiveness

or efficiency, sorry.

And so that process

according to the individuals

I was talking about this morning

is currently started and they think

that process will finish

for lecanemab in the summer.

So summer 2024,

they expect to have a

recommendation on lecanemab

and for aducanumab they are estimating

the autumn of next year.

So that's the hot off

the press this morning

NHS England story, we'll

have to wait and see.

- That's huge.

- I mean that is a difficult,

I don't want to belittle

the challenges there.

We perhaps can talk about the challenges

in terms of how actually

giving these drugs in a minute.

But the challenge from the

point of view of getting

through the nice process

is that there is no good

measure at the moment

of the burden that Alzheimer's disease

and other Dementias have in the UK.

We don't measure it in the right way

because so many people are

doing unpaid care in families

and so they are struggling

with how to measure what a drug saves

and therefore what is worth giving.

So I think that process

will be challenging,

but it has been done in the states.

Europe are also doing it at the moment.

These drugs are the first ones we have

and we will obviously

have to work with them

to ensure they have the

best information possible

to make those decisions

and the companies will

work with them as well.

- And what are the challenges

in delivering it then on the ground?

- Ah, well we are very lucky.

We work in a centre

where we have fantastic

multidisciplinary teams

and we have amazing diagnostic techniques

and we're used to giving these drugs.

So, we are able to give these drugs now,

but if you go to a local memory service,

they do not have the same

sort of level of access

to those diagnostic tests

or monitoring tests like MRI

and Nick might want to

talk about that in a second

because there are things we

need to do to improve that.

They also don't have infusion suites

and nurses where you can give these drugs

and acute hospitals where

if something does go wrong,

you can have the assistance

and the treatment you need.

So right now as a whole in the

UK the service isn't ready.

And what we're doing and

working really hard to try

and help NHS England with and

groups across the country with

is understanding what

we need to put in place

so that services are ready

in terms of staffing,

in terms of diagnostics and in

terms of new ways of working.

I mean, Nick, do you want to

talk about MRI for example?

- Yeah, I think this is gonna

be a major, major challenge

to health systems around the

world and the NHS already,

let's say stretched to be kind,

will find this a real challenge.

And a real tragedy for equity

would be if this only becomes

something that's available to those people

who can pay for it.

So it will transform the

pressure and timeliness

of diagnosis or the need for

that because historically

it hasn't mattered very much.

You hadn't, didn't lose time.

So we've seen that

transformation in cancer

where time was of the essence.

And now, we may be in a

situation where time is brain,

if you like, the delays in diagnosis

will cost you brain cells.

- [Cath] Like stroke.

- And with a relentless

and progressive neurogenerative disease

like Alzheimer's disease,

this is something that not

just that is progressing,

but it's gathering momentum

and it's impact across

the brain is spreading

and accelerating.

So time it will be important

to be able to make a diagnosis

and most people never get

a very precise diagnosis

around the world.

But even in places like the UK,

so we will have to gear up to

make a more secure diagnosis,

which will mean amyloid

PET scan or lumbar puncture

or potentially in the future a blood test

and we'll have to make a secure diagnosis.

But that's only the first

half of the challenge.

We talked earlier about

these side effects,

which if picked up you stop

dosing or you slow dosing

and you can manage them,

we will need to monitor for these things.

So in some of the trials

people might have many MRI

magnetic resonance imaging, brain scans

throughout regular intervals

and they certainly will

need to be able to have it

if there was any sign of

something not being right.

So this, that might take

up a number of weeks

of the total UK MRI capacity

if everybody who was eligible

was put on a drug tomorrow.

- I should say, I think that

one of the beneficial effects

already of these drugs even

though they're not approved yet,

is they're kick-starting the process

for better Dementia care

in the UK generally.

So there was the sense I think

that if someone had Dementia,

it really didn't matter how

quickly diagnosis was made

and it really didn't matter

matter what diagnosis

was made if it was accurate or not,

because there was almost nothing

that could be really done.

Now that changes that perception

and now we have to pull

our socks up clinically

and it's easy for me to say as a PhD,

we have to pull our socks up clinically

to make the service better,

not just for these drugs,

but for the drugs that

are coming down the line.

- Yeah, and I guess

I've also thought about

the fact that if you were

giving drugs to people

and they've already developed symptoms,

so the non-genetic types that

we might be in a situation

where that whilst people are

gaining six months or so,

they might need other therapies

outside of pharmacological.

And so I think, so I may be biassed

as a speech and language therapist,

but I can imagine that we are also looking

at adjunct trials in the future

where you look at the

pharmacological alongside

the say speech therapy or psychological

or occupational interventions

and the broader advantages.

This is all very exciting,

but I do have some more questions.

So I'm gonna start with Dr. Mummery.

I know this show is all

about drug treatments,

but we can't have you on the show

without asking about ALN-APP

and your work on this new

type of gene silencing.

- Okay, well let me take

a ti a tiny step back

from that Anna to, to

gene silencing in general

because I think one of the thing,

if I may, one of the things

that we talked about,

anti-amyloid monoclonal

antibodies only so far,

and just to take a further

step back, actually,

there are 141 different therapies

being looked at right now,

141, that's brilliant.

But look at cancer, thousands.

So we've got a way to

go, but it's brilliant

and it's a lot more than it used to be

and only 16% of those this year

are in anti-amyloid therapies.

That means there's a lot of other things

being looked at in addition to amyloid.

And that's important because

it's a complex disease

and we need to look at

amyloid in conjunction,

I thought you were

gonna mention it earlier

with other therapies so that we can try

and combine things potentially

to enhance that slowing of disease

or potentially halt it, right?

So just to take that step back,

one of the things we are looking at now

is instead of using antibodies to try

and mop up these proteins in

the brain amyloid and tower,

the two that you've mentioned,

we're trying to work upstream.

So coming back to the genetics,

again, back in that circle,

what happens if you target

the gene that produces

that protein and reduce

its ability to translate

into the protein and therefore reduce

production of the protein

in the first place?

Okay, so working far upstream

of mocking is deposited

and you mentioned the ALN-APP drug,

and that is one that we've

been looking at very recently.

That is an anti-amyloid drug.

And what it does is it targets

the amyloid precursor protein gene.

So this is upstream of amyloid production

and tries to reduce it by interfering

with the natural cell process.

It tries to reduce the messages coming

from that pro that gene and

their translation is the protein

that work is currently involved

a phase one safety trial,

and I think we now have

26 people in the world

in that trial.

So far it's safe and so far

the interim results suggest

it's promising that it's

doing what we want it to do,

which is reduce the proteins

that are being produced from that gene.

But it's very, very early days.

But the one other that

I wanted to come back to

and mention that's not

amyloid is against tau

is the most advanced

gene silencing treatment

we've got in Alzheimer's disease.

And that treatment, again,

it silences the gene

in a slightly different way.

It's an antisense oligonucleotide.

So instead of targeting

the cell's own machinery,

what it does is effectively

it prevents the mRNA,

the messenger from the gene

being translated in the protein.

And that has now completed

a phase one trial.

So it's gone into a bigger phase two trial

with 700 odd people in the

first trial was 46 in the world.

And it has shown its safe

and it has shown that it

does what it says on the tin,

it reduces tau in the spinal

fluid and in the brain.

And coming back to what we said before

about anti amyloids and reducing tau,

this drug looks like, and it's early days,

we need to validate this

looks like it reduces tau

in the brain much more

than those other drugs did.

So it might be a good one for combination,

but like I said,

we have to wait and see

what the later trials show.

But that's the gene

silencing Alzheimer's story

at the minute.

- In a nutshell. Thank

you so much Dr. Mummery.

I feel like we need a series of podcasts

all about these exciting

and promising interventions

and I know they're also,

I mean, there's gonna be challenges ahead

despite this exciting stuff going on.

So just before we finish,

I wonder if you could just

comment on either what you are,

perhaps both what you are

excited about for the future,

just the thing you're most

excited about and the thing

that you see as the biggest challenge

or controversy for the future.

Perhaps Professor Hardy,

you could go first.

- Well, the challenges

I think are the ones we just talked about

organising health systems here in the UK

and around the world.

That's challenge number one.

A challenge two,

I think is getting better

at early diagnosis.

And here we're very, very

fortunate in having I think,

the best fluid biomarker lab in the world.

Actually it's in this building

in the lab next to me.

We're very fortunate and I

think that fluid biomarkers

together with imaging are

gonna be absolutely crucial

and we're very fortunate

to be able to do that.

But getting the biomarkers,

getting better at early diagnosis

is gonna be a real challenge I think.

- Yeah, okay. That makes sense. Thank you.

And let's move on, Professor Fox.

- Yeah, so I agree delivery and equity.

I think it's gonna be very challenging.

The people with Dementia

are already isolated

and disadvantaged or

their families are hugely,

if now that within that

group you have a sense

that you may be missing out on a therapy.

I mean, that is tragic and wrong.

I find myself very excited by the thought

I mean, it's very exciting just to think

that we are slowing this disease

where, which we've watched

and I have to say, not just

because it circles back

to how you started these questions, Anna,

I feel a particular excitement

about those families

who've seen this thing

come down its generation,

generation after generation

to be able to say,

"Actually we could stop

this gene doing this to you

or to your children."

- Actually worth saying, Nick,

just that when we found

the mutation at first,

Carol Jennings, who we've discussed, said,

"I don't think this is

gonna help my generation,

but I do hope it helps my

children's generation."

And at the time I would've said,

"Yeah, we're gonna get

sorted in a few years."

But actually Carol was

more realistic than I was.

And I do think that we are gonna be able

in the next generation of

families, and like Nick said,

a lot of the next generation

are coming into to the clinics here now.

We will be able to do something

for the next generation.

And that is very rewarding.

- I agree with everything

the others have said

in terms of the challenges.

I suppose one particular element

that I think we are gonna

have to learn in Dementia

that we just haven't had to

do before, which is great,

but it is going to be a

significant challenge,

is having discussions with

people discuss about risks

and benefits of treatments

and making sure we manage expectations

and give people the

information in the right way.

That's a big challenge

when people, as John said,

haven't even been diagnosing

anything other than Dementia.

So that's gonna be a major shift

in the way people manage things.

In terms of what I'm really excited about,

I mean, I'm biassed,

but I am really excited

about genetic therapies

in all their different forms,

in both genetic diseases

and in sporadic.

And the reason for that

is, if you look at things

like the spinal muscular atrophy story,

that we've seen people,

effectively, it's a genetic disease,

but effectively it is being cured

by giving treatments early

enough and in the right way.

So I think that's super exciting.

And the final thing that

I've had to do recently,

and it's an amazing feeling,

is if you give a drug

that you know makes a

difference to someone,

which is what I've been

doing with lecanemab

recently in one of the trials,

that's a really great

feeling for them and for you.

And that's got to be something

that I find unbelievably exciting so.

- Yeah, it's super exciting.

Well, if you need any help

writing those consent forms

in an accessible, language,

cognitive, friendly way,

give me a shout.

But I'm afraid this is all

we have time for today.

So if you just can't get

enough of this topic,

visit the Dementia Researcher website

where you will find a full transcript,

biographies on our guests, blogs,

and much, much more on the topic.

And I'd like to thank

our incredible guests,

Dr. Cath Mummery, Professor Nick Fox,

and Professor Sir John Hardy.

Thank you for coming.

I am Dr. Anna Volkmer

and you've been listening

to the Dementia Researcher Podcast.

Goodbye everybody.

- Thanks Anna. Bye.

- Thank you. Bye.

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